WO2022164239A1 - Pyrazole-carboxamide derivative compound and use thereof - Google Patents

Pyrazole-carboxamide derivative compound and use thereof Download PDF

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WO2022164239A1
WO2022164239A1 PCT/KR2022/001522 KR2022001522W WO2022164239A1 WO 2022164239 A1 WO2022164239 A1 WO 2022164239A1 KR 2022001522 W KR2022001522 W KR 2022001522W WO 2022164239 A1 WO2022164239 A1 WO 2022164239A1
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methyl
chlorophenyl
dichlorophenyl
pyrazole
carboxamide
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PCT/KR2022/001522
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French (fr)
Korean (ko)
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배수열
김보경
이지혜
김영훈
박철영
양혜경
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주식회사 파미노젠
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel pyrazole-carboxamide derivative compound and its use for the prevention or treatment of related diseases based on an antagonist/inverse agonist effect specific to cannabinoid receptor 1 thereof.
  • the endocannabinoid system is composed of endocannabinoids, receptors, transporters, and enzymes, and plays an important role in a wide variety of physiological processes. have. (Howlett, AC, Annu. Pharmacol. Toxicol . 1995, 35, 607-634; Pacher, P. et. al, FEBS J. 2013, 280, 1918-1943; Lu, Y. et. al, Can. J. Physiol. Pharmacol . 2017, 95, 311-327).
  • CB1 and CB2 Two different subtypes of the human cannabinoid receptor (subtypes, CB1 and CB2) have been isolated, all of which belong to the G protein coupled receptor superfamily.
  • Cannabinoid receptor CB1 together with CB2 receptor and endocanabinoid ligand (endocanabinoid: ex. anandamide, 2-AG, etc.), constitutes an endocanabinoid system that plays an important role in maintaining energy homeostasis.
  • the CB1 receptor is mainly distributed in the central nervous system including the brain of mammals including humans and is known to be involved in energy metabolism and appetite regulation. known to be involved.
  • rimonabant SR141716A
  • SR141716A The selective CB1 receptor antagonist, rimonabant (SR141716A)
  • rimonabant inhibited the activity of CB1 receptors in the central nervous system (CNS) and was withdrawn from the market due to serious side effects such as depression and suicidal ideation (Christensen, R. et al., Lancet , 2013, 23, 4751). -4760).
  • appetite regulation by CB1 receptors is not limited to CB1 receptors present in the brain, but appetite is also regulated by CB1 receptors present in peripheral tissues. It has already been verified by many research results (Tam J. et al., Cell Metab . 2012, 16(2), 167-179).
  • CB1 receptor-activator-based type 2 diabetes treatment agent that does not pass through the blood-brain barrier and minimizes side effects by specifically controlling only the activity of CB1 receptors in peripheral tissues.
  • peripheral tissue-specific CB1 receptor inhibitors have been developed by several research groups (Chorvat, R. et al. Bioorg. Med. Chem. Lett . 2013, 23, 4751-4760; Kunos, G. et al., Br. J. Pharmacol . 2011, 163, 1423-1431).
  • Representative peripheral tissue-specific CB1 receptor inhibitors with high potential for success recently developed are AM6545 and JD5037.
  • the first candidate, AM6545 was developed by Dr. Developed/reported by the Kunos group.
  • AM6545 was developed through modification of the existing CB1 receptor inhibitor, Rimonabant, and showed a high affinity for the CB1 receptor compared to its parent, rimonabant, while its ability to cross the blood vessel-brain barrier was 14 times lower. It also did not affect the various behavioral effects mediated by CB1 receptors present in the brain.
  • AM6545 improves insulin resistance, fatty liver, and leptin resistance in type 2 diabetes, improves glucose homeostasis and plasma lipid profile, and increases adiponectin production regardless of the weight loss effect. For the first time, it showed the possibility of developing peripheral tissue-specific CB1 receptor inhibitors for the treatment of type 2 diabetes (Tam J. et al., J. Clin Invest . 2010, 120(8), 2953-2966).
  • JD5037 a second peripheral tissue-specific CB1 receptor inhibitor candidate developed by US venture company Jenrin Discovery, also has a low ability to cross the blood-brain barrier, and various behavioral effects mediated by CB1 receptors in the brain similar to AM6545. It had no effect on type 2 diabetes by improving insulin and leptin resistance and plasma lipid profile (Tam J. et al., Cell Metab . 2012, 16(2)). , 2953-2966).
  • a compound having an antagonist/inverse agonist effect specific for selectively peripheral CB1 receptors is effective in various diseases such as diabetes, metabolic disease, dyslipidemia, alcoholic liver disease or non-alcoholic liver disease without side effects related to the central nervous system. drugs can be developed.
  • It is also an object of the present invention to provide a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.
  • an object of the present invention is based on the specific inhibitory effect of the novel compound on cannabinoid receptor 1 (CB1), the compound, its isomer, its solvate or a pharmaceutically acceptable salt thereof It is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, including.
  • 'halogen' refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), unless otherwise specified.
  • alkyl' refers to a saturated, straight-chain or branched hydrocarbon radical represented by C n H 2n+1 , and specifically, between 1 and 6, respectively, 1 to refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, 1-10, or 1-20 carbon atoms.
  • these radicals include, but are not limited to, the methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • the term 'C 1 -C 6 alkyl' refers to a linear or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • 'cycloalkyl' or 'cycloalkyl' denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound.
  • the term 'C 3 -C 6 cycloalkyl' refers to a cyclic hydrocarbon residue having 3 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • aryl refers to mono- or poly-cyclic carbocy having 2 to 30 carbon atoms, 6 to 14 carbon atoms, or 1 to 6 carbon atoms, having one or more aromatic rings, fused or non-fused. refers to a click ring system, and examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.
  • heteroaryl as used herein, unless otherwise stated, includes atoms other than carbon and one or more heteroatoms.
  • the heteroatoms are atoms selected from the group consisting of O, N, Se and S. may include one or more.
  • the number of carbon atoms is not particularly limited, but preferably has 2 to 30, 6 to 14, or 1 to 6 carbon atoms, and the heteroaryl group may be monocyclic or polycyclic.
  • heteroaryl group examples include a thiophene group, a furanyl group, a pyrrole group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, a triazinyl group Jolyl group, acridyl group, pyridazinyl group, pyrazinyl group, quinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, pyridopyrimidyl group, pyridopyrazinyl group, pyrazinopyrazinyl group , isoquinolinyl group, indolyl group, carbazolyl group, benzoxazolyl group, benzimidazolyl group, benzo
  • R 1 is H or halogen
  • R 2 is H, halogen or CN
  • R 3 and R 4 are each independently H or halogen
  • Q is substituted or unsubstituted aryl or heteroaryl
  • L is , , , , or ego
  • L 1 is C 1 -C 6 alkyl
  • R' and R'' may each independently be substituted with H or C 1 -C 3 alkyl
  • Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.
  • R 1 may be H or Cl.
  • R 2 may be H or CN.
  • R 3 may be Cl.
  • R 4 may be H or Cl.
  • aryl may be any one selected from the following structures;
  • the heteroaryl may be any one selected from the following structures:
  • X is hydrogen or halogen
  • L may be any one selected from the following structures:
  • L 1 is C 1 -C 3 alkyl
  • R' and R'' may be H.
  • Het may be a compound that is unsubstituted or substituted with haloalkyl, and is a 4-6 membered aromatic heterocyclic compound including N or O in 2 to 4 rings.
  • Het may be any one selected from the following structures:
  • Y is H or CX 3
  • X is halogen
  • the compound may be any one selected from the group consisting of the following compounds:
  • a pharmaceutical composition comprising the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof including overexpression or hyperactivity of cannabinoid receptor 1 It provides a pharmaceutical composition for the prevention or treatment of diseases caused by
  • the cannabinoid receptor 1 ( To provide a method for preventing or treating diseases caused by overexpression or overactivation of cannabinoid receptor 1).
  • the pyrazole-carboxamide derivative compound for the preparation of a medicament for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, the pyrazole-carboxamide derivative compound, an isomer thereof , a solvate thereof or a pharmaceutically acceptable salt thereof.
  • the disease caused by overexpression or overactivity of the cannabinoid receptor 1 may be one or more selected from the group consisting of diabetes, metabolic disease, dyslipidemia, alcoholic liver disease, and non-alcoholic liver disease, but is not limited thereto.
  • prevention refers to any action that inhibits or delays a disease caused by overexpression or overactivation of cannabinoid receptor 1.
  • treatment refers to any action in which the symptoms of an individual suspected of and onset of a disease caused by overexpression or overactivation of cannabinoid receptor 1 are improved or beneficially changed.
  • the "pharmaceutically acceptable” means exhibiting properties that are not toxic to cells or humans exposed to the composition.
  • the "pharmaceutically effective amount” means that the amount of the compound administered is effective in alleviating or reducing to some extent one or more symptoms of the disorder being treated, or delaying the onset of clinical markers or symptoms of a disease requiring prevention. means quantity.
  • a pharmacologically effective amount may have an effect of 1) reversing the rate of disease progression, 2) inhibiting further progression of the disease to some extent, and/or 3) alleviating to some extent one or more symptoms associated with the disease ( Preferably, it means an amount having the effect of removing).
  • a pharmacologically effective amount can be empirically determined by testing the compound in known in vivo and in vitro model systems for a disease in need of treatment.
  • the isomers may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, depending on the presence of an asymmetric carbon center of the pyrazole-carboxamide derivative compound, all isomers and mixtures of these isomers are included within the scope of the present invention.
  • the solvate may comprise a stoichiometric or non-stoichiometric amount of a solvent that is bound by non-covalent intermolecular forces.
  • Preferred solvents include nonvolatile, nontoxic, or suitable solvents for human administration, for example, ethanol, methanol, propanol, methylene chloride, and the like, but are not limited thereto.
  • the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, Inorganic acid salts prepared with phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid , glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, Organic acid salts prepared from succinic acid
  • the pharmaceutically acceptable salt may be hydrochloric acid as the inorganic acid and methanesulfonic acid as the organic acid.
  • saline As the pharmaceutically acceptable carrier, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components may be mixed and used, and if necessary, an antioxidant , buffers, bacteriostats, and other conventional additives may be added, but the present invention is not limited thereto.
  • the pharmaceutical composition or pharmaceutical composition may be provided as a pharmaceutical composition including an active ingredient alone, or one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutical composition or route of administration of the pharmaceutical composition is not limited thereto, but is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.
  • the pharmaceutical composition or pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected.
  • an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected.
  • oral administration can be preferably selected from the viewpoint of selecting a more effective absorption route.
  • the pharmaceutical composition or a preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the composition is preferably administered at 0.01 to 1000 mg/kg/day, preferably 0.1 to 500 mg/kg/day, but is not limited thereto. The administration may be administered once a day, or divided into several administrations. The above dosages are not intended to limit the scope in any way.
  • the pharmaceutical composition or pharmaceutical composition When formulating the pharmaceutical composition or pharmaceutical composition, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used.
  • the compound provided as an embodiment of the present invention may be prepared according to the following preparation method, but is not particularly limited thereto, and may be prepared by a method known in various literatures.
  • novel pyrazole-carboxamide derivative compounds of formula (1) may contain one or more asymmetric carbons, and thus racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. It may exist as an isomer. Such isomers can be separated by conventional techniques, for example, column chromatography of the novel pyrazole carboxamide derivative compound of Formula 1 or resolution such as HPLC. Alternatively, stereoisomers of each of the compounds of Formula 1 can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configurations.
  • the novel pyrazole-carboxamide derivative compound of Formula 1 can be prepared from pharmaceutically acceptable non-toxic acids derived from inorganic acids and organic acids.
  • the acids are acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloroic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like.
  • Citric acid, hydrobromoic acid, hydrochloroic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred.
  • novel pyrazole-carboxamide derivative compound provided as an aspect of the present invention exhibits antagonist/inverse agonist activity specific to cannabinoid receptor 1, thereby effectively preventing or treating related diseases. There are technical effects.
  • CB1 protein is an analysis result of the interaction between CB1 protein and taranabant, known as a CB1 inhibitor (Taranabant, inverse agonist).
  • 2 is a scatter plot showing docking energy score results for 102 compounds of synthetic candidate materials.
  • Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) pyrazine-2-carboxylate (2- 2f) was prepared similarly to the process described for compound (2-3a) above.
  • Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) -2-fluorobenzoate (2 -2o) was prepared similarly to the process described for compound (2-3a) above.
  • the organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure.
  • SBDD Structure-Based Drug Design
  • LBDD Ligand-Based Drug Design
  • the x-ray tertiary crystal structure (PDB code: 5U09) of the CB1 target protein was obtained from the Protein Data Bank (https://www.rcsb.org)
  • the Discovery Studio program DSSAULT SYSTEMS
  • the solvent molecules of the protein were removed, and a structure was obtained in which the protonation of the protein residue was calculated at pH 7.4, and a structure in which the ionization state was calculated based on pH 6.5 to 8.5 of the ligand.
  • CB1 protein is an analysis result of the interaction of CB1 protein with Taranabant (inverse agonist) known as a CB1 inhibitor, forming hydrogen bonds with Ser123 and Ser383, and forming strong hydrophobic pockets (Met103, Asp104, Ile105, Ile119, Phe170, Val196, Trp279). , Trp356, Ala380, Met384, Cys386).
  • Synthetic candidates 102 compounds were analyzed for binding forms between protein molecules and ligands using the Discovery Studio docking program. 40 kinds of final example compounds were discovered by analysis by docking energy score and visual inspection.
  • '- CDOCKER_INTERACTION_ENERGY' means protein-ligand binding energy and is calculated in kcal/mol units.
  • 'LigScore2' means protein-ligand binding affinity, and is calculated in pKi (-log Ki).
  • Table 5 below shows the protein-ligand binding energy (-CDOCKER_INTERACTION_ENERGY) and protein-ligand binding affinity (LigScore2) for the compounds selected by applying the CADD (Computer-Aided Drug Design) technology.
  • Example LigScore2 (pKi) -CDOCKER INTERACTION ENERGY (kcal/mol) One 7.66 64.44 2 7.50 66.71 3 7.25 61.21 4 7.37 67.51 5 7.61 68.04 6 7.53 62.99 7 6.98 54.00 8 6.84 55.05 9 6.87 56.02 10 7.28 58.61 11 7.63 64.28 12 7.51 61.12 13 6.36 45.53 14 4.88 28.99 15 7.62 61.68 16 7.22 54.93 17 7.24 60.38 18 7.19 55.00 19 7.75 64.89 20 7.65 65.14 21 7.53 62.01 22 7.67 64.25 23 5.81 43.57 24 7.14 56.10 25 6.80 56.23 26 7.12 56.20 27 6.95 57.47 28 7.14 56.99 29 7.31 57.98 30 7.52 57.80 31 7.32 59.86 32 6.96 63.64 33 7.04 62.99 34 6.81 61.35 35 6.87 58.03 36 6.78
  • a cAMP ELISA assay was performed using Rimonabant, an existing developed material, as a control.
  • CHO-GLP1R-CB1R cells were cultured for one day in DMEM medium containing 10% fetal bovine serum (FBS) and 1% antibiotics in an environment of 5% CO 2 37 °C. The next day, the cells were cultured in a medium without FBS for 30 minutes, and a CB1 inhibitor compound (including any one of the compounds of Examples 1 to 40) dissolved in DMSO was added and reacted for 30 minutes [compound final concentration ( ⁇ M)) : 0.1, 1, 2.5, 5, 10, 20]. 10 uM forskolin and 10 nM CP55,940 were added to the cells and incubated for 1 hour. After removing the solution, PBS and 0.1M HCl were added to wash the cells 3 times.
  • FBS fetal bovine serum
  • cAMP was measured using the Direct cAMP ELISA kit (Enzo Life Sciences, Lausen, Switzerland; Catalog # ADI-900-066). Absorbance was measured at 405 nm wavelength using an ELISA reader.
  • Example IC50 (Rimonabant) 2 2.56 (1.08) 3 1.13 (1.08) 4 7.09 (1.08) 5 5.6 (9.3) 6 6.7 (9.3) 7 0.52 (1.08) 8 0.85 (1.08) 9 0.49 (1.08) 10 0.48 (1.08) 12 1.12 (1.08) 13 0.48 (1.08) 14 0.66 (1.08) 16 1.25 (1.08) 17 10.4 (9.3) 18 2.55 (1.08) 19 2.9 (9.3) 37 1.56 (3.20) 38 3.54 (3.20) 39 4.25 (3.20) 40 2.75 (3.20)
  • the amount of the compound in the reaction mixture was quantified by LC-MS/MS after pretreatment of the liver microsome metabolic stability test result, and expressed as a percentage compared to the initial amount.
  • the blood-brain barrier (BBB) penetration test of the CB1 inhibitor compound was evaluated in ICR mice. All subjects were fasted for at least 16 hours prior to compound administration. A single dose (10 mg/kg) of a CB1 inhibitor compound (Examples 5, 6, 19) or rimonabant was suspended in 10 mL of a mixed solvent (4% DMSO; 8% Tween 80; 88% saline) and then orally administered to mice. . Mice were sacrificed 1, 2, and 4 hours after compound administration and analyzed. At each autopsy point, the mouse was anesthetized, and about 1 ml of blood was collected by laparotomy. The blood collected was immediately stored in an ice-cooled state (about 4°C).
  • a mixed solvent 4% DMSO; 8% Tween 80; 88% saline
  • CB1 inhibitor compounds Examples 5, 6, 19
  • rimonabant were measured using LC-MS/MS methods in mouse plasma and brain tissue collected to examine the BBB permeability of the drug.
  • the brain/plasma ratio of the compound 1, 2, and 4 hours after administration of the compound to the mouse is shown in Table 8 below.

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Abstract

A novel pyrazole-carboxamide derivative compound provided as one example of the present invention exhibits an antagonist activity specific to cannabinoid receptor 1, and thus has a technical effect of effectively preventing or treating diseases caused by overexpression or overactivity of cannabinoid receptor 1, such as diabetes, metabolic diseases, dyslipidemia, alcoholic liver disease, non-alcoholic liver diseases, and the like.

Description

피라졸-카르복스아미드 유도체 화합물 및 이의 용도Pyrazole-carboxamide derivative compounds and uses thereof
본 발명은 신규한 피라졸-카르복스아미드 유도체 화합물 및 이의 카나비노이드 수용체 1(Cannabinoid receptor 1)에 특이적인 길항제/역효능제 효과에 기반한 관련 질환의 예방 또는 치료 용도에 관한 것이다.The present invention relates to a novel pyrazole-carboxamide derivative compound and its use for the prevention or treatment of related diseases based on an antagonist/inverse agonist effect specific to cannabinoid receptor 1 thereof.
엔도카나비노이드 시스템 (endocannabinoid system)은 엔도카나비노이드 (endocannabinoids), 수용체 (receptors), 트랜스포터 (trnasporters) 그리고 효소(enzymes)로 구성되어 있으며, 아주 다양한 생리학적 프로세스 (physiological process)에 있어서 중요한 역할을 담당하고 있다. (Howlett, A. C., Annu. Pharmacol. Toxicol. 1995, 35, 607-634; Pacher, P. et. al, FEBS J. 2013, 280, 1918-1943; Lu, Y. et. al, Can. J. Physiol. Pharmacol. 2017, 95, 311-327).The endocannabinoid system is composed of endocannabinoids, receptors, transporters, and enzymes, and plays an important role in a wide variety of physiological processes. have. (Howlett, AC, Annu. Pharmacol. Toxicol . 1995, 35, 607-634; Pacher, P. et. al, FEBS J. 2013, 280, 1918-1943; Lu, Y. et. al, Can. J. Physiol. Pharmacol . 2017, 95, 311-327).
인간의 카나비노이드 수용체의 상이한 두 아형(subtype, CB1 및 CB2)이 단리되어 졌고, 이들 모두는 G 단백질 결합 수용체 상과 (superfamily)에 속한다. 카나비노이드 수용체 CB1은 CB2 수용체 및 엔도카나비노이드 리간드 (endocanabinoid: ex. anandamide, 2-AG 등)와 함께 에너지 항상성 (energy homeostasis) 유지에 중요한 역할을 하는 엔도카나비노이드 시스템 (endocanabinoid system)을 구성하고 있다. CB1 수용체는 인간을 포함한 포유류의 뇌를 비롯한 중추신경계에 주로 분포하며 에너지대사와 식욕조절에 관여하는 것으로 알려져 있고 CB2 수용체는 말초조직, 특히 면역 세포에 주로 분포되어 있고 통증을 포함한 여러 가지 염증발현에 관여하는 것으로 알려져 있다. Two different subtypes of the human cannabinoid receptor (subtypes, CB1 and CB2) have been isolated, all of which belong to the G protein coupled receptor superfamily. Cannabinoid receptor CB1, together with CB2 receptor and endocanabinoid ligand (endocanabinoid: ex. anandamide, 2-AG, etc.), constitutes an endocanabinoid system that plays an important role in maintaining energy homeostasis. The CB1 receptor is mainly distributed in the central nervous system including the brain of mammals including humans and is known to be involved in energy metabolism and appetite regulation. known to be involved.
선택적 CB1 수용체 길항제인 리모나반트(rimonabant, SR141716A)는 임상실험에서 비만환자의 체중을 효과적으로 감소시키며, 또한 비만과 관련된 당뇨나 심혈관질환등의 대사증후군 질병도 완화시킬 수 있다는 것이 증명된 이후 CB1 수용체는 비만 및 비만 관련 대사증후군 질환을 치료할 수 있는 유망한 표적이 되었다. 하지만 리모나반트는 중추신경계 (CNS, central nervous system)에 있는 CB1 수용체의 활성을 억제하면서 우울증, 자살충동과 같은 심각한 부작용으로 시장에서 퇴출되었다 (Christensen, R. et al., Lancet, 2013, 23, 4751-4760). 하지만 CB1 수용체에 의한 식욕조절은 뇌에 존재하는 CB1 수용체에만 국한된 기능이 아니라 말초조직에 존재하는 CB1 수용체에 의해서도 식욕이 조절되며, 이것은 말초조직 CB1 수용체에 의한 렙틴 (Leptin)에 대한 민감성 조절을 통한 것으로 이미 많은 연구결과들에 의해 검증되었다 (Tam J. et al., Cell Metab. 2012, 16(2), 167-179).The selective CB1 receptor antagonist, rimonabant (SR141716A), effectively reduces body weight in obese patients in clinical trials, and can also alleviate obesity-related metabolic syndrome diseases such as diabetes and cardiovascular disease. and obesity-related metabolic syndrome diseases. However, rimonabant inhibited the activity of CB1 receptors in the central nervous system (CNS) and was withdrawn from the market due to serious side effects such as depression and suicidal ideation (Christensen, R. et al., Lancet , 2013, 23, 4751). -4760). However, appetite regulation by CB1 receptors is not limited to CB1 receptors present in the brain, but appetite is also regulated by CB1 receptors present in peripheral tissues. It has already been verified by many research results (Tam J. et al., Cell Metab . 2012, 16(2), 167-179).
앞에서 설명한 바와 같이, 기존에 개발된 CB1 수용체 저해제들은 말초조직 CB1 수용체의 활성을 억제함으로써 식욕과 체중을 감소시키고 인슐린 저항성 및 베타세포 성장 및 기능 향상을 통하여 포도당 항상성을 향상시킴으로써 제2형 당뇨 개선효과를 보인다. 그러나, 뇌에 작용하는 특성으로 인하여 심각한 부작용을 발생시켜 시장 및 임상시험에서 퇴출되었다. 이러한 이유로 혈관-뇌 장벽(blood-brain barrier)은 통과하지 않고 말초조직에 존재하는 CB1 수용체의 활성만을 특이적으로 제어하여 부작용을 최소화한 CB1 수용체-활성제어 기반 제2형 당뇨 치료제를 개발하기 위한 많은 연구들이 수행되어 왔으며 최근 몇몇 연구그룹에 의하여 말초조직 특이적 CB1 수용체 저해제들이 개발되었다 (Chorvat, R. et al. Bioorg. Med. Chem. Lett. 2013, 23, 4751-4760; Kunos, G. et al., Br. J. Pharmacol. 2011, 163, 1423-1431). 최근 개발된 성공 가능성이 높은 대표적 말초조직 특이적 CB1 수용체 저해제는 AM6545와 JD5037이다.As described above, the previously developed CB1 receptor inhibitors reduce appetite and weight by inhibiting the activity of CB1 receptors in peripheral tissues, and improve glucose homeostasis through insulin resistance and beta cell growth and function, thereby improving type 2 diabetes. looks like However, due to its properties acting on the brain, it caused serious side effects and was withdrawn from the market and clinical trials. For this reason, to develop a CB1 receptor-activator-based type 2 diabetes treatment agent that does not pass through the blood-brain barrier and minimizes side effects by specifically controlling only the activity of CB1 receptors in peripheral tissues. Many studies have been conducted and recently, peripheral tissue-specific CB1 receptor inhibitors have been developed by several research groups (Chorvat, R. et al. Bioorg. Med. Chem. Lett . 2013, 23, 4751-4760; Kunos, G. et al., Br. J. Pharmacol . 2011, 163, 1423-1431). Representative peripheral tissue-specific CB1 receptor inhibitors with high potential for success recently developed are AM6545 and JD5037.
첫번째 후보물질인 AM6545는 미국 NIH의 Dr. Kunos 그룹에 의하여 개발/보고되었다. AM6545는 기존 CB1 수용체 저해제인 리모나반트 (Rimonabant)의 변형을 통하여 개발되었으며 모체인 리모나반트에 비교하여 CB1 수용체에 대한 높은 친화력을 나타낸 반면 혈관-뇌 장벽을 통과하는 능력은 14배 정도 낮았다. 또한 뇌에 존재하는 CB1 수용체에 의해 매개되는 다양한 행동 효과에는 영향을 주지 않았다. AM6545는 체중감소 효과와 관계없이 제2형 당뇨에서 나타나는 인슐린 저항성, 지방간, 렙틴 (Leptin) 저항성을 향상시키고 포도당 항상성 및 혈장지질수치 (plasma lipid profile)를 향상시키고 아디포넥틴 (Adiponectin) 생성을 증가시킴으로써 제2형 당뇨치료를 위한 말초조직 특이적 CB1 수용체 저해제 개발 가능성을 최초로 보여주었다 (Tam J. et al., J. Clin Invest. 2010, 120(8), 2953-2966). The first candidate, AM6545, was developed by Dr. Developed/reported by the Kunos group. AM6545 was developed through modification of the existing CB1 receptor inhibitor, Rimonabant, and showed a high affinity for the CB1 receptor compared to its parent, rimonabant, while its ability to cross the blood vessel-brain barrier was 14 times lower. It also did not affect the various behavioral effects mediated by CB1 receptors present in the brain. AM6545 improves insulin resistance, fatty liver, and leptin resistance in type 2 diabetes, improves glucose homeostasis and plasma lipid profile, and increases adiponectin production regardless of the weight loss effect. For the first time, it showed the possibility of developing peripheral tissue-specific CB1 receptor inhibitors for the treatment of type 2 diabetes (Tam J. et al., J. Clin Invest . 2010, 120(8), 2953-2966).
미국 벤처회사인 Jenrin Discovery에 의해 개발된 두번째 말초조직 특이적 CB1 수용체 저해제 후보물질인 JD5037도 혈관-뇌 장벽을 통과하는 능력인 낮고, AM6545와 비슷하게 뇌에 존재하는 CB1 수용체에 의해 매개되는 다양한 행동 효과에는 영향을 주지 않았으며 인슐린 및 렙틴 (Leptin) 저항성과 혈장지질수치 (plasma lipid profile)을 향상시킴으로써 제2형 당뇨 개선 효과를 보였다 (Tam J. et al., Cell Metab. 2012, 16(2), 2953-2966).JD5037, a second peripheral tissue-specific CB1 receptor inhibitor candidate developed by US venture company Jenrin Discovery, also has a low ability to cross the blood-brain barrier, and various behavioral effects mediated by CB1 receptors in the brain similar to AM6545. It had no effect on type 2 diabetes by improving insulin and leptin resistance and plasma lipid profile (Tam J. et al., Cell Metab . 2012, 16(2)). , 2953-2966).
따라서, 선택적으로 말초 CB1 수용체에 특이적인 길항제/역효능제 효과를 갖는 화합물의 개발은 중추신경계에 관련된 부작용 없이 당뇨, 대사성질환, 이상지질혈증, 알코올성 간질환 또는 비알코올성 간질환 등 다양한 질병에서 효과적인 약물을 개발할 수 있다.Therefore, the development of a compound having an antagonist/inverse agonist effect specific for selectively peripheral CB1 receptors is effective in various diseases such as diabetes, metabolic disease, dyslipidemia, alcoholic liver disease or non-alcoholic liver disease without side effects related to the central nervous system. drugs can be developed.
본 발명의 목적은 신규한 피라졸-카르복스아미드 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.It is an object of the present invention to provide a novel pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.
또한, 본 발명의 목적은 상기 신규한 화합물과 약제학적으로 허용가능한 담체를 포함하는 약제학적 조성물을 제공하는 것이다.It is also an object of the present invention to provide a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.
또한, 본 발명의 목적은 상기 신규한 화합물의 카나비노이드 수용체 1(Cannabinoid receptor 1, CB1)에 대한 특이적 억제 효과에 기반하여, 상기 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 포함하는, 카나비노이드 수용체 1의 과발현 또는 과활성으로부터 유발된 질환의 예방 또는 치료를 위한 약학적 조성물을 제공하는 것이다.In addition, an object of the present invention is based on the specific inhibitory effect of the novel compound on cannabinoid receptor 1 (CB1), the compound, its isomer, its solvate or a pharmaceutically acceptable salt thereof It is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, including.
본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 기술적 과제로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 아래의 기재로부터 당업계 통상의 기술자에게 명확하게 이해될 수 있을 것이다.The technical problems to be achieved by the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description.
아래 열거된 정의는 본 발명을 기술하기 위해 사용된 다양한 용어들의 정의이다. 이들 정의는 달리 제한되지 않는 한, 개별적으로 또는 이들을 포함하는 용어의 일부분으로서 본 명세서 전체에 적용된다.The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of terms encompassing them, unless otherwise limited.
본 명세서에 사용되는 용어 '할로겐'은 다른 언급이 없으면, 플루오르(F), 염소(Cl), 브롬(Br) 또는 요오드(I)를 의미한다.As used herein, the term 'halogen' refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), unless otherwise specified.
본 명세서에 사용되는 용어 '알킬'은 다른 언급이 없으면, CnH2n+1로 표시되는 포화된, 직쇄형 또는 분지형의 탄화수소 라디칼을 지칭하며, 구체적으로 각각 1 내지 6개 사이, 1 내지 8개 사이, 1 내지 10개 사이, 또는 1 내지 20개 사이의 탄소 원자를 포함하는 포화된, 직쇄형 또는 분지형의 탄화수소 라디칼을 지칭한다. 이들 라디칼의 예로는 메틸, 에틸, 프로필, 이소프로필,　n-부틸,　t-부틸, 네오펜틸,　n-헥실, 헵틸, 옥틸 라디칼이 포함되지만, 이들로 제한되는 것은 아니다. 예를 들어, 본 명세서에 사용되는 용어 'C1-C6 알킬'은 다른 언급이 없으면, 탄소수 1 내지 6개의 직쇄형 또는 분지형의 탄화수소 잔기를 의미한다. 이의 예로는 메틸, 에틸, 프로필, 이소프로필,　n-부틸,　sec-부틸,　t-부틸,　n-펜틸,　n-헥실 등을 들 수 있으나, 이들로 제한되는 것은 아니다.The term 'alkyl' as used herein, unless otherwise stated, refers to a saturated, straight-chain or branched hydrocarbon radical represented by C n H 2n+1 , and specifically, between 1 and 6, respectively, 1 to refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, 1-10, or 1-20 carbon atoms. Examples of these radicals include, but are not limited to, the methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. For example, as used herein, the term 'C 1 -C 6 alkyl' refers to a linear or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
본 명세서에 사용되는 용어 '시클로알킬' 또는 '사이클로알킬'은 다른 언급이 없으면 모노시클릭 또는 폴리시클릭 포화 또는 부분적으로 불포화된 카보시클릭 고리　화합물로부터 유래하는 1가 기를 나타낸다. 예를 들어, 본 명세서에 사용되는 용어 'C3-C6 사이클로알킬'은 다른 언급이 없으면, 탄소수 3 내지 6개의 고리형의 탄화수소 잔기를 의미한다. 이의 예로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸 등을 들 수 있으나, 이들로 제한되는 것은 아니다.The term 'cycloalkyl' or 'cycloalkyl' as used herein, unless otherwise stated, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, as used herein, the term 'C 3 -C 6 cycloalkyl' refers to a cyclic hydrocarbon residue having 3 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
본 명세서에서 사용되는 용어 '아릴'은 다른 언급이 없으면, 융합 또는 비-융합된 하나 이상의 방향족 고리를 갖는, 탄소수 2 내지 30, 6 내지 14 또는 1 내지 6개의 모노- 또는 폴리-시클릭 카르보시클릭 고리 시스템을 지칭하고, 아릴의 예로는 페닐, 나프틸, 테트라히드로나프틸, 인덴일, 안드라세닐 등을 포함하지만, 이로 제한되지는 않는다.As used herein, unless otherwise stated, the term 'aryl' refers to mono- or poly-cyclic carbocy having 2 to 30 carbon atoms, 6 to 14 carbon atoms, or 1 to 6 carbon atoms, having one or more aromatic rings, fused or non-fused. refers to a click ring system, and examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.
본 명세서에서 사용되는 용어 '헤테로아릴'은 다른 언급이 없으면, 탄소가 아닌 원자, 이종원자를 1 이상 포함하는 것으로서, 구체적으로 상기 이종 원자는 O, N, Se 및 S 등으로 이루어진 군에서 선택되는 원자를 1 이상 포함할 수 있다. 탄소수는 특별히 한정되지 않으나, 탄소수 2 내지 30, 6 내지 14 또는 1 내지 6인 것이 바람직하며, 상기 헤테로아릴기는 단환식 또는 다환식일 수 있다. 헤테로아릴기의 예로는 티오펜기, 퓨라닐기, 피롤기, 이미다졸릴기, 티아졸릴기, 옥사졸릴기, 옥사디아졸릴기, 피리딜기, 바이피리딜기, 피리미딜기, 트리아지닐기, 트리아졸릴기, 아크리딜기, 피리다지닐기, 피라지닐기, 퀴놀리닐기, 퀴나졸리닐기, 퀴녹살리닐기, 프탈라지닐기, 피리도 피리미딜기, 피리도 피라지닐기, 피라지노 피라지닐기, 이소퀴놀리닐기, 인돌릴기, 카바졸릴기, 벤즈옥사졸릴기, 벤즈이미다졸릴기, 벤조티아졸릴기, 벤조카바졸릴기, 벤조티오펜기, 디벤조티오펜기, 벤조퓨라닐기, 페난쓰롤리닐기(phenanthroline), 티아졸릴기, 이소옥사졸릴기, 옥사디아졸릴기, 티아디아졸릴기, 페노티아지닐기 및 디벤조퓨라닐기 등이 있으나, 이에 한정되는 것은 아니다.The term 'heteroaryl' as used herein, unless otherwise stated, includes atoms other than carbon and one or more heteroatoms. Specifically, the heteroatoms are atoms selected from the group consisting of O, N, Se and S. may include one or more. The number of carbon atoms is not particularly limited, but preferably has 2 to 30, 6 to 14, or 1 to 6 carbon atoms, and the heteroaryl group may be monocyclic or polycyclic. Examples of the heteroaryl group include a thiophene group, a furanyl group, a pyrrole group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, a triazinyl group Jolyl group, acridyl group, pyridazinyl group, pyrazinyl group, quinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, pyridopyrimidyl group, pyridopyrazinyl group, pyrazinopyrazinyl group , isoquinolinyl group, indolyl group, carbazolyl group, benzoxazolyl group, benzimidazolyl group, benzothiazolyl group, benzocarbazolyl group, benzothiophene group, dibenzothiophene group, benzofuranyl group, pe Nonthrolinyl group (phenanthroline), thiazolyl group, isoxazolyl group, oxadiazolyl group, thiadiazolyl group, phenothiazinyl group, dibenzofuranyl group, and the like, but are not limited thereto.
본 발명의 일 양태로서, 하기 화학식 1로 표시되는 피라졸-카르복스아미드(pyrazole-carboxamide) 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 제공한다:As an aspect of the present invention, there is provided a pyrazole-carboxamide derivative compound represented by the following formula (1), an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022001522-appb-img-000001
Figure PCTKR2022001522-appb-img-000001
상기 화학식 1에 있어서,In Formula 1,
R1은 H 또는 할로겐이고,R 1 is H or halogen,
R2는 H, 할로겐 또는 CN이며,R 2 is H, halogen or CN;
R3 및 R4는 각각 독립적으로 H 또는 할로겐이고,R 3 and R 4 are each independently H or halogen,
Q는 치환 또는 비치환된 아릴 또는 헤테로아릴이며,Q is substituted or unsubstituted aryl or heteroaryl,
L은
Figure PCTKR2022001522-appb-img-000002
,
Figure PCTKR2022001522-appb-img-000003
,
Figure PCTKR2022001522-appb-img-000004
,
Figure PCTKR2022001522-appb-img-000005
,
Figure PCTKR2022001522-appb-img-000006
또는
Figure PCTKR2022001522-appb-img-000007
이고, L is
Figure PCTKR2022001522-appb-img-000002
,
Figure PCTKR2022001522-appb-img-000003
,
Figure PCTKR2022001522-appb-img-000004
,
Figure PCTKR2022001522-appb-img-000005
,
Figure PCTKR2022001522-appb-img-000006
or
Figure PCTKR2022001522-appb-img-000007
ego,
L1은 C1-C6 알킬이며, L 1 is C 1 -C 6 alkyl,
R' 및 R''는 각각 독립적으로 H 또는 C1-C3 알킬로 치환될 수 있고,R' and R'' may each independently be substituted with H or C 1 -C 3 alkyl,
Het는 할로알킬로 치환 또는 비치환된, 4 내지 6원자 방향족 또는 비방향족의 헤테로 고리화합물로서, N 또는 O를 1 내지 4개 고리 내 포함한다. Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.
구체적으로, 상기 R1은 H 또는 Cl일 수 있다.Specifically, R 1 may be H or Cl.
구체적으로, 상기 R2는 H 또는 CN일 수 있다.Specifically, R 2 may be H or CN.
구체적으로, 상기 R3는 Cl일 수 있다.Specifically, R 3 may be Cl.
구체적으로, 상기 R4는 H 또는 Cl일 수 있다.Specifically, R 4 may be H or Cl.
구체적으로, 상기 아릴은 하기 구조에서 선택된 어느 하나일 수 있고;Specifically, the aryl may be any one selected from the following structures;
Figure PCTKR2022001522-appb-img-000008
Figure PCTKR2022001522-appb-img-000008
(상기 구조에 있어서, X는 수소 또는 할로겐임)(In the above structure, X is hydrogen or halogen)
상기 헤테로아릴은 하기 구조에서 선택된 어느 하나일 수 있다:The heteroaryl may be any one selected from the following structures:
Figure PCTKR2022001522-appb-img-000009
Figure PCTKR2022001522-appb-img-000009
(상기 구조에 있어서, X는 수소 또는 할로겐임).(In the above structure, X is hydrogen or halogen).
구체적으로, 상기 L은 하기 구조에서 선택된 어느 하나일 수 있다:Specifically, L may be any one selected from the following structures:
Figure PCTKR2022001522-appb-img-000010
Figure PCTKR2022001522-appb-img-000011
Figure PCTKR2022001522-appb-img-000012
Figure PCTKR2022001522-appb-img-000013
Figure PCTKR2022001522-appb-img-000014
Figure PCTKR2022001522-appb-img-000015
Figure PCTKR2022001522-appb-img-000010
Figure PCTKR2022001522-appb-img-000011
Figure PCTKR2022001522-appb-img-000012
Figure PCTKR2022001522-appb-img-000013
Figure PCTKR2022001522-appb-img-000014
Figure PCTKR2022001522-appb-img-000015
(상기 구조에 있어서, L1은 C1-C3 알킬임).(In the above structure, L 1 is C 1 -C 3 alkyl).
구체적으로, 상기 R' 및 R''는 H일 수 있다.Specifically, R' and R'' may be H.
구체적으로, 상기 Het는 할로알킬로 치환 또는 비치환되고, N 또는 O를 2 내지 4개 고리 내 포함하는 4 내지 6원자 방향족 헤테로 고리화합물인 화합물일 수 있다.Specifically, Het may be a compound that is unsubstituted or substituted with haloalkyl, and is a 4-6 membered aromatic heterocyclic compound including N or O in 2 to 4 rings.
구체적으로, 상기 Het는 하기 구조에서 선택된 어느 하나일 수 있다:Specifically, Het may be any one selected from the following structures:
Figure PCTKR2022001522-appb-img-000016
Figure PCTKR2022001522-appb-img-000016
(상기 구조에 있어서, Y는 H 또는 CX3이고, X는 할로겐임).(In the above structure, Y is H or CX 3 , and X is halogen).
구체적으로, 상기 화합물은 하기 화합물들로 이루어진 군에서 선택된 어느 하나일 수 있다:Specifically, the compound may be any one selected from the group consisting of the following compounds:
N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(3-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(4-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(2-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(3-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신,(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신,(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
3-(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산,3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;
3-(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산,3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
(S)-N-(3-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
(S)-N-(4-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
N-(2-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(3-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(4-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(3-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(4-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
N-(3-아미노-3-옥소프로필)-6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
N-(4-((3-아미노-3-옥소프로필)카바모일)-3-클로로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
N-(4-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(4-((3-아미노-3-옥소프로필)카바모일)-3-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복스아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide,
N-(3-아미노-3-옥소프로필)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드,N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(3-아미노-3-옥소프로필)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드,N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
N-(5-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-((3-아미노-3-옥소프로필)카바모일)-5-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-((3-아미노-3-옥소프로필)카바모일)-4-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide;
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아마이드, N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-carboxamide,
N-(2-아미노-2-옥소에틸)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드,N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(2-아미노-2-옥소에틸)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드, 및N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide, and
N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드.N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide.
본 발명의 일 양태로서, 상기 피라졸-카르복스아미드 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 담체를 포함하는 약제학적 조성물을 제공한다.In one aspect of the present invention, there is provided a pharmaceutical composition comprising the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
또한, 본 발명의 일 양태로서, 상기 피라졸-카르복스아미드 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 포함하는, 카나비노이드 수용체 1(Cannabinoid receptor 1)의 과발현 또는 과활성으로부터 유발된 질환의 예방 또는 치료를 위한 약학적 조성물을 제공한다.In addition, as an aspect of the present invention, the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, including overexpression or hyperactivity of cannabinoid receptor 1 It provides a pharmaceutical composition for the prevention or treatment of diseases caused by
또한, 본 발명의 일 양태로서, 상기 피라졸-카르복스아미드 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의 약학적 유효량을 개체에 투여하는 단계를 포함하는, 카나비노이드 수용체 1(Cannabinoid receptor 1)의 과발현 또는 과활성으로부터 유발된 질환을 예방 또는 치료하는 방법을 제공한다.In addition, as an aspect of the present invention, the cannabinoid receptor 1 ( To provide a method for preventing or treating diseases caused by overexpression or overactivation of cannabinoid receptor 1).
또한, 본 발명의 일 양태로서, 카나비노이드 수용체 1(Cannabinoid receptor 1)의 과발현 또는 과활성으로부터 유발된 질환의 예방 또는 치료를 위한 약제의 제조를 위한, 상기 피라졸-카르복스아미드 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In addition, as an aspect of the present invention, for the preparation of a medicament for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, the pyrazole-carboxamide derivative compound, an isomer thereof , a solvate thereof or a pharmaceutically acceptable salt thereof.
상기 카나비노이드 수용체 1의 과발현 또는 과활성으로부터 유발된 질환은, 당뇨, 대사성질환, 이상지질혈증, 알코올성 간질환 및 비알코올성 간질환으로부터 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.The disease caused by overexpression or overactivity of the cannabinoid receptor 1 may be one or more selected from the group consisting of diabetes, metabolic disease, dyslipidemia, alcoholic liver disease, and non-alcoholic liver disease, but is not limited thereto.
상기 "예방"이란, 카나비노이드 수용체 1의 과발현 또는 과활성으로부터 유발된 질환을 억제시키거나 또는 지연시키는 모든 행위를 말한다.The "prevention" refers to any action that inhibits or delays a disease caused by overexpression or overactivation of cannabinoid receptor 1.
상기 "치료"란, 카나비노이드 수용체 1의 과발현 또는 과활성으로부터 유발된 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 말한다.The "treatment" refers to any action in which the symptoms of an individual suspected of and onset of a disease caused by overexpression or overactivation of cannabinoid receptor 1 are improved or beneficially changed.
상기 "약학적으로 허용되는"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다.The "pharmaceutically acceptable" means exhibiting properties that are not toxic to cells or humans exposed to the composition.
상기 "약학적 유효량"은 투여되는　화합물의 양이 치료하는 장애의 하나 또는 그 이상의 증상을 어느 정도 경감 또는 줄이거나, 예방을 요하는 질병의 임상학적 마커 또는 증상의 개시를 지연시키는데 유효한 활성성분의 량을 의미한다. 따라서, 약리학적 유효량은, 1) 질환의 진행 속도를 역전시키는 효과, 2) 질환의 그 이상의 진행을 어느 정도 금지시키는 효과, 및/또는 3) 질환과 관련된 하나 또는 그 이상의 증상을 어느 정도 경감(바람직하게는, 제거)하는 효과를 가지는 량을 의미한다. 약리학적 유효량은 치료를 요하는 질병에 대한 공지된 생채내(in vivo) 및 생체외(in vitro) 모델 시스템에서　화합물을 실험함으로써 경험적으로 결정될 수 있다.The "pharmaceutically effective amount" means that the amount of the compound administered is effective in alleviating or reducing to some extent one or more symptoms of the disorder being treated, or delaying the onset of clinical markers or symptoms of a disease requiring prevention. means quantity. Thus, a pharmacologically effective amount may have an effect of 1) reversing the rate of disease progression, 2) inhibiting further progression of the disease to some extent, and/or 3) alleviating to some extent one or more symptoms associated with the disease ( Preferably, it means an amount having the effect of removing). A pharmacologically effective amount can be empirically determined by testing the compound in known in vivo and in vitro model systems for a disease in need of treatment.
상기 이성질체는 상기 피라졸-카르복스아미드 유도체 화합물의 비대칭 탄소중심의 존재에 따라, R 또는 S　이성질체, 라세믹　화합물, 부분입체이성체 혼합물, 또는 개개 부분입체이성체로서 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다.The isomers may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, depending on the presence of an asymmetric carbon center of the pyrazole-carboxamide derivative compound, all isomers and mixtures of these isomers are included within the scope of the present invention.
상기 용매화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 용매를 포함할 수 있다. 상기 용매로 바람직한 것은 비휘발성, 비독성 또는 인간에게 투여되기에 적합한 용매들을 들 수 있으며, 예를 들면, 에탄올, 메탄올, 프로판올, 메틸렌클로라이드 등이 있으나, 이에 제한되는 것은 아니다.The solvate may comprise a stoichiometric or non-stoichiometric amount of a solvent that is bound by non-covalent intermolecular forces. Preferred solvents include nonvolatile, nontoxic, or suitable solvents for human administration, for example, ethanol, methanol, propanol, methylene chloride, and the like, but are not limited thereto.
상기 약학적으로 허용가능한 염으로서, 약제학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 주석산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산, 만델산, 뮤크산, 질산, 파모산, 판토텐산, 숙신산, 타르타르산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 캄포르설폰산, 또는 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트리에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 예를 들면, 상기　약제학적으로 허용 가능한 염은 무기산으로서 염산, 유기산으로서 메탄술폰산일 수 있다.As the pharmaceutically acceptable salt, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, Inorganic acid salts prepared with phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid , glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, Organic acid salts prepared from succinic acid and tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, camphorsulfonic acid, sulfonic acid salts prepared from naphthalenesulfonic acid, glycine, arginine, lysine, etc. There are amino acid salts prepared with , and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts in the present invention are not limited by these listed salts. For example, the 　 pharmaceutically acceptable salt may be hydrochloric acid as the inorganic acid and methanesulfonic acid as the organic acid.
상기 약제학적으로 허용가능한 담체로서, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수　있으나, 이에 제한되는 것은 아니다.As the pharmaceutically acceptable carrier, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components may be mixed and used, and if necessary, an antioxidant , buffers, bacteriostats, and other conventional additives may be added, but the present invention is not limited thereto.
상기 약제학적 조성물 또는 약학적 조성물은 유효성분을 단독으로 포함하거나, 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함하여 약학적 조성물로 제공될 수 있다.The pharmaceutical composition or pharmaceutical composition may be provided as a pharmaceutical composition including an active ingredient alone, or one or more pharmaceutically acceptable carriers, excipients or diluents.
상기 약제학적 조성물 또는 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다.The pharmaceutical composition or route of administration of the pharmaceutical composition is not limited thereto, but is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.
상기 약제학적 조성물 또는 약학적 조성물은 경구 또는 비경구 투여할 수 있으며, 비경구 투여시 피부 외용 또는 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식을 선택하는 것이 바람직하나, 이에 한정되는 것은 아니며, 보다 효과적인 흡수경로를 선택한다는 관점에서 바람직하게는 구강투여를 택할 수 있다.The pharmaceutical composition or pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected. However, it is not limited thereto, and oral administration can be preferably selected from the viewpoint of selecting a more effective absorption route.
상기 약제학적 조성물 또는 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 상기 조성물은 0.01 ~ 1000 mg/kg/day로, 바람직하게는 0.1 ~ 500 mg/kg/day로 투여하는 것이 바람직하나 이에 한정되지 않는다. 상기 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 그 범위를 한정하는 것은 아니다.The pharmaceutical composition or a preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the composition is preferably administered at 0.01 to 1000 mg/kg/day, preferably 0.1 to 500 mg/kg/day, but is not limited thereto. The administration may be administered once a day, or divided into several administrations. The above dosages are not intended to limit the scope in any way.
상기 약제학적 조성물 또는 약학적 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propyleneglycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로 제라틴 등이 사용될 수 있다.When formulating the pharmaceutical composition or pharmaceutical composition, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used.
본 발명의 일 양태로서 제공되는 화합물은 하기의 제조방법에 따라 제조될 수 있으나, 특별히 이에 제한되는 것은 아니고, 각종 문헌에 알려져 있는 방법으로 제조할 수 있다.The compound provided as an embodiment of the present invention may be prepared according to the following preparation method, but is not particularly limited thereto, and may be prepared by a method known in various literatures.
[반응식 1][Scheme 1]
Figure PCTKR2022001522-appb-img-000017
Figure PCTKR2022001522-appb-img-000017
반응식 1에서와 같이, 화합물 (1-6)의 합성은 이미 문헌에 보고된 바와 같이 고리화 반응화 가수분해 반응을 통해 [표 1]에서와 같이 화합물 (1-6)을 제조한다(Song K.-S. et al., BMC, 2009, 17, 3080-3092; Kotagiri et al., OPRD 2007, 11, 910-912).As in Scheme 1, the synthesis of compound (1-6) prepares compound (1-6) as shown in [Table 1] through a cyclization reaction hydrolysis reaction as previously reported in the literature (Song K. .-S. et al., BMC , 2009, 17, 3080-3092; Kotagiri et al., OPRD 2007 , 11, 910-912).
화합물compound R1R1 R2R2 R3R3 R4R4
1-6a1-6a ClCl HH ClCl ClCl
1-6b1-6b HH HH ClCl HH
1-6c1-6c HH CNCN ClCl HH
[반응식 2][Scheme 2]
Figure PCTKR2022001522-appb-img-000018
Figure PCTKR2022001522-appb-img-000018
반응식 2에서와 같이, 화합물 (1-6) 과 다양한 방향족 아민 (2-1) 과 아미드결합 (amide coupling) 반응을 통해 화합물 (2-2)를 얻었다. 에스터 화합물 (2-2)는 가수분해 반응을 통해 [표 2]에서와 같이 화합물 (2-3)을 얻었다. 카르복실산 화합물 (2-3)은 [표 3]에서와 같이 다양한 아민유도체 (2-4)와 아미드결합 반응을 통해 실시예 1 내지 40 화합물을 제조한다.As in Scheme 2, compound (1-6) and various aromatic amines (2-1) Compound (2-2) was obtained through an amide coupling reaction. The ester compound (2-2) was hydrolyzed to obtain compound (2-3) as shown in [Table 2]. Carboxylic acid compounds (2-3) were prepared in Examples 1 to 40 through an amide bond reaction with various amine derivatives (2-4) as shown in [Table 3].
화합물compound 중간체intermediate R1R1 R2R2 R3R3 R4R4 QQ
2-3a2-3a 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000019
Figure PCTKR2022001522-appb-img-000019
2-3b2-3b 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000020
Figure PCTKR2022001522-appb-img-000020
2-3c2-3c 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000021
Figure PCTKR2022001522-appb-img-000021
2-3d2-3d 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000022
Figure PCTKR2022001522-appb-img-000022
2-3e2-3e 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000023
Figure PCTKR2022001522-appb-img-000023
2-3f2-3f 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000024
Figure PCTKR2022001522-appb-img-000024
2-3g2-3g 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000025
Figure PCTKR2022001522-appb-img-000025
2-3h2-3h 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000026
Figure PCTKR2022001522-appb-img-000026
2-3i2-3i 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000027
Figure PCTKR2022001522-appb-img-000027
2-3j2-3j 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000028
Figure PCTKR2022001522-appb-img-000028
2-3k2-3k 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000029
Figure PCTKR2022001522-appb-img-000029
2-3l2-3l 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000030
Figure PCTKR2022001522-appb-img-000030
2-3m2-3m 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000031
Figure PCTKR2022001522-appb-img-000031
2-3n2-3n 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000032
Figure PCTKR2022001522-appb-img-000032
2-3o2-3o 1-6a1-6a ClCl HH ClCl ClCl
Figure PCTKR2022001522-appb-img-000033
Figure PCTKR2022001522-appb-img-000033
2-3p2-3p 1-6b1-6b HH HH ClCl HH
Figure PCTKR2022001522-appb-img-000034
Figure PCTKR2022001522-appb-img-000034
2-3q2-3q 1-6c1-6c HH CNCN ClCl HH
Figure PCTKR2022001522-appb-img-000035
Figure PCTKR2022001522-appb-img-000035
상기 화학식 1의 신규한 피라졸-카르복스아미드 유도체 화합물은 1개 이상의 비대칭 탄소를 함유할 수 있고, 따라서 라세미체, 라세믹 혼합물, 단일의 에난티오머, 부분입체이성체 혼합물 및 각각의 부분입체이성체로서 존재할 수 있다. 이러한 이성질체는 종래기술, 예를 들어 화학식 1의 신규한피라졸 카르복스아미드 유도체 화합물 관 크로마토그래피 또는 HPLC 등의 분할에 의해 분리가 가능하다. 또는, 화학식 1의 화합물 각각의 입체이성질체는 공지된 배열의 광학적으로 순수한 출발 물질 및 또는 시약을 사용하여 입체특이적으로 합성할 수 있다.The novel pyrazole-carboxamide derivative compounds of formula (1) may contain one or more asymmetric carbons, and thus racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. It may exist as an isomer. Such isomers can be separated by conventional techniques, for example, column chromatography of the novel pyrazole carboxamide derivative compound of Formula 1 or resolution such as HPLC. Alternatively, stereoisomers of each of the compounds of Formula 1 can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configurations.
상기 화학식 1의 신규한 피라졸-카르복스아미드 유도체 화합물은 무기산 및 유기산으로부터 유도된 약학적으로 허용가능한 비독성 산으로부터 제조할 수 있다. 상기 산은 아세트산, 벤젠설폰산, 벤조산, 캄퍼설폰산, 시트르산, 에탄설폰산, 푸마르산, 글루콘산, 글루탐산, 하이드로브롬산, 하이드로클로로산, 이세티온산, 락트산, 말레산, 말산, 만델산, 메탄설폰산, 점액산, 질산, 파모산, 판토텐산, 인산, 숙신산, 황산, 타르타르산, p-톨루엔설폰산 산 등을 포함한다. 시트르산, 하이드로브로모산, 하이드로클로로산, 말레산, 인산, 황산 및 타르타르산이 특히 바람직하다.The novel pyrazole-carboxamide derivative compound of Formula 1 can be prepared from pharmaceutically acceptable non-toxic acids derived from inorganic acids and organic acids. The acids are acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloroic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Citric acid, hydrobromoic acid, hydrochloroic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred.
본 발명의 일 양태로서 제공되는 신규한 신규한 피라졸-카르복스아미드 유도체 화합물은 카나비노이드 수용체 1(Cannabinoid receptor 1)에 특이적인 길항제/역효능제 활성을 나타내어, 관련 질환을 효과적으로 예방 또는 치료할 수 있는 기술적 효과가 존재한다.The novel pyrazole-carboxamide derivative compound provided as an aspect of the present invention exhibits antagonist/inverse agonist activity specific to cannabinoid receptor 1, thereby effectively preventing or treating related diseases. There are technical effects.
다만, 상기한 효과로 한정되는 것은 아니며, 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.However, it is not limited to the above-described effects, and it should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims.
도 1은 CB1 단백질과 CB1 억제제로 알려진 타라나반트(Taranabant, inverse agonist)의 상호작용에 대한 분석 결과이다. 1 is an analysis result of the interaction between CB1 protein and taranabant, known as a CB1 inhibitor (Taranabant, inverse agonist).
도 2는 합성 후보 물질 102종 화합물에 대한 도킹 에너지 스코어 결과를 산점도 (Scatter plot)로 나타낸 것이다. 2 is a scatter plot showing docking energy score results for 102 compounds of synthetic candidate materials.
이하, 보다 구체적으로 설명하기 위해 제조예 및 실시예를 들어 상세하게 설명하기로 한다. 그러나, 하기 제조예 및 실시예는 예시적인 것으로, 발명의 범위가 이에 제한되는 것은 아니다.Hereinafter, in order to explain in more detail, it will be described in detail with reference to Preparation Examples and Examples. However, the following Preparation Examples and Examples are illustrative, and the scope of the invention is not limited thereto.
제조예. 중간체 화합물의 제조manufacturing example. Preparation of intermediate compounds
1. 화합물 (1-6a)의 제조1. Preparation of compound (1-6a)
(단계 1) 리튬 염 화합물 (1-3a)의 제조 (Step 1) Preparation of lithium salt compound (1-3a)
리튬 비스(트리메틸실릴)아미드 (62.5 mL, 1 M in THF solution, 62.5 mmol)의 다이에틸 에터 (250 mL) 용액을 1-(4-클로로페닐)프로판-1-온 (1-1a) (10.5 g, 62.3 mmol)의 다이에틸 에터 (50 mL)에 -78 ℃에서 30분 동안 천천히 적가하였다. 반응혼합물을 같은 온도에서 1시간 동안 더 교반한 후 다이에틸 옥살레이트 (9.6 mL, 70.8 mmol)를 넣었다. 반응혼합물을 상온에서 16시간 동안 교반한 후 흰색 침천물을 거르고 디에틸 에터로 세척 후 진공하에서 건조하여 흰색고체의 리튬 염 화합물 (1-3a) (5.44 g, 32%)을 얻었다. A solution of lithium bis(trimethylsilyl)amide (62.5 mL, 1 M in THF solution, 62.5 mmol) in diethyl ether (250 mL) was mixed with 1-(4-chlorophenyl)propan-1-one (1-1a) (10.5 g, 62.3 mmol) of diethyl ether (50 mL) was slowly added dropwise at -78 °C for 30 min. The reaction mixture was further stirred at the same temperature for 1 hour, and then diethyl oxalate (9.6 mL, 70.8 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 16 hours, the white precipitate was filtered, washed with diethyl ether, and dried under vacuum to form a white solid lithium salt compound (1-3a) (5.44 g, 32%) was obtained.
(단계 2) 에틸 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실레이트 (1-5a)의 합성(Step 2) Synthesis of ethyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylate (1-5a)
리튬 염 화합물 (1-3a) (5.44 g, 19.8 mmol)의 에탄올 (30.2 mL) 용액에 (2,4-다이클로로페닐)하이드라진 하이드로클로라이드 (1-4a) (5.07 g, 23.7 mmol)를 넣은 후 상온에서 16시간 동안 교반하였다. 침천물을 거른 후 에탄올과 다이에틸 에터의 순서로 씻은 후 진공하에서 건조하여 노란색 고체 하이드라존 화합물 (4.95 g)를 얻었다. 이 하이드라존 화합물 (4.95 g)을 아세트산 (39.3 mL)에 녹인 후 24시간 동안 가열환류 하였다. 반응혼합물을 차가운 물 (200 mL)에 부은 후 에틸 아세테이트 (330 mL)로 추출한 후 ant 황산나트륨으로 수분을 제거한 후, 감압하에 농축하여 화합물 (1-5a) (5.0 g, 35%)를 연한노란색 고체형태로 얻었다. After adding (2,4-dichlorophenyl)hydrazine hydrochloride (1-4a) (5.07 g, 23.7 mmol) to a solution of lithium salt compound (1-3a) (5.44 g, 19.8 mmol) in ethanol (30.2 mL) The mixture was stirred at room temperature for 16 hours. After filtering the precipitate, it was washed with ethanol and diethyl ether in that order, and dried under vacuum to obtain a yellow solid hydrazone compound (4.95 g). This hydrazone compound (4.95 g) was dissolved in acetic acid (39.3 mL) and heated to reflux for 24 hours. The reaction mixture was poured into cold water (200 mL), extracted with ethyl acetate (330 mL), dried with ant sodium sulfate, and concentrated under reduced pressure to give compound (1-5a) (5.0 g, 35%) as a pale yellow solid. obtained in the form
(단계 3) 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a)의 합성(Step 3) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a)
에스터 화합물 (1-5a) (5.0 g)의 메탄올 (40 mL) 용액을 수산화칼륨 (1.7 g) 수용액 (40 mL)에 넣은 후 3시간동안 가열환류 하였다. 반응혼합물을 찬물(100 mL)에 넣은 후 10% 염산수용액을 이용하여 산도가 1이 될 때가지 적가하였다. 고체침전물을 여과한 후 물로 씻고 진공하에서 건조하여 화합물 (1-6a) (4.4 g, 57%)을 얻었다.A solution of the ester compound (1-5a) (5.0 g) in methanol (40 mL) was placed in an aqueous solution of potassium hydroxide (1.7 g) (40 mL), and then heated to reflux for 3 hours. After putting the reaction mixture in cold water (100 mL), it was added dropwise using a 10% aqueous hydrochloric acid solution until the acidity reached 1. The solid precipitate was filtered, washed with water and dried under vacuum to obtain compound (1-6a) (4.4 g, 57%).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 7.34-7.40 (3H, m), 7.65-7.76 (4H, m); LRMS (ESI) m/z 382.6 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 7.34-7.40 (3H, m), 7.65-7.76 (4H, m); LRMS (ESI) m/z 382.6 (M + +1).
2. 화합물 (1-6b)의 제조2. Preparation of compound (1-6b)
프로피오페논 (1-1b) 와 (4-클로로페닐)하이드라진 (1-4b)를 사용하여 상기 화합물 (1-6a)에서 기술된 공정과 유사하게 제조하였다. It was prepared similarly to the process described in the above compound (1-6a) using propiophenone (1-1b) and (4-chlorophenyl)hydrazine (1-4b).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6)δ 2.46 (3H, s), 7.47-7.58 (3H, m), 7.68 (2H, m), 7.76 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz); LRMS (ESI) m/z 313.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 )δ 2.46 (3H, s), 7.47-7.58 (3H, m), 7.68 (2H, m), 7.76 (2H, d, J = 8.4 Hz) , 7.83 (2H, d, J = 8.4 Hz); LRMS (ESI) m/z 313.8 (M + +1).
3. 화합물 (1-6c)의 제조3. Preparation of compound (1-6c)
3-프로피오닐벤조나이트릴 (1-1c) 와 (4-클로로페닐)하이드라진 (1-4b)를 사용하여 상기 화합물 (1-6a)에서 기술된 공정과 유사하게 제조하였다. Using 3-propionylbenzonitrile (1-1c) and (4-chlorophenyl)hydrazine (1-4b), it was prepared similarly to the process described for compound (1-6a) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6)δ 2.50 (3H, s), 7.52-7.66 (2H, m), 7.69-7.86 (5H, m), 8.11 (1H, m); LRMS (ESI) m/z 338.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 )δ 2.50 (3H, s), 7.52-7.66 (2H, m), 7.69-7.86 (5H, m), 8.11 (1H, m); LRMS (ESI) m/z 338.8 (M + +1).
4. 화합물 (2-2a)의 제조4. Preparation of compound (2-2a)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) (1.000 g, 2.620 mmol), 메틸 2-아미노벤조에이트 (2-1a) (0.436 g, 2.882 mmol), 1-[비스(다이메틸아미노)메틸렌]-1H-1,2,3-트라이아졸로[4,5-b]피리디늄 3-옥사이드 헥사플루오로포스페이트(HATU, 1.196 g, 3.144 mmol) 그리고 N,N-다이아이소프로필에틸아민(0.685 mL, 3.930 mmol)을 실온에서 N,N-다이메틸폼아마이드(10 mL)에 녹인 용액을 같은 온도에서 12 시간 동안 교반하였다. 반응 혼합물에 물(5 mL)을 넣고 교반하여 석출된 고체를 여과하고 물로 세척 및 건조하여 메틸 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트(1.180 g, 87.5 %)를 흰색고체 형태로 얻었다.5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) (1.000 g, 2.620 mmol), methyl 2-amino Benzoate (2-1a) (0.436 g, 2.882 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide A solution of hexafluorophosphate (HATU, 1.196 g, 3.144 mmol) and N,N-diisopropylethylamine (0.685 mL, 3.930 mmol) in N,N-dimethylformamide (10 mL) at room temperature was the same The temperature was stirred for 12 hours. Water (5 mL) was added to the reaction mixture, stirred, the precipitated solid was filtered, washed with water, and dried to methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamido)benzoate (1.180 g, 87.5%) was obtained as a white solid.
분광학 데이터: LRMS (ESI) m/z 515.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 515.8 (M + +1).
5. 화합물 (2-2b)의 제조5. Preparation of compound (2-2b)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 3-아미노벤조에이트 (2-1b)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-aminobenzoate (2-1b) was prepared similarly to the process described for compound (2-2a) using
분광학 데이터: LRMS (ESI) m/z 515.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 515.8 (M + +1).
6. 화합물 (2-2c)의 제조6. Preparation of compound (2-2c)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 4-아미노벤조에이트 (2-1c)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-aminobenzoate (2-1c) was prepared similarly to the process described for compound (2-2a) using
분광학 데이터: LRMS (ESI) m/z 515.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 515.8 (M + +1).
7. 화합물 (2-2d)의 제조7. Preparation of compound (2-2d)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 6-아미노니코티네이트 (2-1d)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 6-aminonicotinate (2-1d ) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 516.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 516.8 (M + +1).
8. 화합물 (2-2e)의 제조8. Preparation of compound (2-2e)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 5-아미노니코티네이트 (2-1e)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminonicotinate (2-1e ) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 516.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 516.8 (M + +1).
9. 화합물 (2-2f)의 제조9. Preparation of compound (2-2f)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 5-아미노피라진-2-카복실레이트 (2-1f)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminopyrazine-2-carboxylate ( 2-1f) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 517.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 517.8 (M + +1).
10. 화합물 (2-2g)의 제조10. Preparation of compound (2-2g)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 4-아미노-2-클로로벤조에이트 (2-1g)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-2-chlorobenzoate ( 2-1 g) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 550.2 (M++1).Spectroscopy data: LRMS (ESI) m/z 550.2 (M + +1).
11. 화합물 (2-2h)의 제조11. Preparation of compound (2-2h)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 4-아미노-3-플루오로벤조에이트 (2-1h)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-3-fluorobenzoate (2-1h) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 533.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 533.8 (M + +1).
12. 화합물 (2-2i)의 제조12. Preparation of compound (2-2i)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 4-아미노-2-플루오로벤조에이트 (2-1i)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-2-fluorobenzoate (2-1i) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 533.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 533.8 (M + +1).
13. 화합물 (2-2j)의 제조13. Preparation of compound (2-2j)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 2-아미노아이소니코티네이트 (2-1j)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 2-aminoisonicotinate (2- 1j) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 516.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 516.8 (M + +1).
14. 화합물 (2-2k)의 제조14. Preparation of compound (2-2k)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 5-아미노니코티네이트 (2-1k)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminonicotinate (2-1k ) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 516.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 516.8 (M + +1).
15. 화합물 (2-2l)의 제조15. Preparation of compound (2-2l)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 4-아미노니코티네이트 (2-1l)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-aminonicotinate (2-11) ) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 516.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 516.8 (M + +1).
16. 화합물 (2-2m)의 제조16. Preparation of compound (2-2m)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 3-아미노-4-플루오로벤조에이트 (2-1m)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-amino-4-fluorobenzoate (2-1m) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 533.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 533.8 (M + +1).
17. 화합물 (2-2n)의 제조17. Preparation of compound (2-2n)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 3-아미노-5-플루오로벤조에이트 (2-1n)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-amino-5-fluorobenzoate (2-1n) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 533.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 533.8 (M + +1).
18. 화합물 (2-2o)의 제조18. Preparation of compound (2-2o)
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6a) 와 메틸 5-아미노-2-플루오로벤조에이트 (2-1o)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-amino-2-fluorobenzoate (2-1o) was prepared similarly to the process described for compound (2-2a) above.
분광학 데이터: LRMS (ESI) m/z 533.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 533.8 (M + +1).
19. 화합물 (2-2p)의 제조19. Preparation of compound (2-2p)
1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복실산 (1-6b) 와 메틸 4-아미노벤조에이트 (2-1c)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. The above compound (2-) using 1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid (1-6b) and methyl 4-aminobenzoate (2-1c) Prepared similarly to the process described in 2a).
분광학 데이터: LRMS (ESI) m/z 446.9 (M++1).Spectroscopy data: LRMS (ESI) m/z 446.9 (M + +1).
20. 화합물 (2-2q)의 제조20. Preparation of compound (2-2q)
1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복실산 (1-6c) 와 메틸 4-아미노벤조에이트 (2-1c)를 사용하여 상기 화합물 (2-2a)에서 기술된 공정과 유사하게 제조하였다. Using 1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6c) and methyl 4-aminobenzoate (2-1c) Thus, it was prepared similarly to the process described for compound (2-2a).
분광학 데이터: LRMS (ESI) m/z 471.9 (M++1).Spectroscopy data: LRMS (ESI) m/z 471.9 (M + +1).
21. 화합물 (2-3a)의 제조21. Preparation of compound (2-3a)
수산화 리튬(0.047 g, 1.943 mmol)을 실온에서 테트라하이드로퓨란(3 mL)/메탄올(1 mL)/물(1 mL)에 녹인 용액에 메틸 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트 (2-2a) (0.500 g, 0.971 mmol)를 첨가하고 같은 온도에서 18 시간 동안 교반하였다. 반응 혼합물을 감압 하에서 용매를 제거하여 얻어진 농축물에 물을 붓고 에틸 아세테이트로 추출하였다. 유기층을 1N-염산 수용액, 정제수의 순서로 씻어주고 무수 황산 마그네슘으로 수분을 제거한 후 여과하였다. 감압하에서 농축하여 생성된 화합물 (2-3a) (0.350 g, 72.0 %, 황백색고체)을 추가적인 정제과정 없이 사용하였다.To a solution of lithium hydroxide (0.047 g, 1.943 mmol) in tetrahydrofuran (3 mL)/methanol (1 mL)/water (1 mL) at room temperature, methyl 2-(5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate (2-2a) (0.500 g, 0.971 mmol) was added and stirred at the same temperature for 18 hours. did. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in this order, dried with anhydrous magnesium sulfate, and then filtered. Compound (2-3a) (0.350 g, 72.0 %, off-white solid) obtained by concentration under reduced pressure was used without further purification.
분광학 데이터: LRMS (ESI) m/z 501.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 501.8 (M + +1).
22. 화합물 (2-3b)의 제조22. Preparation of compound (2-3b)
메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트 (2-2b)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Using methyl 3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2-2b) Thus, it was prepared similarly to the process described for compound (2-3a).
분광학 데이터: LRMS (ESI) m/z 501.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 501.8 (M + +1).
23. 화합물 (2-3c)의 제조23. Preparation of compound (2-3c)
메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트 (2-2c)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Using methyl 4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2-2c) Thus, it was prepared similarly to the process described for compound (2-3a).
분광학 데이터: LRMS (ESI) m/z 501.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 501.8 (M + +1).
24. 화합물 (2-3d)의 제조24. Preparation of compound (2-3d)
메틸 6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코티네이트 (2-2d)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 6- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) nicotinate (2-2d) It was prepared similarly to the process described for compound (2-3a) using
분광학 데이터: LRMS (ESI) m/z 502.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 502.7 (M + +1).
25. 화합물 (2-3e)의 제조25. Preparation of compound (2-3e)
메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜리네이트 (2-2e)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinate (2-2e) It was prepared similarly to the process described for compound (2-3a) using
분광학 데이터: LRMS (ESI) m/z 502.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 502.7 (M + +1).
26. 화합물 (2-3f)의 제조26. Preparation of compound (2-3f)
메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복실레이트 (2-2f)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) pyrazine-2-carboxylate (2- 2f) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 503.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 503.7 (M + +1).
27. 화합물 (2-3g)의 제조27. Preparation of compound (2-3 g)
메틸 2-클로로-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트 (2-2g)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2- 2g) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 536.2 (M++1).Spectroscopy data: LRMS (ESI) m/z 536.2 (M + +1).
28. 화합물 (2-3h)의 제조28. Preparation of compound (2-3h)
메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-3-플루오로벤조에이트 (2-2h)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoate (2 -2h) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 519.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 519.8 (M + +1).
29. 화합물 (2-3i)의 제조29. Preparation of compound (2-3i)
메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조에이트 (2-2i)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate (2 -2i) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 519.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 519.8 (M + +1).
30. 화합물 (2-3j)의 제조30. Preparation of compound (2-3j)
메틸 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코티네이트 (2-2j)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinate (2-2j) was prepared similarly to the process described for compound (2-3a) using
분광학 데이터: LRMS (ESI) m/z 502.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 502.7 (M + +1).
31. 화합물 (2-3k)의 제조31. Preparation of compound (2-3k)
메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코티네이트 (2-2k)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) nicotinate (2-2k) It was prepared similarly to the process described for compound (2-3a) using
분광학 데이터: LRMS (ESI) m/z 502.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 502.7 (M + +1).
32. 화합물 (2-3l)의 제조32. Preparation of compound (2-3l)
메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜리네이트 (2-2l)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinate (2-2l) It was prepared similarly to the process described for compound (2-3a) using
분광학 데이터: LRMS (ESI) m/z 502.7 (M++1).Spectroscopy data: LRMS (ESI) m/z 502.7 (M + +1).
33. 화합물 (2-3m)의 제조33. Preparation of compound (2-3m)
메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-4-플루오로벤조에이트 (2-2m)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoate (2 -2m) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 519.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 519.8 (M + +1).
34. 화합물 (2-3n)의 제조34. Preparation of compound (2-3n)
메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-5-플루오로벤조에이트 (2-2n)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoate (2 -2n) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 519.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 519.8 (M + +1).
35. 화합물 (2-3o)의 제조35. Preparation of compound (2-3o)
메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조에이트 (2-2o)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) -2-fluorobenzoate (2 -2o) was prepared similarly to the process described for compound (2-3a) above.
분광학 데이터: LRMS (ESI) m/z 519.8 (M++1).Spectroscopy data: LRMS (ESI) m/z 519.8 (M + +1).
36. 화합물 (2-3p)의 제조36. Preparation of compound (2-3p)
메틸 4-(1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아미도)벤조에이트 (2-2p)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다. The above compound (2-3a) using methyl 4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoate (2-2p) It was prepared similarly to the process described in
분광학 데이터: LRMS (ESI) m/z 432.9 (M++1).Spectroscopy data: LRMS (ESI) m/z 432.9 (M + +1).
37. 화합물 (2-3q)의 제조37. Preparation of compound (2-3q)
메틸 4-(1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트 (2-2q)를 사용하여 상기 화합물 (2-3a)에서 기술된 공정과 유사하게 제조하였다.methyl 4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate (2-2q) It was prepared analogously to the process described for compound (2-3a).
분광학 데이터: LRMS (ESI) m/z 457.9 (M++1).Spectroscopy data: LRMS (ESI) m/z 457.9 (M + +1).
상기 제조된 중간체들을 정리하면 하기 표 3과 같다.The prepared intermediates are summarized in Table 3 below.
중간체intermediate IUPAC 명명 및 구조식IUPAC Naming and Structural Formula 구조식constitutional formula
1-1a1-1a 1-(4-클로로페닐)프로판-1-온1-(4-chlorophenyl)propan-1-one
Figure PCTKR2022001522-appb-img-000036
Figure PCTKR2022001522-appb-img-000036
1-1b1-1b 프로피오페논propiophenone
Figure PCTKR2022001522-appb-img-000037
Figure PCTKR2022001522-appb-img-000037
1-1c1-1c 3-프로피오닐벤조나이트릴3-propionylbenzonitrile
Figure PCTKR2022001522-appb-img-000038
Figure PCTKR2022001522-appb-img-000038
1-4a1-4a (2,4-다이클로로페닐)하이드라진(2,4-dichlorophenyl)hydrazine
Figure PCTKR2022001522-appb-img-000039
Figure PCTKR2022001522-appb-img-000039
1-4b1-4b (4-클로로페닐)하이드라진(4-chlorophenyl)hydrazine
Figure PCTKR2022001522-appb-img-000040
Figure PCTKR2022001522-appb-img-000040
2-1a2-1a 메틸 2-아미노벤조에이트Methyl 2-aminobenzoate
Figure PCTKR2022001522-appb-img-000041
Figure PCTKR2022001522-appb-img-000041
2-1b2-1b 메틸 3-아미노벤조에이트Methyl 3-aminobenzoate
Figure PCTKR2022001522-appb-img-000042
Figure PCTKR2022001522-appb-img-000042
2-1c2-1c 메틸 4-아미노벤조에이트Methyl 4-aminobenzoate
Figure PCTKR2022001522-appb-img-000043
Figure PCTKR2022001522-appb-img-000043
2-1d2-1d 메틸 6-아미노니코티네이트Methyl 6-aminonicotinate
Figure PCTKR2022001522-appb-img-000044
Figure PCTKR2022001522-appb-img-000044
2-1e2-1e 메틸 5-아미노니코티네이트Methyl 5-aminonicotinate
Figure PCTKR2022001522-appb-img-000045
Figure PCTKR2022001522-appb-img-000045
2-1f2-1f 메틸 5-아미노피라진-2-카복실레이트Methyl 5-aminopyrazine-2-carboxylate
Figure PCTKR2022001522-appb-img-000046
Figure PCTKR2022001522-appb-img-000046
2-1g2-1 g 메틸 4-아미노-2-클로로벤조에이트Methyl 4-amino-2-chlorobenzoate
Figure PCTKR2022001522-appb-img-000047
Figure PCTKR2022001522-appb-img-000047
2-1h2-1h 메틸 4-아미노-3-플루오로벤조에이트Methyl 4-amino-3-fluorobenzoate
Figure PCTKR2022001522-appb-img-000048
Figure PCTKR2022001522-appb-img-000048
2-1i2-1i 메틸 4-아미노-2-플루오로벤조에이트Methyl 4-amino-2-fluorobenzoate
Figure PCTKR2022001522-appb-img-000049
Figure PCTKR2022001522-appb-img-000049
2-1j2-1j 메틸 2-아미노아이소니코티네이트Methyl 2-aminoisonicotinate
Figure PCTKR2022001522-appb-img-000050
Figure PCTKR2022001522-appb-img-000050
2-1k2-1k 메틸 5-아미노니코티네이트Methyl 5-aminonicotinate
Figure PCTKR2022001522-appb-img-000051
Figure PCTKR2022001522-appb-img-000051
2-1l2-1l 메틸 4-아미노니코티네이트Methyl 4-aminonicotinate
Figure PCTKR2022001522-appb-img-000052
Figure PCTKR2022001522-appb-img-000052
2-1m2-1m 메틸 3-아미노-4-플루오로벤조에이트Methyl 3-amino-4-fluorobenzoate
Figure PCTKR2022001522-appb-img-000053
Figure PCTKR2022001522-appb-img-000053
2-1n2-1n 메틸 3-아미노-5-플루오로벤조에이트Methyl 3-amino-5-fluorobenzoate
Figure PCTKR2022001522-appb-img-000054
Figure PCTKR2022001522-appb-img-000054
2-1o2-1o 메틸 5-아미노-2-플루오로벤조에이트Methyl 5-amino-2-fluorobenzoate
Figure PCTKR2022001522-appb-img-000055
Figure PCTKR2022001522-appb-img-000055
2-4a2-4a 2-아미노아세트아마이드2-Aminoacetamide
Figure PCTKR2022001522-appb-img-000056
Figure PCTKR2022001522-appb-img-000056
2-4b2-4b 메틸 글리시네이트methyl glycinate
Figure PCTKR2022001522-appb-img-000057
Figure PCTKR2022001522-appb-img-000057
2-4c2-4c (S)-피롤리딘-2-카복스아마이드(S)-pyrrolidine-2-carboxamide
Figure PCTKR2022001522-appb-img-000058
Figure PCTKR2022001522-appb-img-000058
2-4d2-4d 2-아미노에테인-1-설폰아마이드2-Aminoethane-1-sulfonamide
Figure PCTKR2022001522-appb-img-000059
Figure PCTKR2022001522-appb-img-000059
2-4e2-4e 3-아미노프로판아마이드3-Aminopropanamide
Figure PCTKR2022001522-appb-img-000060
Figure PCTKR2022001522-appb-img-000060
2-4f2-4f 메틸 3-아미노프로파노에이트Methyl 3-aminopropanoate
Figure PCTKR2022001522-appb-img-000061
Figure PCTKR2022001522-appb-img-000061
2-4g2-4 g 5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-아민5-(trifluoromethyl)-1,3,4-oxadiazol-2-amine
Figure PCTKR2022001522-appb-img-000062
Figure PCTKR2022001522-appb-img-000062
2-4h2-4h 5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-아민5-(trifluoromethyl)-1,2,4-oxadiazol-3-amine
Figure PCTKR2022001522-appb-img-000063
Figure PCTKR2022001522-appb-img-000063
2-4i2-4i (5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)메탄아민(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methanamine
Figure PCTKR2022001522-appb-img-000064
Figure PCTKR2022001522-appb-img-000064
2-4j2-4j (1,3,4-옥사다이아졸-2-일)메탄아민(1,3,4-oxadiazol-2-yl)methanamine
Figure PCTKR2022001522-appb-img-000065
Figure PCTKR2022001522-appb-img-000065
2-4k2-4k (1,2,4-옥사다이아졸-3-일)메탄아민(1,2,4-oxadiazol-3-yl)methanamine
Figure PCTKR2022001522-appb-img-000066
Figure PCTKR2022001522-appb-img-000066
1-3a1-3a 에틸4-(4-클로로페닐)-3-메틸-4-옥시도-2-옥소뷰텐-3-오에이트 리튬염Ethyl4-(4-chlorophenyl)-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt
Figure PCTKR2022001522-appb-img-000067
Figure PCTKR2022001522-appb-img-000067
1-3b1-3b 에틸4-페닐-3-메틸-4-옥시도-2-옥소뷰텐-3-오에이트 리튬염Ethyl4-phenyl-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt
Figure PCTKR2022001522-appb-img-000068
Figure PCTKR2022001522-appb-img-000068
1-3c1-3c 에틸4-(3-사이아노페닐)-3-메틸-4-옥시도-2-옥소뷰텐-3-오에이트 리튬염Ethyl4-(3-cyanophenyl)-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt
Figure PCTKR2022001522-appb-img-000069
Figure PCTKR2022001522-appb-img-000069
1-5a1-5a 에틸 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실레이트Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate
Figure PCTKR2022001522-appb-img-000070
Figure PCTKR2022001522-appb-img-000070
1-5b1-5b 에틸 1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복실레이트Ethyl 1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate
Figure PCTKR2022001522-appb-img-000071
Figure PCTKR2022001522-appb-img-000071
1-5c1-5c 에틸1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복실레이트Ethyl 1- (4-chlorophenyl) -5- (3-cyanophenyl) -4-methyl-1H-pyrazole-3-carboxylate
Figure PCTKR2022001522-appb-img-000072
Figure PCTKR2022001522-appb-img-000072
1-6a1-6a 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복실산5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
Figure PCTKR2022001522-appb-img-000073
Figure PCTKR2022001522-appb-img-000073
1-6b1-6b 1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복실산1-(4-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid
Figure PCTKR2022001522-appb-img-000074
Figure PCTKR2022001522-appb-img-000074
1-6c1-6c 1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복실산1-(4-Chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
Figure PCTKR2022001522-appb-img-000075
Figure PCTKR2022001522-appb-img-000075
2-2a2-2a 메틸 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate
Figure PCTKR2022001522-appb-img-000076
Figure PCTKR2022001522-appb-img-000076
2-2b2-2b 메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate
Figure PCTKR2022001522-appb-img-000077
Figure PCTKR2022001522-appb-img-000077
2-2c2-2c 메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate
Figure PCTKR2022001522-appb-img-000078
Figure PCTKR2022001522-appb-img-000078
2-2d2-2d 메틸 6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코티네이트Methyl 6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinate
Figure PCTKR2022001522-appb-img-000079
Figure PCTKR2022001522-appb-img-000079
2-2e2-2e 메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜리네이트Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinate
Figure PCTKR2022001522-appb-img-000080
Figure PCTKR2022001522-appb-img-000080
2-2f2-2f 메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복실레이트Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylate
Figure PCTKR2022001522-appb-img-000081
Figure PCTKR2022001522-appb-img-000081
2-2g2-2g 메틸 2-클로로-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트Methyl 2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate
Figure PCTKR2022001522-appb-img-000082
Figure PCTKR2022001522-appb-img-000082
2-2h2-2h 메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-3-플루오로벤조에이트Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoate
Figure PCTKR2022001522-appb-img-000083
Figure PCTKR2022001522-appb-img-000083
2-2i2-2i 메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조에이트Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate
Figure PCTKR2022001522-appb-img-000084
Figure PCTKR2022001522-appb-img-000084
2-2j2-2j 메틸 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코티네이트Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinate
Figure PCTKR2022001522-appb-img-000085
Figure PCTKR2022001522-appb-img-000085
2-2k2-2k 메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코티네이트Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinate
Figure PCTKR2022001522-appb-img-000086
Figure PCTKR2022001522-appb-img-000086
2-2l2-2l 메틸 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜리네이트Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinate
Figure PCTKR2022001522-appb-img-000087
Figure PCTKR2022001522-appb-img-000087
2-2m2-2m 메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-4-플루오로벤조에이트Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoate
Figure PCTKR2022001522-appb-img-000088
Figure PCTKR2022001522-appb-img-000088
2-2n2-2n 메틸 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-5-플루오로벤조에이트Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoate
Figure PCTKR2022001522-appb-img-000089
Figure PCTKR2022001522-appb-img-000089
2-2o2-2o 메틸 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조에이트Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate
Figure PCTKR2022001522-appb-img-000090
Figure PCTKR2022001522-appb-img-000090
2-2p2-2p 메틸 4-(1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아미도)벤조에이트Methyl 4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoate
Figure PCTKR2022001522-appb-img-000091
Figure PCTKR2022001522-appb-img-000091
2-2q2-2q 메틸 4-(1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조에이트Methyl 4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate
Figure PCTKR2022001522-appb-img-000092
Figure PCTKR2022001522-appb-img-000092
2-3a2-3a 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid
Figure PCTKR2022001522-appb-img-000093
Figure PCTKR2022001522-appb-img-000093
2-3b2-3b 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid
Figure PCTKR2022001522-appb-img-000094
Figure PCTKR2022001522-appb-img-000094
2-3c2-3c 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid
Figure PCTKR2022001522-appb-img-000095
Figure PCTKR2022001522-appb-img-000095
2-3d2-3d 6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴산6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid
Figure PCTKR2022001522-appb-img-000096
Figure PCTKR2022001522-appb-img-000096
2-3e2-3e 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid
Figure PCTKR2022001522-appb-img-000097
Figure PCTKR2022001522-appb-img-000097
2-3f2-3f 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복실산5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylic acid
Figure PCTKR2022001522-appb-img-000098
Figure PCTKR2022001522-appb-img-000098
2-3g2-3g 2-클로로-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid
Figure PCTKR2022001522-appb-img-000099
Figure PCTKR2022001522-appb-img-000099
2-3h2-3h 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-3-플루오로벤조산4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoic acid
Figure PCTKR2022001522-appb-img-000100
Figure PCTKR2022001522-appb-img-000100
2-3i2-3i 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조산4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid
Figure PCTKR2022001522-appb-img-000101
Figure PCTKR2022001522-appb-img-000101
2-3j2-3j 2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴산2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid
Figure PCTKR2022001522-appb-img-000102
Figure PCTKR2022001522-appb-img-000102
2-3k2-3k 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴산5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid
Figure PCTKR2022001522-appb-img-000103
Figure PCTKR2022001522-appb-img-000103
2-3l2-3l 4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid
Figure PCTKR2022001522-appb-img-000104
Figure PCTKR2022001522-appb-img-000104
2-3m2-3m 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-4-플루오로벤조산3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoic acid
Figure PCTKR2022001522-appb-img-000105
Figure PCTKR2022001522-appb-img-000105
2-3n2-3n 3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-5-플루오로벤조산3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoic acid
Figure PCTKR2022001522-appb-img-000106
Figure PCTKR2022001522-appb-img-000106
2-3o2-3o 5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조산5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid
Figure PCTKR2022001522-appb-img-000107
Figure PCTKR2022001522-appb-img-000107
2-3p2-3p 4-(1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아미도)벤조산4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoic acid
Figure PCTKR2022001522-appb-img-000108
Figure PCTKR2022001522-appb-img-000108
2-3q2-3q 4-(1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산4-(1-(4-Chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid
Figure PCTKR2022001522-appb-img-000109
Figure PCTKR2022001522-appb-img-000109
실시예. 화합물의 합성Example. synthesis of compounds
실시예 1Example 1
N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3a) (0.100 g, 0.200 mmol), 1-[비스(다이메틸아미노)메틸렌]-1H-1,2,3-트라이아졸로[4,5-b]피리디늄 3-옥사이드 헥사플루오로포스페이트(HATU, 0.091 g, 0.240 mmol) 그리고 N,N-다이아이소프로필에틸아민(0.070 mL, 0.399 mmol)을 실온에서 N,N-다이메틸폼아마이드(1 mL)에 녹인 용액에 2-아미노아세트아마이드 (2-4a) (0.018 g, 0.240 mmol)를 가하고 같은 온도에서 30 분 동안 교반하였다. 반응 혼합물에 물을 붓고 에틸 아세테이트로 추출하였다. 유기층을 1N-염산 수용액, 정제수 순서로 씻어주고 무수 황산 마그네슘으로 수분을 제거한 후 여과하여 감압 하에서 농축하였다. 농축물을 컬럼 크로마토그래피법(SiO2, 5 g 카트리지; 메탄올/다이클로로메테인 = 5 %)으로 정제 및 농축하여 N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드(0.080 g, 71.9 %)를 흰색고체 형태로 얻었다.2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3a) (0.100 g, 0.200 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.091 g, 0.240 mmol) and 2-aminoacetamide (2-4a) (0.018) in a solution of N,N-diisopropylethylamine (0.070 mL, 0.399 mmol) in N,N-dimethylformamide (1 mL) at room temperature g, 0.240 mmol) and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 5 g cartridge; methanol/dichloromethane = 5 %) and concentrated to N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl )-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (0.080 g, 71.9 %) was obtained as a white solid. .
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.72 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 (2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 557.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.72 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 ( 2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 557.8 (M + +1).
실시예 2Example 2
N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 557.7 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 557.7 (M + +1).
실시예 3Example 3
N-(4-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.71 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 557.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.71 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64 7.75 (4H, m); LRMS (ESI) m/z 557.9 (M + +1).
실시예 4Example 4
N-(2-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3a)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3a) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 (2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 571.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 (2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 571.9 (M + +1).
실시예 5Example 5
N-(3-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.32 (3H, s), 2.36 (2H, t, J = 7.0 Hz), 3.42-3.47 (2H, m), 6.85 (s, 1H), 7.33-7.40 (10H, m), 8.31 (1H, s), 8.44-8.47 (2H, m), 10.31 (1H, s); LRMS (ESI) m/z 571.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.32 (3H, s), 2.36 (2H, t, J = 7.0 Hz), 3.42-3.47 (2H, m), 6.85 (s, 1H) , 7.33-7.40 (10H, m), 8.31 (1H, s), 8.44-8.47 (2H, m), 10.31 (1H, s); LRMS (ESI) m/z 571.9 (M + +1).
실시예 6Example 6
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 2.35 (2H, t, J = 7.0 Hz), 3.42-3.45 (2H, br m), 6.85 (1H, s), 7.27-7.94 (12H, m), 8.42 (1H, br s), 10.40 (1H, s); LRMS (ESI) m/z 571.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (3H, s), 2.35 (2H, t, J = 7.0 Hz), 3.42-3.45 (2H, br m), 6.85 (1H, s) ), 7.27-7.94 (12H, m), 8.42 (1H, br s), 10.40 (1H, s); LRMS (ESI) m/z 571.9 (M + +1).
실시예 7Example 7
(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b) (0.150 g, 0.300 mmol), 1-[비스(다이메틸아미노)메틸렌]-1H-1,2,3-트라이아졸로[4,5-b]피리디늄 3-옥사이드 헥사플루오로포스페이트(HATU, 0.137 g, 0.359 mmol) 그리고 N,N-다이아이소프로필에틸아민(0.104 mL, 0.599 mmol)을 실온에서 N,N-다이메틸폼아마이드(1 mL)에 녹인 용액에 메틸 글리시네이트(0.032 g, 0.359 mmol)를 가하고 같은 온도에서 30 분 동안 교반하였다. 반응 혼합물에 물을 붓고 에틸 아세테이트로 추출하였다. 유기층을 1N-염산 수용액으로 씻어주고 무수 황산 마그네슘으로 수분을 제거한 후 여과하여 감압 하에서 농축한 후 수산화 리튬(0.014 g, 0.583 mmol)을 실온에서 테트라하이드로퓨란(0.3 mL)/메탄올(0.1 mL)/물(0.1 mL)에 녹인 용액을 첨가하고 상온에서 12 시간 동안 교반하였다. 반응 혼합물을 감압 하에서 용매를 제거하여 얻어진 농축물에 물을 붓고 에틸 아세테이트로 추출하였다. 유기층을 1N-염산 수용액, 정제수의 순서로 씻어주고 무수 황산 마그네슘으로 수분을 제거한 후 여과한 후 감압하에서 농축하였다. 농축물을 컬럼 크로마토그래피법(SiO2, 5 g 카트리지; 메탄올/다이클로로메테인 = 5 %)으로 정제 및 농축하여 (3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신 (0.08 g, 48%)를 미황색 고체 형태로 얻었다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) (0.150 g, 0.300 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.137 g, 0.359) mmol) and methyl glycinate (0.032 g, 0.359 mmol) in a solution of N,N-diisopropylethylamine (0.104 mL, 0.599 mmol) in N,N-dimethylformamide (1 mL) at room temperature. and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Lithium hydroxide (0.014 g, 0.583 mmol) was added to tetrahydrofuran (0.3 mL)/methanol (0.1 mL)/ A solution in water (0.1 mL) was added and stirred at room temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 5 g cartridge; methanol/dichloromethane = 5 %) and concentrated (3-(5-(4-chlorophenyl)-1-(2,4-) Dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine (0.08 g, 48%) was obtained in the form of a pale yellow solid.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.74 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 558.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.74 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 558.8 (M + +1).
실시예 8Example 8
(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 메틸 글리시네이트 (2-4b)를 사용하여 상기 (실시예 7)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and methyl glycy It was prepared analogously to the process described above (Example 7) using nate (2-4b).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.42-7.53 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 558.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.42-753 (4H, m), 7.64 7.75 (4H, m); LRMS (ESI) m/z 558.8 (M + +1).
실시예 9Example 9
3-(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 메틸 3-아미노프로파노에이트 (2-4f)를 사용하여 상기 (실시예 7)에서 기술된 공정과 유사하게 제조하였다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and methyl 3- Prepared analogously to the process described above (Example 7) using aminopropanoate (2-4f).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.42 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.81 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.42 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.81 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 572.8 (M + +1).
실시예 10Example 10
3-(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 3-아미노프로파노에이트 (2-4f)를 사용하여 상기 (실시예 7)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 3-amino Prepared analogously to the process described above (Example 7) using propanoate (2-4f).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.38 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.38 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 572.8 (M + +1).
실시예 11Example 11
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 - Carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 2-아미노에테인-1-설폰아마이드 (2-4d)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 2-amino Prepared similarly to the process described above (Example 1) using ethane-1-sulfonamide (2-4d).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 3.25 (2H, t, J = 7.2 Hz), 3.63-3.66 (2H, m), 6.97 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.40-7.93 (8H, m), 8.34 (1H, s), 8.59-8.62 (1H, m), 10.34 (1H, s); LRMS (ESI) m/z 607.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (3H, s), 3.25 (2H, t, J = 7.2 Hz), 3.63-3.66 (2H, m), 6.97 (2H, s) , 7.28 (2H, d, J = 8.4 Hz), 7.40-7.93 (8H, m), 8.34 (1H, s), 8.59-8.62 (1H, m), 10.34 (1H, s); LRMS (ESI) m/z 607.9 (M + +1).
실시예 12Example 12
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 - Carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 2-아미노에테인-1-설폰아마이드 (2-4d)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 2-amino Prepared similarly to the process described above (Example 1) using ethane-1-sulfonamide (2-4d).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 3.38 (2H, t, J = 6.3 Hz), 3.52 (2H, t, J = 6.3 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 607.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 3.38 (2H, t, J = 6.3 Hz), 3.52 (2H, t, J = 6.3 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 607.9 (M + +1).
실시예 13Example 13
(S)-N-(3-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 (S)-피롤리딘-2-카복스아마이드 (2-4c)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and (S) -Pyrrolidine-2-carboxamide (2-4c) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 1.83-2.18 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 16.1, 5.4, 1.4 Hz), 3.59 (1H, ddd, J = 16.1, 9.3, 5.6 Hz), 4.05 (1H, dd, J = 6.9, 1.8 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.75 (4H, m), 7.79 (1H, m), 8.30 (1H, m); LRMS (ESI) m/z 597.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.83-2.18 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 16.1, 5.4, 1.4 Hz), 3.59 ( 1H, ddd, J = 16.1, 9.3, 5.6 Hz), 4.05 (1H, dd, J = 6.9, 1.8 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.75 ( 4H, m), 7.79 (1H, m), 8.30 (1H, m); LRMS (ESI) m/z 597.9 (M + +1).
실시예 14Example 14
(S)-N-(4-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 (S)-피롤리딘-2-카복스아마이드 (2-4c)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and (S) -Pyrrolidine-2-carboxamide (2-4c) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 1.82-2.20 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 15.1, 5.4, 1.4 Hz), 3.56 (1H, ddd, J = 15.1, 9.3, 5.6 Hz), 4.26 (1H, dd, J = 7.4, 7.1 Hz), 7.33-7.40 (3H, m), 7.46 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.64-7.75 (4H, m); LRMS (ESI) m/z 597.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.82-2.20 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 15.1, 5.4, 1.4 Hz), 3.56 ( 1H, ddd, J = 15.1, 9.3, 5.6 Hz), 4.26 (1H, dd, J = 7.4, 7.1 Hz), 7.33-7.40 (3H, m), 7.46 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.64-7.75 (4H, m); LRMS (ESI) m/z 597.9 (M + +1).
실시예 15Example 15
N-(2-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3a)와 (1,2,4-옥사다이아졸-3-일)메탄아민 (2-4k)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3a) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 (2H, m), 7.64-7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 ( 2H, m), 7.64-7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M + +1).
실시예 16Example 16
N-(3-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 (1,2,4-옥사다이아졸-3-일)메탄아민 (2-4k)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3b) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 4.59 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.82 (5H, m), 8.29 (1H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 4.59 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M + +1).
실시예 17Example 17
N-(4-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 (1,2,4-옥사다이아졸-3-일)메탄아민 (2-4k)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3c) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64-7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64 7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M + +1).
실시예 18Example 18
N-(3-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 (1,3,4-옥사다이아졸-2-일)메탄아민 (2-4j)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3b) and (1, Prepared similarly to the process described above (Example 1) using 3,4-oxadiazol-2-yl)methanamine (2-4j).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 4.71 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.82 (5H, m), 8.29 (1H, m), 8.45 (1H, s); LRMS (ESI) m/z 582.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 4.71 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m), 8.45 (1H, s); LRMS (ESI) m/z 582.8 (M + +1).
실시예 19Example 19
N-(4-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 (1,3,4-옥사다이아졸-2-일)메탄아민 (2-4j)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3c) and (1, Prepared similarly to the process described above (Example 1) using 3,4-oxadiazol-2-yl)methanamine (2-4j).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 4.19 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.58-7.63 (3H, m), 7.80-7.83 (2H, m), 8.02 (2H, d, J = 8.4 Hz), 10.56 (1H, s), 10.99 (1H, s); LRMS (ESI) m/z 582.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (3H, s), 4.19 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.58-7.63 (3H, m), 7.80-7.83 (2H, m), 8.02 (2H, d, J = 8.4 Hz), 10.56 (1H, s), 10.99 ( 1H, s); LRMS (ESI) m/z 582.8 (M + +1).
실시예 20Example 20
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3b)와 5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-아민 (2-4h)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 5-( Prepared analogously to the process described above (Example 1) using trifluoromethyl)-1,2,4-oxadiazol-3-amine (2-4h).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 7.28 (2H, d, J = 8.4 Hz), 7.43-7.68 (4H, m), 7.81-7.84 (2H, m), 8.03 (1H, d, J = 10.0 Hz), 8.53 (1H, d, J = 8.4 Hz), 8.56 (1H, s), 8.75 (1H, d, J = 4.0 Hz), 10.43 91H, s); LRMS (ESI) m/z 636.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (3H, s), 7.28 (2H, d, J = 8.4 Hz), 7.43-7.68 (4H, m), 7.81-7.84 (2H, m), 8.03 (1H, d, J = 10.0 Hz), 8.53 (1H, d, J = 8.4 Hz), 8.56 (1H, s), 8.75 (1H, d, J = 4.0 Hz), 10.43 91H, s ); LRMS (ESI) m/z 636.8 (M + +1).
실시예 21Example 21
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-아민 (2-4h)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 5-( Prepared analogously to the process described above (Example 1) using trifluoromethyl)-1,2,4-oxadiazol-3-amine (2-4h).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.39 (3H, s), 7.29-7.87 (8H, m), 8.24-8.30 (2H, m), 8.76 (1H, s), 8.86 (1H, s); LRMS (ESI) m/z 636.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (3H, s), 7.29-7.87 (8H, m), 8.24-8.30 (2H, m), 8.76 (1H, s), 8.86 ( 1H, s); LRMS (ESI) m/z 636.8 (M + +1).
실시예 22Example 22
5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3c)와 5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-아민 (2-4g)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 5-( Prepared similarly to the process described above (Example 1) using trifluoromethyl)-1,3,4-oxadiazol-2-amine (2-4 g).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.48 (3H, s), 7.33-7.40 (3H, m), 7.48 (2H, m), 7.56 (2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 636.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (3H, s), 7.33-7.40 (3H, m), 7.48 (2H, m), 7.56 (2H, m), 7.64-7.75 ( 4H, m); LRMS (ESI) m/z 636.8 (M + +1).
실시예 23Example 23
N-(3-아미노-3-옥소프로필)-6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴산 (2-3d)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3d) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.40 (2H, t, J = 6.5 Hz), 6.97 (1H, dd, J = 7.7, 0.5 Hz), 7.33-7.40 (3H, m), 7.64-7.80 (5H, m), 8.56 (1H, dd, J = 1.8, 0.5 Hz); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.40 (2H, t, J = 6.5 Hz), 6.97 (1H) , dd, J = 7.7, 0.5 Hz), 7.33-7.40 (3H, m), 7.64-7.80 (5H, m), 8.56 (1H, dd, J = 1.8, 0.5 Hz); LRMS (ESI) m/z 572.8 (M + +1).
실시예 24Example 24
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산산 (2-3e)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinic acid (2-3e) and 3 -Aminopropanamide (2-4e) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.59-7.75 (5H, m), 7.89 (1H, d, J = 8.9 Hz), 8.47 (1H, d, J = 1.8 Hz); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.59-7.75 (5H, m), 7.89 (1H, d, J = 8.9 Hz), 8.47 (1H, d, J = 1.8 Hz); LRMS (ESI) m/z 572.8 (M + +1).
실시예 25Example 25
N-(4-((3-아미노-3-옥소프로필)카바모일)-3-클로로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
2-클로로-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3g)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3 g) and 3-aminopropanamide (2-4e) were prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.04 (1H, dd, J = 8.2, 1.2 Hz), 7.33-7.40 (3H, m), 7.60 (1H, d, J = 1.2 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2 Hz); LRMS (ESI) m/z 606.3(M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.04 (1H) , dd, J = 8.2, 1.2 Hz), 7.33-7.40 (3H, m), 7.60 (1H, d, J = 1.2 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2) Hz); LRMS (ESI) m/z 606.3 (M + +1).
실시예 26Example 26
N-(4-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-3-플루오로벤조산 (2-3h)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoic acid (2-3h ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 6.98 (1H, d, J = 8.2 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (4H, m), 7.85 (1H, dd, J = 8.2, 1.8 Hz), 7.96 (1H, d, J = 1.8 Hz); LRMS (ESI) m/z 589.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 6.98 (1H) , d, J = 8.2 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (4H, m), 7.85 (1H, dd, J = 8.2, 1.8 Hz), 7.96 (1H, d, J = 1.8) Hz); LRMS (ESI) m/z 589.8 (M + +1).
실시예 27Example 27
N-(4-((3-아미노-3-옥소프로필)카바모일)-3-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조산 (2-3i)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid (2-3i ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.28 (1H, dd, J = 8.2, 1.5 Hz), 7.33-7.40 (3H, m), 7.45 (1H, d, J = 1.5 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2 Hz); LRMS (ESI) m/z 589.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.28 (1H) , dd, J = 8.2, 1.5 Hz), 7.33-7.40 (3H, m), 7.45 (1H, d, J = 1.5 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2) Hz); LRMS (ESI) m/z 589.8 (M + +1).
실시예 28Example 28
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복스아마이드N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복실산 (2-3f)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylic acid (2-3f) and 3-aminopropanamide (2-4e) were prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (t, 3H, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.76 (4H, m), 8.73 (1H, s), 9.09 (1H, s); LRMS (ESI) m/z 573.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (t, 3H, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.76 (4H, m), 8.73 (1H, s), 9.09 (1H, s); LRMS (ESI) m/z 573.8 (M + +1).
실시예 29Example 29
N-(3-아미노-3-옥소프로필)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide
2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴산 (2-3j)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid (2-3j) and 3- Prepared analogously to the process described above (Example 1) using aminopropanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.58 (1H, dd, J = 4.7, 1.5 Hz), 7.64-7.75 (5H, m), 8.43 (1H, d, J = 4.7 Hz); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.58 (1H, dd, J = 4.7, 1.5 Hz), 7.64-7.75 (5H, m), 8.43 (1H, d, J = 4.7 Hz); LRMS (ESI) m/z 572.8 (M + +1).
실시예 30Example 30
N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴산 (2-3k)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3k) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.38 (2H, t, J = 7.2 Hz), 2.33 (3H, s), 3.05 (2H, br), 6.87 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 7.39 (1H, s), 7.50 (2H, d, J = 8.8 Hz), 7.62-7.86 (3H, m), 8.73-8.75 (3H, m), 9.09 (1H, s), 10.69 (1H, s); LRMS (ESI) m/z 572.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.38 (2H, t, J = 7.2 Hz), 2.33 (3H, s), 3.05 (2H, br), 6.87 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 7.39 (1H, s), 7.50 (2H, d, J = 8.8 Hz), 7.62-7.86 (3H, m), 8.73-8.75 (3H, m), 9.09 ( 1H, s), 10.69 (1H, s); LRMS (ESI) m/z 572.8 (M + +1).
실시예 31Example 31
N-(3-아미노-3-옥소프로필)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산 (2-3l)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid (2-3l) and 3 -Aminopropanamide (2-4e) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.42 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (5H, m), 8.02 (1H, dd, J = 5.1, 1.9 Hz), 8.57 (1H, d, J = 5.1 Hz) ; LRMS (ESI) m/z 572.8(M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.42 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (5H, m), 8.02 (1H, dd, J = 5.1, 1.9 Hz), 8.57 (1H, d, J = 5.1 Hz); LRMS (ESI) m/z 572.8 (M + +1).
실시예 32Example 32
N-(5-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-4-플루오로벤조산 (2-3m)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoic acid (2-3m ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.33-7.40 (3H, m), 7.62-7.75 (5H, m), 8.29 (1H, d, J = 1.9 Hz); LRMS (ESI) m/z 589.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.30 (1H) , d, J = 8.8 Hz), 7.33-7.40 (3H, m), 7.62-7.75 (5H, m), 8.29 (1H, d, J = 1.9 Hz); LRMS (ESI) m/z 589.8 (M + +1).
실시예 33Example 33
N-(3-((3-아미노-3-옥소프로필)카바모일)-5-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-5-플루오로벤조산 (2-3n)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoic acid (2-3n ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.38 (2H, t, J = 6.5 Hz), 7.21 (1H, dd, J = 1.8, 1.6 Hz), 7.33-7.40 (3H, m), 7.64-7.77 (5H, m), 8.14 (1H, dd, J = 1.8, 1.3 Hz); LRMS (ESI) m/z 589.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.38 (2H, t, J = 6.5 Hz), 7.21 (1H) , dd, J = 1.8, 1.6 Hz), 7.33-7.40 (3H, m), 7.64-7.77 (5H, m), 8.14 (1H, dd, J = 1.8, 1.3 Hz); LRMS (ESI) m/z 589.8 (M + +1).
실시예 34Example 34
N-(3-((3-아미노-3-옥소프로필)카바모일)-4-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)-2-플루오로벤조산 (2-3o)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다.5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid (2-3o ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.33-7.40 (3H, m), 7.44 (1H, dd, J = 8.5, 1.5 Hz), 7.64-7.75 (4H, m), 8.28 (1H, d, J = 1.5 Hz); LRMS (ESI) m/z 589.8 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.29 (1H) , d, J = 8.5 Hz), 7.33-7.40 (3H, m), 7.44 (1H, dd, J = 8.5, 1.5 Hz), 7.64-7.75 (4H, m), 8.28 (1H, d, J = 1.5) Hz); LRMS (ESI) m/z 589.8 (M + +1).
실시예 35Example 35
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide
4-(1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아미도)벤조산 (2-3p)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4- (1- (4-chlorophenyl) -4-methyl-5-phenyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3p) and 3-aminopropanamide (2-4e) It was prepared similarly to the process described above (Example 1) using
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.58 (7H, m), 7.66-7.85 (6H, m); LRMS (ESI) m/z 503.0 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.58 (7H, m), 7.66-7.85 (6H, m); LRMS (ESI) m/z 503.0 (M + +1).
실시예 36Example 36
N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아마이드N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-Carboxamide
4-(1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조산 (2-3q)와 3-아미노프로판아마이드 (2-4e)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3q) with 3-aminopropanamide (2-4e) was prepared similarly to the process described in (Example 1) above.
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.45 (2H, t, J = 6.5 Hz), 2.52 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.60 (5H, m), 7.59-7.68 (3H, m), 7.72 (1H, ddd, J = 8.1, 1.8, 1.4 Hz), 7.82 (2H, m), 8.11 (1H, dd, J = 1.9, 1.8 Hz); LRMS (ESI) m/z 528.0 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (2H, t, J = 6.5 Hz), 2.52 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.60 (5H, m), 7.59-7.68 (3H, m), 7.72 (1H, ddd, J = 8.1, 1.8, 1.4 Hz), 7.82 (2H, m), 8.11 (1H, dd, J = 1.9, 1.8 Hz) ); LRMS (ESI) m/z 528.0 (M + +1).
실시예 37Example 37
N-(2-아미노-2-옥소에틸)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide
2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴산 (2-3j)와 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid (2-3j) and 2- It was prepared similarly to the process described above (Example 1) using aminoacetamide (2-4a).
분광학 데이터: 분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.51 (3H, s), 3.73 (2H, t, J = 6.2 Hz), 7.23 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.53 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.67-7.77 (3H, m), 8.43 (2H, d, J = 7.2 Hz), 8.91 (1H, m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M++1).Spectroscopy data: Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (3H, s), 3.73 (2H, t, J = 6.2 Hz), 7.23 (1H, s), 7.45 (2H, d) , J = 8.4 Hz), 7.53 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.67-7.77 (3H, m), 8.43 (2H, d, J = 7.2 Hz), 8.91 (1H) , m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M + +1).
실시예 38Example 38
N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴산 (2-3k)와 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3k) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.33 (3H, s), 3.85 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.62-7.86 (3H, m), 8.78 (2H, d, J = 7.2 Hz), 8.91 (1H, t, J = 5.6 Hz), 9.10 (1H, d, J = 2.0 Hz), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.33 (3H, s), 3.85 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.62-7.86 (3H, m), 8.78 (2H, d, J = 7.2 Hz), 8.91 (1H, t, J = 5.6 Hz), 9.10 (1H, d, J = 2.0 Hz), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M + +1).
실시예 39Example 39
N-(2-아미노-2-옥소에틸)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산 (2-3l)과 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid (2-3l) and 2 -Aminoacetamide (2-4a) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.51 (3H, s), 3.74 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.22 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.61-7.83 (5H, m), 8.57 (2H, d, J = 7.2 Hz), 8.91 (1H, m), 9.12 (1H, d, J = 2.0 Hz), 10.5 (1H, s); LRMS (ESI) m/z 557.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (3H, s), 3.74 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.22 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.61-7.83 (5H, m), 8.57 (2H, d, J = 7.2 Hz), 8.91 (1H, m), 9.12 (1H, d, J = 2.0 Hz) , 10.5 (1H, s); LRMS (ESI) m/z 557.9 (M + +1).
실시예 40Example 40
N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린산 (2-3e)와 2-아미노아세트아마이드 (2-4a)를 사용하여 상기 (실시예 1)에서 기술된 공정과 유사하게 제조하였다. 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinic acid (2-3e) and 2 -Aminoacetamide (2-4a) was prepared similarly to the process described above (Example 1).
분광학 데이터: 1H NMR (400 MHz, DMSO-d6) δ 2.50 (3H, s), 3.73 (2H, t, J = 5.8 Hz), 7.09 (1H, s), 7.39 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.60-7.95 (4H, m), 8.78-8.91 (3H, m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M++1).Spectroscopy data: 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (3H, s), 3.73 (2H, t, J = 5.8 Hz), 7.09 (1H, s), 7.39 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.60-7.95 (4H, m), 8.78-8.91 (3H, m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M + +1).
상기 실시예 1 내지 40 화합물을 정리하면 하기 표 4와 같다.The compounds of Examples 1 to 40 are summarized in Table 4 below.
실시예Example IUPAC 명명 및 구조식IUPAC Naming and Structural Formula 중간체intermediate
1One N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000110
N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000110
 		2-3a2-3a
22 N-(3-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000111
N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000111
 		2-3b2-3b
33 N-(4-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000112
N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000112
 		2-3c2-3c
44 N-(2-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000113
N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000113
 		2-3a2-3a
55 N-(3-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000114
N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000114
 		2-3b2-3b
66 N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000115
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide
Figure PCTKR2022001522-appb-img-000115
 		2-3c2-3c
77 (3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신
Figure PCTKR2022001522-appb-img-000116
(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine
Figure PCTKR2022001522-appb-img-000116
 		2-3b2-3b
88 (4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신
Figure PCTKR2022001522-appb-img-000117
(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine
Figure PCTKR2022001522-appb-img-000117
 		2-3c2-3c
99 3-(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산
Figure PCTKR2022001522-appb-img-000118
3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid
Figure PCTKR2022001522-appb-img-000118
 		2-3b2-3b
1010 3-(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산
Figure PCTKR2022001522-appb-img-000119
3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid
Figure PCTKR2022001522-appb-img-000119
 		2-3c2-3c
1111 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000120
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -Carboxamide
Figure PCTKR2022001522-appb-img-000120
 		2-3b2-3b
1212 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000121
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -Carboxamide
Figure PCTKR2022001522-appb-img-000121
 		2-3c2-3c
1313 (S)-N-(3-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000122
(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000122
 		2-3b2-3b
1414 (S)-N-(4-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000123
(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000123
 		2-3c2-3c
1515 N-(2-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000124
N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000124
 		2-3a2-3a
1616 N-(3-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000125
N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000125
 		2-3b2-3b
1717 N-(4-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000126
N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000126
 		2-3c2-3c
1818 N-(3-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000127
N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000127
 		2-3b2-3b
1919 N-(4-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000128
N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000128
 		2-3c2-3c
2020 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000129
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000129
 		2-3b2-3b
2121 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000130
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000130
 		2-3c2-3c
2222 5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000131
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000131
 		2-3c2-3c
2323 N-(3-아미노-3-옥소프로필)-6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드
Figure PCTKR2022001522-appb-img-000132
N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
Figure PCTKR2022001522-appb-img-000132
 		2-3d2-3d
2424 N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드
Figure PCTKR2022001522-appb-img-000133
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
Figure PCTKR2022001522-appb-img-000133
 		2-3e2-3e
2525 N-(4-((3-아미노-3-옥소프로필)카바모일)-3-클로로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000134
N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000134
 		2-3g2-3g
2626 N-(4-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000135
N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000135
 		2-3h2-3h
2727 N-(4-((3-아미노-3-옥소프로필)카바모일)-3-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000136
N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000136
 		2-3i2-3i
2828 N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복스아마이드
Figure PCTKR2022001522-appb-img-000137
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide
Figure PCTKR2022001522-appb-img-000137
 		2-3f2-3f
2929 N-(3-아미노-3-옥소프로필)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드
Figure PCTKR2022001522-appb-img-000138
N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide
Figure PCTKR2022001522-appb-img-000138
 		2-3j2-3j
3030 N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드
Figure PCTKR2022001522-appb-img-000139
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
Figure PCTKR2022001522-appb-img-000139
 		2-3k2-3k
3131 N-(3-아미노-3-옥소프로필)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드
Figure PCTKR2022001522-appb-img-000140
N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
Figure PCTKR2022001522-appb-img-000140
 		2-3l2-3l
3232 N-(5-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000141
N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000141
 		2-3m2-3m
3333 N-(3-((3-아미노-3-옥소프로필)카바모일)-5-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000142
N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000142
 		2-3n2-3n
3434 N-(3-((3-아미노-3-옥소프로필)카바모일)-4-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000143
N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000143
 		2-3o2-3o
3535 N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000144
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide
Figure PCTKR2022001522-appb-img-000144
 		2-3p2-3p
3636 N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아마이드
Figure PCTKR2022001522-appb-img-000145
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-Carboxamide
Figure PCTKR2022001522-appb-img-000145
 		2-3q2-3q
3737 N-(2-아미노-2-옥소에틸)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드
Figure PCTKR2022001522-appb-img-000146
N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide
Figure PCTKR2022001522-appb-img-000146
 		2-3j2-3j
3838 N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드
Figure PCTKR2022001522-appb-img-000147
N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide
Figure PCTKR2022001522-appb-img-000147
 		2-3k2-3k
3939 N-(2-아미노-2-옥소에틸)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드
Figure PCTKR2022001522-appb-img-000148
N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
Figure PCTKR2022001522-appb-img-000148
 		2-3l2-3l
4040 N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드
Figure PCTKR2022001522-appb-img-000149
N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide
Figure PCTKR2022001522-appb-img-000149
 		2-3e2-3e
실험예 1. 분자도킹 모의실험을 이용한 구조기반 가상 스크리닝Experimental Example 1. Structure-based virtual screening using molecular docking simulation
합성 후보 물질에서 CB1 타겟을 저해하는 화합물을 효율적으로 선별하기 위해 분자모델링 기술을 적용하였다. 컴퓨터 시뮬레이션은 크게 두 가지 기준으로 적용할 수 있는데 타겟 단백질 3차 결정구조가 밝혀져 있는 경우 단백질의 3차원 구조를 이용하는 SBDD(Structure-Based Drug Design)와 리간드의 구조만을 알고 있을 때 적용할 수 있는 LBDD(Ligand-Based Drug Design)가 있다. Molecular modeling technology was applied to efficiently select compounds that inhibit the CB1 target from synthetic candidates. Computer simulation can be applied according to two main criteria. SBDD (Structure-Based Drug Design), which uses the three-dimensional structure of the protein when the tertiary crystal structure of the target protein is known, and LBDD, which can be applied when only the structure of the ligand is known. (Ligand-Based Drug Design).
CB1 타겟 단백질의 x-ray 결정구조가 밝혀져 있으므로 단백질 구조 기반의 방법(SBDD)인 분자도킹 모의 실험을 통해 합성 후보 물질 102종을 평가하였다. Since the x-ray crystal structure of the CB1 target protein has been elucidated, 102 synthetic candidates were evaluated through molecular docking simulation, a protein structure-based method (SBDD).
(1) 단백질 및 리간드 준비(1) Protein and Ligand Preparation
CB1 타겟 단백질의 x-ray 3차 결정구조(PDB code:　5U09）를 Protein Data Bank(https://www.rcsb.org)로부터 얻었다. 단백질 준비과정을 위해 Discovery Studio 프로그램(DASSAULT SYSTEMS)을 이용하여 단백질의 용매 분자가 제거되었고, pH 7.4에서 단백질 잔기의 양성자화(protonation)가 계산된 구조를 얻었다. 리간드는 pH 6.5 ~ 8.5 기반으로 이온화(ionization) 상태가 계산된 구조를 얻었다.The x-ray tertiary crystal structure (PDB code: 　5U09) of the CB1 target protein was obtained from the Protein Data Bank (https://www.rcsb.org) For the protein preparation process, the Discovery Studio program (DASSAULT SYSTEMS) was used. The solvent molecules of the protein were removed, and a structure was obtained in which the protonation of the protein residue was calculated at pH 7.4, and a structure in which the ionization state was calculated based on pH 6.5 to 8.5 of the ligand.
도 1은 CB1 단백질과 CB1 억제제로 알려진 Taranabant(inverse agonist)의 상호작용에 대한 분석결과로 Ser123, Ser383와 수소 결합을 형성하며, 강력한 소수성 포켓(Met103, Asp104, Ile105, Ile119, Phe170, Val196, Trp279, Trp356, Ala380, Met384, Cys386)을 형성하는 것으로 확인된다.1 is an analysis result of the interaction of CB1 protein with Taranabant (inverse agonist) known as a CB1 inhibitor, forming hydrogen bonds with Ser123 and Ser383, and forming strong hydrophobic pockets (Met103, Asp104, Ile105, Ile119, Phe170, Val196, Trp279). , Trp356, Ala380, Met384, Cys386).
(2) 단백질-리간드 도킹(2) protein-ligand docking
합성 후보 물질 102종 화합물을 Discovery Studio 도킹 프로그램을 이용하여 단백질 분자와 리간드의 결합 형태를 분석하였다. 도킹 에너지 스코어 및 육안 선별(Visual Inspection)로 분석하여 최종 실시예 화합물 40종을 발굴하였다. Synthetic candidates 102 compounds were analyzed for binding forms between protein molecules and ligands using the Discovery Studio docking program. 40 kinds of final example compounds were discovered by analysis by docking energy score and visual inspection.
도 2는 합성 후보 물질 102종에 대한 도킹 에너지 스코어 결과를 산점도 (Scatter plot)로 나타낸 것이다. '- CDOCKER_INTERACTION_ENERGY'는 단백질-리간드 결합 에너지를 의미하며, kcal/mol 단위로 계산된다. 'LigScore2'는 단백질-리간드 결합 친화도를 의미하며, pKi(-log Ki) 단위로 계산된다.2 is a scatter plot showing docking energy score results for 102 synthetic candidate materials. '- CDOCKER_INTERACTION_ENERGY' means protein-ligand binding energy and is calculated in kcal/mol units. 'LigScore2' means protein-ligand binding affinity, and is calculated in pKi (-log Ki).
하기 표 5에 CADD(Computer-Aided Drug Design) 기술을 응용해 선별된 화합물에 대한 단백질-리간드 결합에너지(-CDOCKER_INTERACTION_ENERGY) 및 단백질-리간드 결합 친화도(LigScore2)를 나타내었다.Table 5 below shows the protein-ligand binding energy (-CDOCKER_INTERACTION_ENERGY) and protein-ligand binding affinity (LigScore2) for the compounds selected by applying the CADD (Computer-Aided Drug Design) technology.
실시예Example LigScore2 (pKi)LigScore2 (pKi) -CDOCKER INTERACTION ENERGY
(kcal/mol)-CDOCKER INTERACTION ENERGY
(kcal/mol)
1One 7.667.66 64.4464.44
22 7.507.50 66.7166.71
33 7.257.25 61.2161.21
44 7.377.37 67.5167.51
55 7.617.61 68.0468.04
66 7.537.53 62.9962.99
77 6.986.98 54.0054.00
88 6.846.84 55.0555.05
99 6.876.87 56.0256.02
1010 7.287.28 58.6158.61
1111 7.637.63 64.2864.28
1212 7.517.51 61.1261.12
1313 6.366.36 45.5345.53
1414 4.884.88 28.9928.99
1515 7.627.62 61.6861.68
1616 7.227.22 54.9354.93
1717 7.247.24 60.3860.38
1818 7.197.19 55.0055.00
1919 7.757.75 64.8964.89
2020 7.657.65 65.1465.14
2121 7.537.53 62.0162.01
2222 7.677.67 64.2564.25
2323 5.815.81 43.5743.57
2424 7.147.14 56.1056.10
2525 6.806.80 56.2356.23
2626 7.127.12 56.2056.20
2727 6.956.95 57.4757.47
2828 7.147.14 56.9956.99
2929 7.317.31 57.9857.98
3030 7.527.52 57.8057.80
3131 7.327.32 59.8659.86
3232 6.966.96 63.6463.64
3333 7.047.04 62.9962.99
3434 6.816.81 61.3561.35
3535 6.876.87 58.0358.03
3636 6.786.78 57.6057.60
3737 6.476.47 54.9954.99
3838 6.606.60 57.0257.02
3939 7.227.22 59.0259.02
4040 6.856.85 57.1457.14
실험예 2. 카나비노이드 수용체 1에 대한 억제활성 평가Experimental Example 2. Evaluation of inhibitory activity on cannabinoid receptor 1
실시예 화합물의 카나비노이드 수용체 1 (Cannabinoid receptor 1; CB1)에 대한 억제활성을 평가하기 위해, 기존 개발물질인 Rimonabant를 대조군으로 하여 cAMP ELISA assay를 실시하였다.In order to evaluate the inhibitory activity of the example compound on cannabinoid receptor 1 (CB1), a cAMP ELISA assay was performed using Rimonabant, an existing developed material, as a control.
구체적으로, CHO-GLP1R-CB1R 세포는 5 % CO2 37 ℃ 환경에서 10 % 우태아 소 혈청 (fetal bovine serum, FBS)과 1% 항생제를 포함하는 DMEM 배지에서 하루동안 배양되었다. 다음날, FBS가 없는 배지에서 세포를 30분 동안 배양하고, DMSO에 녹인 CB1 억제제 화합물(실시예 1 내지 40의 화합물 중 어느 하나를 포함)을 첨가하여 30분동안 반응시켰다 [화합물 최종 농도(μM): 0.1, 1, 2.5, 5, 10, 20]. 10uM의 forskolin 및 10nM CP55,940을 세포에 첨가하고 1시간동안 배양하였다. 용액을 제거한 후 PBS 및 0.1M HCl을 첨가하여 세포를 3회 세척하였다. 세포추출물은 원심분리를 하여 100uL의 상층액을 사용하였다. Direct cAMP ELISA kit (Enzo Life Sciences, Lausen, Switzerland; Catalog # ADI-900-066)를 사용하여 cAMP를 측정하였다. 흡광도는　ELISA reader를 이용하여 405 nm 파장에서 측정하였다.Specifically, CHO-GLP1R-CB1R cells were cultured for one day in DMEM medium containing 10% fetal bovine serum (FBS) and 1% antibiotics in an environment of 5% CO 2 37 °C. The next day, the cells were cultured in a medium without FBS for 30 minutes, and a CB1 inhibitor compound (including any one of the compounds of Examples 1 to 40) dissolved in DMSO was added and reacted for 30 minutes [compound final concentration (μM)) : 0.1, 1, 2.5, 5, 10, 20]. 10 uM forskolin and 10 nM CP55,940 were added to the cells and incubated for 1 hour. After removing the solution, PBS and 0.1M HCl were added to wash the cells 3 times. The cell extract was centrifuged and 100 uL of the supernatant was used. cAMP was measured using the Direct cAMP ELISA kit (Enzo Life Sciences, Lausen, Switzerland; Catalog # ADI-900-066). Absorbance was measured at 405 nm wavelength using an ELISA reader.
그 결과를 하기 표 6에 나타내었고, 화합물의 CB1 수용체 활성억제 효과는 IC50(μM)로 표시하였다.The results are shown in Table 6 below, and the CB1 receptor activity inhibitory effect of the compound was expressed as IC 50 (μM).
실시예Example IC50 (Rimonabant)IC50 (Rimonabant)
22 2.56 (1.08)2.56 (1.08)
33 1.13 (1.08)1.13 (1.08)
44 7.09 (1.08)7.09 (1.08)
55 5.6 (9.3)5.6 (9.3)
66 6.7 (9.3)6.7 (9.3)
77 0.52 (1.08)0.52 (1.08)
88 0.85 (1.08)0.85 (1.08)
99 0.49 (1.08)0.49 (1.08)
1010 0.48 (1.08)0.48 (1.08)
1212 1.12 (1.08)1.12 (1.08)
1313 0.48 (1.08)0.48 (1.08)
1414 0.66 (1.08)0.66 (1.08)
1616 1.25 (1.08)1.25 (1.08)
1717 10.4 (9.3)10.4 (9.3)
1818 2.55 (1.08)2.55 (1.08)
1919 2.9 (9.3)2.9 (9.3)
3737 1.56 (3.20)1.56 (3.20)
3838 3.54 (3.20)3.54 (3.20)
3939 4.25 (3.20)4.25 (3.20)
4040 2.75 (3.20)2.75 (3.20)
실험예 3. 간(liver) 마이크로솜 대사안정성 시험Experimental Example 3. Liver microsomal metabolic stability test
대사 안정성 시험은 인간(human) 간 마이크로솜 (UltraPool TM HLM 150, Corning®) 및 마우스(mouse) 간 마이크로솜 (CD-1 Mouse Pooled Liver Microsomes, Corning®)에서 평가되었다. 최종 반응 혼합물 중 마이크로솜이 0.2 mg/mL 단백질(protein) 농도가 되도록 반응 혼합물을 준비하고, 100 mM 포스페이트 완충액(pH 7.4), 1 mM NADPH 과 함께 37 ℃에서 5분간 사전 인큐베이션(pre-incubation)해 준 뒤 CB1 저해제 화합물(실시예 5, 6, 17, 19) 또는 리모나반트(Rimonabant)를 최종 1 μM 농도가 되도록 첨가하여 반응을 시작하였다. 양성 대조군(positive control)으로 베라파밀(Verapamil) 1 uM을 사용하였다. 반응 시작 후 0, 30분에 내부 표준(internal standard)이 포함된 반응정지액(stop solution, acetonitrile)을 첨가하여 반응을 종료하였다.Metabolic stability tests were evaluated in human liver microsomes (UltraPool™ HLM 150, Corning ® ) and mouse liver microsomes (CD-1 Mouse Pooled Liver Microsomes, Corning ® ). Prepare the reaction mixture so that the microsomes in the final reaction mixture have a concentration of 0.2 mg/mL protein, and pre-incubate for 5 minutes at 37 ° C with 100 mM phosphate buffer (pH 7.4) and 1 mM NADPH. After giving the CB1 inhibitor compound (Examples 5, 6, 17, 19) or rimonabant (Rimonabant) was added to a final concentration of 1 μM to start the reaction. 1 uM of Verapamil was used as a positive control. At 0 and 30 minutes after the start of the reaction, a stop solution (acetonitrile) containing an internal standard was added to terminate the reaction.
하기 표 7과 같이, 간 마이크로좀 대사안정성 시험 결과를 전처리 후 LC-MS/MS로 반응 혼합물(reaction mixture) 중 화합물의 양을 정량하여 초기량 대비 %로 나타내었다.As shown in Table 7 below, the amount of the compound in the reaction mixture was quantified by LC-MS/MS after pretreatment of the liver microsome metabolic stability test result, and expressed as a percentage compared to the initial amount.
실시예Example human
(% remaining)human
(% remaining) 		mouse
(% remaining)mouse
(% remaining)
55 35.435.4 67.767.7
66 51.251.2 86.286.2
1717 32.532.5 3.13.1
1919 83.883.8 59.459.4
RimonabantRimonabant 48.348.3 8.08.0
VerapamilVerapamil 32.232.2 35.335.3
실험예 4. 화합물 뇌혈관장벽(BBB) 투과 분석Experimental Example 4. Compound brain-vascular barrier (BBB) permeation analysis
CB1 저해제 화합물의 뇌혈관장벽 (Blood-brain barrier, BBB) 투과 확인 여부 시험은 ICR 마우스에서 평가되었다. 모든 개체는 화합물 투여 전 16시간 이상 절식 하였다. 마우스에 CB1 저해제 화합물(실시예 5, 6, 19) 또는 리모나반트를 단일 용량(10 mg/kg)을 혼합용매(4% DMSO; 8% Tween 80; 88% saline) 10mL에 현탁시킨 후 경구 투여하였다. 화합물 투여 후 1, 2, 4시간 후 마우스를 희생(sacrifice)시키고 분석하였다. 각 부검 포인트마다 마우스를 마취하고, 개복하여 채혈을 약 1ml 실시하였다. 채혈한 혈액은 즉시 빙냉상태 (약 4℃)로 보관하였다. 채혈 후 혈액은 5,000 rpm에서 5분간 원심분리하여 혈장을 분리한 다음 즉시 빙냉상태로 보관한 후, 분리된 혈장을 tube에 담아 초저온 냉동고 (약 -70℃)에 보관하였다. 채혈 후 saline을 이용하여 관류를 실시한 다음 뇌를 적출하고, 적출한 뇌는 tube에 담아 초저온 냉동고에 보관하였다. 약물의 BBB 투과성을 알아보기 위해 수집한 마우스 혈장 및 뇌 조직을 LC-MS/MS 방법을 사용하여 CB1 저해제 화합물(실시예 5, 6, 19) 또는 리모나반트의 농도를 측정하였다.The blood-brain barrier (BBB) penetration test of the CB1 inhibitor compound was evaluated in ICR mice. All subjects were fasted for at least 16 hours prior to compound administration. A single dose (10 mg/kg) of a CB1 inhibitor compound (Examples 5, 6, 19) or rimonabant was suspended in 10 mL of a mixed solvent (4% DMSO; 8% Tween 80; 88% saline) and then orally administered to mice. . Mice were sacrificed 1, 2, and 4 hours after compound administration and analyzed. At each autopsy point, the mouse was anesthetized, and about 1 ml of blood was collected by laparotomy. The blood collected was immediately stored in an ice-cooled state (about 4°C). After blood collection, the blood was centrifuged at 5,000 rpm for 5 minutes to separate plasma, and then immediately stored in an ice-cooled state. After blood collection, perfusion was performed using saline, and the brain was extracted, and the extracted brain was placed in a tube and stored in a cryogenic freezer. The concentrations of CB1 inhibitor compounds (Examples 5, 6, 19) or rimonabant were measured using LC-MS/MS methods in mouse plasma and brain tissue collected to examine the BBB permeability of the drug.
마우스에 화합물 투여 1, 2, 4시간 후 화합물의 뇌/혈장 비율은 하기 표 8에 나타내었다.The brain/plasma ratio of the compound 1, 2, and 4 hours after administration of the compound to the mouse is shown in Table 8 below.
실시예Example 1 시간1 hours 2 시간2 hours 4 시간4 hours
55 0.000.00 0.000.00 0.000.00
66 0.000.00 0.000.00 0.010.01
1919 0.080.08 0.170.17 0.190.19
RimonabantRimonabant 0.670.67 0.570.57 0.520.52
발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the invention is indicated by the claims described below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the invention.

Claims (14)

  1. 하기 화학식 1로 표시되는 피라졸-카르복스아미드(pyrazole-carboxamide) 유도체 화합물, 이의 이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:A pyrazole-carboxamide derivative compound represented by the following formula (1), an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022001522-appb-img-000150
    Figure PCTKR2022001522-appb-img-000150
    상기 화학식 1에 있어서,In Formula 1,
    R1은 H 또는 할로겐이고,R 1 is H or halogen,
    R2는 H, 할로겐 또는 CN이며,R 2 is H, halogen or CN;
    R3 및 R4는 각각 독립적으로 H 또는 할로겐이고,R 3 and R 4 are each independently H or halogen,
    Q는 치환 또는 비치환된 아릴 또는 헤테로아릴이며,Q is substituted or unsubstituted aryl or heteroaryl,
    L은
    Figure PCTKR2022001522-appb-img-000151
    ,
    Figure PCTKR2022001522-appb-img-000152
    ,
    Figure PCTKR2022001522-appb-img-000153
    ,
    Figure PCTKR2022001522-appb-img-000154
    ,
    Figure PCTKR2022001522-appb-img-000155
    또는
    Figure PCTKR2022001522-appb-img-000156
    이고,     L is
    Figure PCTKR2022001522-appb-img-000151
    ,
    Figure PCTKR2022001522-appb-img-000152
    ,
    Figure PCTKR2022001522-appb-img-000153
    ,
    Figure PCTKR2022001522-appb-img-000154
    ,
    Figure PCTKR2022001522-appb-img-000155
    or
    Figure PCTKR2022001522-appb-img-000156
    ego,
    L1은 C1-C6 알킬이며, L 1 is C 1 -C 6 alkyl,
    R' 및 R''는 각각 독립적으로 H 또는 C1-C3 알킬로 치환될 수 있고,R' and R'' may each independently be substituted with H or C 1 -C 3 alkyl,
    Het는 할로알킬로 치환 또는 비치환된, 4 내지 6원자 방향족 또는 비방향족의 헤테로 고리화합물로서, N 또는 O를 1 내지 4개 고리 내 포함한다.Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.
  2. 청구항 1에 있어서, 상기 R1은 H 또는 Cl인 화합물.The compound of claim 1, wherein R 1 is H or Cl.
  3. 청구항 1에 있어서, 상기 R2는 H 또는 CN인 화합물.The compound of claim 1, wherein R 2 is H or CN.
  4. 청구항 1에 있어서, 상기 R3는 Cl인 화합물.The compound of claim 1, wherein R 3 is Cl.
  5. 청구항 1에 있어서, 상기 R4는 H 또는 Cl인 화합물.The compound of claim 1, wherein R 4 is H or Cl.
  6. 청구항 1에 있어서, The method according to claim 1,
    상기 아릴은 하기 구조에서 선택된 어느 하나인 화합물이고;The aryl is a compound selected from the following structures;
    Figure PCTKR2022001522-appb-img-000157
    Figure PCTKR2022001522-appb-img-000157
    (상기 구조에 있어서, X는 수소 또는 할로겐임)(In the above structure, X is hydrogen or halogen)
    상기 헤테로아릴은 하기 구조에서 선택된 어느 하나인 화합물:The heteroaryl is any one selected from the following structure:
    Figure PCTKR2022001522-appb-img-000158
    Figure PCTKR2022001522-appb-img-000158
    (상기 구조에 있어서, X는 수소 또는 할로겐임).(In the above structure, X is hydrogen or halogen).
  7. 청구항 1에 있어서, 상기 L은 하기 구조에서 선택된 어느 하나인 화합물: The compound of claim 1, wherein L is any one selected from the following structures:
    Figure PCTKR2022001522-appb-img-000159
    Figure PCTKR2022001522-appb-img-000160
    Figure PCTKR2022001522-appb-img-000161
    Figure PCTKR2022001522-appb-img-000162
    Figure PCTKR2022001522-appb-img-000163
    Figure PCTKR2022001522-appb-img-000164
    Figure PCTKR2022001522-appb-img-000159
    Figure PCTKR2022001522-appb-img-000160
    Figure PCTKR2022001522-appb-img-000161
    Figure PCTKR2022001522-appb-img-000162
    Figure PCTKR2022001522-appb-img-000163
    Figure PCTKR2022001522-appb-img-000164
    (상기 구조에 있어서, L1은 C1-C3 알킬임).(In the above structure, L 1 is C 1 -C 3 alkyl).
  8. 청구항 1에 있어서, 상기 R' 및 R''는 H인 화합물.The compound of claim 1, wherein R' and R'' are H.
  9. 청구항 1에 있어서, 상기 Het는 할로알킬로 치환 또는 비치환되고, N 또는 O를 2 내지 4개 고리 내 포함하는 4 내지 6원자 방향족 헤테로 고리화합물인 화합물.The compound according to claim 1, wherein Het is a 4-6 membered aromatic heterocyclic compound which is unsubstituted or substituted with haloalkyl, and contains N or O in 2 to 4 rings.
  10. 청구항 1에 있어서, 상기 Het는 하기 구조에서 선택된 어느 하나인 화합물:The compound according to claim 1, wherein Het is any one selected from the following structures:
    Figure PCTKR2022001522-appb-img-000165
    Figure PCTKR2022001522-appb-img-000165
    (상기 구조에 있어서, Y는 H 또는 CX3이고, X는 할로겐임).(In the above structure, Y is H or CX 3 , and X is halogen).
  11. 청구항 1에 있어서, 상기 화합물은 하기 화합물들로 이루어진 군에서 선택된 어느 하나인 화합물:The compound according to claim 1, wherein the compound is any one selected from the group consisting of the following compounds:
    N-(2-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    N-(3-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    N-(4-((2-아미노-2-옥소에틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    N-(2-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    N-(3-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
    (3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신,(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
    (4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤조일)글리신,(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
    3-(3-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산,3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;
    3-(4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)벤즈아미도)프로판산,3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;
    5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
    5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((2-설파모일에틸)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
    (S)-N-(3-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
    (S)-N-(4-(2-카바모일피롤리딘-1-카보닐)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
    N-(2-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
    N-(3-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
    N-(4-(((1,2,4-옥사다이아졸-3-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
    N-(3-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
    N-(4-(((1,3,4-옥사다이아졸-2-일)메틸)카바모일)페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
    5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(3-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
    5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,2,4-옥사다이아졸-3-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
    5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-N-(4-((5-(트라이플루오로메틸)-1,3,4-옥사다이아졸-2-일)카바모일)페닐)-1H-피라졸-3-카복스아마이드,5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
    N-(3-아미노-3-옥소프로필)-6-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
    N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
    N-(4-((3-아미노-3-옥소프로필)카바모일)-3-클로로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
    N-(4-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
    N-(4-((3-아미노-3-옥소프로필)카바모일)-3-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
    N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피라진-2-카복스아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide,
    N-(3-아미노-3-옥소프로필)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드,N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
    N-(3-아미노-3-옥소프로필)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
    N-(3-아미노-3-옥소프로필)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드,N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
    N-(5-((3-아미노-3-옥소프로필)카바모일)-2-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
    N-(3-((3-아미노-3-옥소프로필)카바모일)-5-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
    N-(3-((3-아미노-3-옥소프로필)카바모일)-4-플루오로페닐)-5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아마이드,N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
    N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-4-메틸-5-페닐-1H-피라졸-3-카복스아마이드,N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide;
    N-(4-((3-아미노-3-옥소프로필)카바모일)페닐)-1-(4-클로로페닐)-5-(3-사이아노페닐)-4-메틸-1H-피라졸-3-카복스아마이드, N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-carboxamide,
    N-(2-아미노-2-옥소에틸)-2-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)아이소니코틴아마이드,N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
    N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)니코틴아마이드,N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
    N-(2-아미노-2-옥소에틸)-4-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드, 및N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide, and
    N-(2-아미노-2-옥소에틸)-5-(5-(4-클로로페닐)-1-(2,4-다이클로로페닐)-4-메틸-1H-피라졸-3-카복스아미도)피콜린아마이드.N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide.
  12. 청구항 1 내지 11 중 어느 한 항의 화합물과 약제학적으로 허용가능한 담체를 포함하는 약제학적 조성물.12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.
  13. 청구항 1 내지 11 중 어느 한 항의 화합물을 포함하는, 카나비노이드 수용체 1(Cannabinoid receptor 1)의 과발현 또는 과활성으로부터 유발된 질환의 예방 또는 치료를 위한 약학적 조성물.A pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, comprising the compound of any one of claims 1 to 11.
  14. 청구항 13에 있어서, 상기 카나비노이드 수용체 1의 과발현 또는 과활성으로부터 유발된 질환은, 당뇨, 대사성질환, 이상지질혈증, 알코올성 간질환 및 비알코올성 간질환으로 이루어진 군에서 선택된 하나 이상인 약학적 조성물.The method according to claim 13, wherein the disease caused by the overexpression or overactivity of the cannabinoid receptor 1, diabetes, metabolic disease, dyslipidemia, alcoholic liver disease and non-alcoholic liver disease at least one selected from the group consisting of a pharmaceutical composition.
PCT/KR2022/001522 2021-01-28 2022-01-27 Pyrazole-carboxamide derivative compound and use thereof WO2022164239A1 (en)

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