WO2016159577A2 - 1,2-naphthoquinone derivative and method for preparing same - Google Patents

1,2-naphthoquinone derivative and method for preparing same Download PDF

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WO2016159577A2
WO2016159577A2 PCT/KR2016/003031 KR2016003031W WO2016159577A2 WO 2016159577 A2 WO2016159577 A2 WO 2016159577A2 KR 2016003031 W KR2016003031 W KR 2016003031W WO 2016159577 A2 WO2016159577 A2 WO 2016159577A2
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substituted
unsubstituted
compound
formula
alkyl
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PCT/KR2016/003031
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French (fr)
Korean (ko)
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WO2016159577A3 (en
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이휘성
이미정
김보정
이강우
노태철
서강식
김진환
민기남
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주식회사 케이티앤지생명과학
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Publication of WO2016159577A2 publication Critical patent/WO2016159577A2/en
Publication of WO2016159577A3 publication Critical patent/WO2016159577A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to 1,2 naphthoquinone derivatives, methods for preparing the same, and compositions having a therapeutic and prophylactic effect of metabolic diseases containing the same.
  • Metabolic disease refers to syndromes that manifest simultaneously with risk factors such as hypertriglyceridemia, hypertension, abnormal metabolism, abnormal coagulation, and obesity.
  • Heart failure, ischemic heart disease, type 2 diabetes, hypercholesterolemia, Cancer, gallstones, arthritis, arthralgia, staphylococcal disease, sleep apnea, prostatic hyperplasia, and menstrual irregularities are the most threatening conditions for modern people.
  • NASH National Cholesterol Education Program
  • 1 waist circumference is 40 inches (102 cm) in men, 35 inches (88 cm) in women's stomach, obesity, 2 triglycerides of 150 mg / dL or more, 3 HDL
  • Asians when waist circumference is more than 90 cm for males and 80 cm for females, abdominal obesity is somewhat adjusted. According to the recent study, Koreans have about 25% of the population with metabolic disease symptoms. have.
  • NAD + / NADH and NADP + / NADPH ratios are reduced in vivo or in vitro, and ADH and NADPH remain in excess, they are not only used in the fat biosynthesis process, but also in excess of
  • ROS semi-ungsung oxygen species
  • fats due to NAD + and NADP + can be generated in vivo or in vitro to ensure that the NAD + / NADH and NADP + / NADPH ratios remain stable. Oxidation and various energy metabolism can be activated. As a result, if it is possible to activate the mechanism of action to keep the concentration of NAD (P) H continuously low, it is determined that the excess energy is induced to treat various diseases including obesity.
  • N AD (P) H quinone oxidoreductas (EC 1.6.99.2) are called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase, or azo-dye reductase, and these NQOs have two isoforms, NQ02 (ROM. J. INTERN. MED. 2000-2001, yol. 38-39, 33-50).
  • NQO is a flavoprotein, which acts as a catalyst for the dielectron reduction and detoxification of quinones or quicule derivatives.
  • NQO uses both NADH and NADPH as electron donors.
  • NQO activity prevents the formation of highly reactive quinone metabolites, detoxifies benzo (d) pyrene and pinone, and reduces the toxicity of chromium.
  • ⁇ activity is present in all tissues, but activity varies from tissue to tissue. In general, high levels of NQO expression were found in tissues such as cancer cells, liver, stomach and kidneys.
  • NQO gene expression is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet radiation and radiation.
  • NQO is part of a number of cell defense mechanisms induced by oxidative stress. The combined expression of genes involved in these defenses, including NQO, protects against oxidative stress, free radicals and neoplasia.
  • NQO is there have a very broad substrate specificity, in addition to quinone Chemistry quinone-imines, nitro and azo "water may be used as a substrate.
  • NQ01 is mainly distributed in subepithelial endothelial cells. This means that it can act as a defense against compounds absorbed through air, esophagus or blood vessels.
  • gene expression of NQ01 was found to be significantly increased in adipose tissue of humans with metabolic disease, and especially in adipose cells with large adipocyte size, the expression level of NQ01 was significantly higher.
  • NQ01 expression was decreased proportionally with weight loss.
  • MRNA levels of I ⁇ QOl correlated proportionally with GOT and GPT, which are known as markers of fatty liver.
  • NQ01 in obesity-related metabolic diseases is considered to be related to the expression of ⁇ QOl in adipose tissue, adiposity, glucose tolerance, and liver function indices (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346. 2352).
  • the present invention aims to solve the problems of the prior art as described above and the technical problem that has been requested from the past.
  • the present invention provides a 1,2-naphthoquinone derivative having a novel structure.
  • Another object of the present invention is to provide a method for producing the new compound.
  • Another object of the present invention is to provide a method for the treatment and prevention of metabolic diseases using these novel compounds as active ingredients.
  • the present invention is a compound represented by the following formula (1), its pharmaceutically acceptable salts, hydrates, solvates, promers, tautomers, enantiomers are pharmaceutically acceptable moieties ⁇ Isomers To provide.
  • Ri and R 2 ⁇ are each independently selected from a carbon atom, a halogen element, a substituted or unsubstituted C1-C20 alkoxy, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C4-C10 aryl, a substituted or unsubstituted C4-C10 aryloxy , Substituted or unsubstituted C2-C10 heteroaryl, -N0 2 , -NR '! R'2, CO ⁇ R'u-C (0) NR ' 1 R' 2 , -CN,
  • Replacement Paper Rule 26 -SO (0) R'i, -SO CONR'iR ': ! , -NR'i (SO (0) R ' 2 ), -CSNR' ⁇ , or Ri and R 2 are cyclic structures of substituted or unsubstituted c4-io aryl by mutual bonding, or substituted or unsubstituted C2- C10 heteroaryl may have a cyclic structure,
  • R'2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted Or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR ' ⁇ R' ⁇ m'-C ⁇ ClO or substituted or unsubstituted ⁇ ⁇ 2 ; wherein R ′′ 2 are each independently hydrogen, C1- C3 alkyl, or ⁇ ' ⁇ and R " 2, can mutually lead to a cyclic structure of substituted or unsubstituted C4-C10 aryl;
  • R 3 , R 4, R 5 , and R 6 are each independently hydrogen, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, Substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroa 1, substituted or unsubstituted-(CR ' 5 R ' 6 ) m -C4-C10 aryl, substituted or unsubstituted-(CR' 5 R ' 6 ) m -C4-C10 aryloxy, substituted or unsubstituted-(CR' 5 '6) m -C4-C10 hetero Aryl,
  • R'3, R '4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 during roal keel, a substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted - ( CH 2 ) m -C4-piO aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryloxy, -CO (0)
  • R " 3 , or R'3 and R'4 are substituted by mutual bonds Or a cyclic structure of an unsubstituted C4-C10 heterocycloalkyl, or a cyclic structure of a chi or unsubstituted C4-C10 heteroaryl;
  • R ' 5 , and R' 6 are each independently pure or C 1 -C 3 alkyl;
  • R ′′ 3 is C 1 -C 6 alkyl;
  • Q 1 COR 7 and Q 2 is a COR 8 day
  • Qi and Q 2 are double bonds
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted C1-C20 alkoxy, tea or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R '7 , -SO (0) NR' 7 R '8, -S0 3 R' 7, - P0 3 R '7, -CSNR' 7 R '8, or R 7 and R 8 May form a cyclic structure of a substituted or unsubstituted C3-C10 heterocycloalkyl by a mutual bond, or a
  • R'7 and R'8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl
  • substituent is hydroxy, halogen element, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 Heterocythes "Hona, selected from the group consisting of roalkyl, C4-C10 ah, and C2-C10 heteroaryl;
  • n and m are each independently a natural number of 1 to 4.
  • the hetero atom is at least one selected from ⁇ , ⁇ and S;
  • X 5 is N or 0 and X 6 is ⁇ , ⁇ or S;
  • ⁇ is 0 to 1, and when ⁇ is 0, its adjacent carbon atoms form a cyclic structure by direct bonds.
  • the compound of formula (1) as an active ingredient of a therapeutic agent includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, and enantiomers thereof.
  • pharmaceutically acceptable diastereomers all of which are to be construed as being within the scope of the present invention, for convenience of description, are simply abbreviated herein as compounds of formula (1).
  • Formula (1) compound is As can have a novel structure unknown in the conventional, it can be seen in the experimental vein or less, a superior effect on metabolic ring treatment and prevention using the motion mobal effect in vivo in accordance with the present invention Exert.
  • the boiling compound of formula (1) according to the present invention is a redox JL element to induce NAD (P) H: quinone oxidoreductase (NQ01) to increase the ratio of NAD + / NADH in vivo, the ratio of AMP / AT ⁇ Can be increased.
  • NAD NAD
  • NQ01 quinone oxidoreductase
  • the increase in AMP in the cell activates AMPK, which acts as an energy gauge, and promotes fat metabolism with PGCla expression that activates energy metabolism in the mitochondria, thereby compensating for insufficient ATP energy.
  • NAD + is used as a cofactor for glucose and fat metabolism-related enzymes in the body to promote metabolism # and cADPR, which is produced by the breakdown of NAD + , releases Ca 2+ from endoplasmic reticulum (ER) to mitochondrial metabolism.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • Said "pharmaceutically acceptable salts, silver, i acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like.
  • Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Acid moieties formed by sulfonic acids, such as toluenesulfonic acid, etc.
  • pharmaceutically acceptable carboxylic acid salts include metal salts or allitometal salts formed by lithium, sodium, potassium, calcium, magnesium, and the like.
  • Amino acid salts such as lysine, arginine, guanidine, dicyclonuxylamine, N-methyl-D-letter "carmine, tris Organic salts such as (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like.
  • the compounds of formula (1) according to the invention can also be converted to their salts by conventional methods.
  • hydrate refers to non-covalent intermolecular
  • Replacement Paper Rule 26 means a compound of the invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by force.
  • solvate means a compound of the present invention or a salt thereof comprising a stoichiometric or non stoichiometric lifting solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therein are volatile, non-toxic, and / or solvents suitable for administration to humans.
  • prodrug refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example ; Uh, they can achieve bioactivity by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent system. For example, prodric is an ester that facilitates the passage of cell membranes, where the water solubility is detrimental to mobility, but once the water solubility is beneficial, it is hydrolyzed to the carboxylic acid, which is active by metabolism ("Pro" Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by water metabolism to reveal the active site.
  • tautomer is a type of structural isomer that has the same chemical formula or molecular formula but differs in the way in which its members are linked, such as a keto-eno structure, which continues to reciprocate between both isomers. Means change.
  • enantiomer means an isomer that does not overlap with its mirror image, such as the relationship between the right hand and the left hand
  • Isomers are stereoisomers that are not enantiomeric, such as trans and cis, and are limited to pharmaceutically acceptable diastereomers in the present invention, all of their isomers and combinations thereof are also included in the scope of the present invention. .
  • alkyl refers to aliphatic carbon , hydrogen group.
  • ⁇ Alkyl in the invention means “saturated alkyl” which means that it does not contain any alkenes or alkyne moieties, and "unsaturated alkyl” which means that it contains at least one alkene or alkyne moieties. It is used in a concept that includes all, and in detail may be “saturated alkyl (saturated ⁇ kyl)" means that it does not contain any alkenes or alkyne sites. It said alkyl can include branched, straight-chain or cyclic, it also includes structural isomers, fish 3 ⁇ 4 for example, may refer to the case of C3 alkyl, propyl, isopropyl is 3 ⁇ 4.
  • alkene refers to a group of at least two carbon atoms consisting of at least one carbon-carbon double bond
  • alkyne means at least two carbon atoms consisting of at least one carbon-carbon triple bond. Means a group.
  • heterocycloalky is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur or the like.
  • aryl means an aromatic substituent having at least one ring having a shared pi electron system.
  • heteroaryl refers to an aromatic group containing at least one heterocyclic ring.
  • aryl or heteroaryl examples include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like.
  • halogen is an element belonging to group 17 of the periodic table, specifically fluorine, chlorine, cobalt, and iodine.
  • aryloxy means a group bonded to any one of carbon and oxygen constituting an aromatic substituent, for example, when oxygen is bonded to a phenyl group-0-C 6 H 5 , -C 6 H 4- It can be displayed as 0-.
  • the compound of formula (1) may be a compound of formula (2).
  • the compound of formula (2) may be exemplified by the compound of formula (2-1), but the following compounds do not limit the present invention.
  • the compound of formula (1) may be a compound of formula (4).
  • Ri and are each independently H, F, CI, -N (CH 3 ) 2 ,-NHCOCH 3 , or -NHCOC 3 H 5
  • Xi to X4 are each C (H)
  • X 5 And X 6 may each be N
  • 3 ⁇ 4 and 3 ⁇ 4 are each H
  • 3 ⁇ 4 to X4 are each C (H)
  • X 5 and X 6 may be each N.
  • each of R 3 and R 6 independently represents H, a halogen element, a substituted or unsubstituted C1-C9 alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted-(CR ' 5 R' 6)) m -C4-C10 aryl, substituted or unsubstituted - (CR '5 R' 6 ) m -C4- C10 aryloxy, substituted or unsubstituted - (CR '5 R' 6 ) m -C4-C10 heteroaryl
  • Aryl substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted-(CHR ' 5 ) m -NR' 3 R ' 4 , -CO (0) R' 3>
  • R4 is halogen, substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4- C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 aryl, substituted or unsubstituted-(CR , 5 R , 6) m-C4-C10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heteroaryl, substituted or unsubstituted-(CHR ' 5
  • R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryl, substituted Or unsubstituted-(CH 2 ) m -C 4 -C 10 aryloxy, -CO (0)
  • R " 3 , or R'3 and R'4 are substituted or unsubstituted by C4-C10 heterocycloalkyl Cyclic structures or cyclic structures of substituted or unsubstituted C4-C10 heteroaryl;
  • R's, and R'6 are each independently hydrogen or C1-C3 alkyl; R " 3 is C1-
  • substituent is hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl,
  • the hetero atom may be one or more selected from O and S.
  • R 3 and R 6 are each independently H, halogen, substituted or Hsubstituted C1-C9 alkyl
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted is unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted ⁇ is unsubstituted C2-C10 heteroawall, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R' 7 , -SO (0) NR ' 7 R' 8 , -S0 3 R ' 7 ,- P0 3 R ' 7 , -CSNR' 7 R ' 8 , or R 7 and R 8 are mutually bonded to form a cyclic structure of a substituted or unsubstituted C3-C10 heterocycloalkyl, or a substituted or unsubstituted C3-C10 heteroaryl.
  • R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl
  • Q 2 is a single bond when Q ⁇ l substituted or unsubstituted C3 heterocycloalkyl cyclic structure and Q 2 is CO or this CO is: ⁇ Q 2 is a cyclic structure of substituted or unsubstituted C3 heterocycloalkyl. Fulfilling
  • n are each independently a natural number of 1 to 4.
  • the hetero atom may be one or more selected from ⁇ , ⁇ and S.
  • R 7 and 3 ⁇ 4 each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R' 7 , -SO (0) NR ′ 7 R ′ 8 , —CSNR ′ 7 R ′ 8 , or R 7 and 3 ⁇ 4 are cyclic structures of substituted or unsubstituted C3-C5 heterocycloalkyl by a salicylic bond, or substituted or unsubstituted C3-C5 hetero Can lead to the cyclic structure of aryl,
  • R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted NR " 7 R" 8 ; Where R " 7 and R" 8 are each independently
  • Qi is a cyclic structure of unsubstituted C3 heterocycloalkyl and Q 2 is CO or CO and Q 2 is a cyclic structure of unsubstituted heterocycloalkyl, ( ⁇ and Q 2 form a single bond and
  • the hetero atom may be one or more selected from ⁇ , ⁇ and S.
  • the compound of formula (3) and the compound of formula (4) may be exemplified by one or more of the compounds represented below, but the following compounds do not limit the present invention.
  • the present invention also provides a process for preparing the compound of formula (1).
  • Those skilled in the art to which the present invention pertains (“an authorized person”) will be able to prepare compounds by various methods based on the structure of formula (1), and
  • step B) reacting the compound produced in step A) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
  • step D) subjecting the compound produced in step ⁇ ) to cyclization reaction under acidic conditions;
  • Ri, R 2 , and R4 are as defined in claim 1;
  • Z is halogen or R'COO-, where R is substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryloxy or substituted or unsubstituted C4-C10 aryl, wherein the substituents are hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1 -C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5
  • Y is -NH 2 , -NH 3 Z or -N0 2 , where Z is a halogen element.
  • -NH 3 Z may be in a coordination bond between -3 ⁇ 4 and HZ.
  • Base conditions in the present invention can be formed using, but are not limited to, triethyl amine, diisopropylethylamine or pyridine.
  • Acid conditions in the present invention can be formed using nitric acid, acid, acetic acid or acetic anhydride, but are not limited to these.
  • the reduction reaction can be carried out, for example, through a hydrogenation reaction
  • the hydrogenation reaction is well known in the art as a process of reacting hydrogen with a metal catalyst such as Pd / C, Zn Description is omitted below.
  • reaction reaction of step F) may be performed using a reducing agent such as Na 2 S 2 0 4 .
  • cyclized reaction means a reaction that forms a ring in the reaction product.
  • reaction may or may not be included in some cases.
  • the manufacturing method is a first step.
  • step F) The compound produced in step F) is R 7 COO R 7 C0C1, (R 7 ) 2 0, R 7 COOH, RgCOCl, or (R 8 ) 2 0 (wherein R 7 and 3 ⁇ 4 are each independently Reacting under basic conditions or a metal catalyst to produce the final product;
  • the metal catalyst is not limited as long as it is known in the art, and may be, for example, Pd / C, Zn.
  • the manufacturing method is a first step.
  • NR ′′ 7 R ′′ 8 C (0) C1 may be, in particular, dimethyl carbamoyl chloride.
  • step D Subjecting the compound produced in step D) to cyclic reaction under acidic conditions;
  • step E Cyclization of the compound produced in) to produce the final product
  • It provides a manufacturing method comprising a.
  • the cyclic reaction may include reacting with CHR 9 R 10 N92 or Camphorsulfonic cid, wherein R 9 and R 10 are each 3 ⁇ 4 hydrogen, hydroxy and halogen elements. , C1-C10 Alkyl, C2-C10 Alkenyl, C2-C10 Alkynyl, C1-C10 Alkoxy, C1-C10 Alkoxycarbonyl, C3-C8 Cycloalkyl, C2-C8 Heterocycloalkali, C4-C10 Aryl, and C2 One or more selected from the group consisting of -C10 heteroaryl.
  • R 9 , R 10 may be each independently hydrogen, or C 1 -C 10 alkyl, more specifically hydrogen, methyl, ethyl, or propyl.
  • step D 2 subjecting the compound produced in step C 2 ) to a cyclization reaction under acidic conditions
  • step D 2 Optionally reacting the resultant produced in step D 2 ) under basic conditions, followed by selective oxidation reaction; And
  • step F 2 The compound produced in step F 2 ) is R 7 COOH, R 7 C0C1, (R 7 ) 2 0, R 7 COQH, RsCOCl, and (R 8 ) 2 0 (wherein R 7 and Rg are Reacting at least one selected from each independently as defined in claim 1 under a metal catalyst to produce a final product; Manufacturing method comprising a.
  • step A 3 reacting the compound produced in step A 3 ) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
  • step D 3 subjecting the compound produced in step C 3 ) to cyclization reaction in acid conditions;
  • step D 3 optionally reacting the resultant produced in step D 3 ) under basic conditions, followed by selective oxidation reaction;
  • the compound produced in the step 3 ⁇ 4) is (R 3 ) 2 0, (3 ⁇ 4) 2 0, R 3 Z "or 3 ⁇ 4" (wherein R 3 and 3 ⁇ 4 are as defined in claim 1, respectively, Z is Reacting with " a halogen element " to produce the final product;
  • step F 3 reacting the compound produced in step F 3 ) with NR ′′ 7 R ′′ 8 C (0) C1, wherein R ′′ 7 and R ′′ 8 are each independently as defined in claim 1 and And optionally reacting with (R 7 ) 2 0, () 2 0 (wherein R 7 and R 8 are each independently as defined in claim 1) to produce a final product. It provides a manufacturing method.
  • Replacement Paper Rule 26 Generating step may further include.
  • step A4 reacting the compound produced in step A4) with HN0 3 under acidic conditions to introduce -N0 2 into the compound of formula (7);
  • step D 4 subjecting the compound produced in step C 4 ) to cyclization reaction under acidic conditions;
  • step D 4 optionally reacting the compound produced in step D 4 ) under basic conditions, followed by selective oxidation reaction;
  • step E 4 the compound produced in step E 4 ) is (R 3 ) 2 0, (3 ⁇ 4) 2 0, R 3 Z "or 3 ⁇ 4"", where R 3 and R6 are as defined in claim 1, Z ′′ is a halogen element) to produce a final product;
  • step F 4 after reacting the compound produced in step F 4 ) with SO 3 , performing a hydrogenation reaction to produce a final product.
  • the present invention
  • step A 5 reacting the compound produced in step A 5 ) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
  • step D 5 subjecting the compound produced in step C 5 ) to cyclization reaction under acidic conditions;
  • step D 5 Optionally reacting the compound produced in step D 5 ) under basic conditions, followed by selective oxidation reaction; And
  • the compound produced in the step) is (R 3 ) 2 0, (3 ⁇ 4) 2 0, R 3 Z "or RiZ" (wherein R 3 and Re are as defined in claim 1, respectively, Z " Is a halogen element) to produce a final product;
  • Step F 5 The compound produced in Step F 5) R 7 NZ “'orRgNZ'" (however, the R 7 and Rg are as defined in the system 1, each independently, Z ", is a halogen atom) After reacting with, reacting with hydrogenation to produce a final product.
  • the separation of the general mixture may be separated by conventional post-treatment methods such as tube chromatography, recrystallization, and HPLC.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate, tautomer, diastereomer and / or pharmaceutically acceptable diastereomer thereof. Isomers; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; provides a pharmaceutical composition for treating and preventing metabolic diseases.
  • the term "pharmaceutical composition” means a mixture of a compound of the invention with other chemical components such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering a compound, including but not limited to oral, injection, aerosol, parenteral, and topical administration.
  • the pharmaceutical composition may be obtained by reacting an acid compound such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methane couric acid, P-luenesulfonic acid, salicylic acid and the like.
  • terapéuticaally effective amount refers to, to some extent, alleviate or reduce one or more symptoms of the disorder being treated, or delay the onset of a clinical marker or symptom of a disease that requires prevention. It means the amount of active ingredient effective to.
  • the pharmacologically effective amount may be defined as (1) the effect of reversing the rate of progression of the disease, (2) the effect of inhibiting further progression of the disease to some extent, and / or (3) one or more symptoms associated with the disease.
  • Relief preferably
  • Replacement Paper Rule 26 Means an amount having the effect of removing).
  • a pharmacologically effective amount can be determined empirically by experimenting with compounds in known in vivo and in vitro model systems for diseases in need of treatment.
  • carrier is defined as a compound that facilitates the addition of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the incorporation of many organic compounds into living cells or tissues.
  • diot is defined as a compound that is not only to stabilize the biologically active form of the compound of interest, but also to be soluble in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. After normal use, the buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents are rarely modifying the biological activity of a compound.
  • the compounds used herein may be administered to a human patient as such or in combination with other active ingredients as in combination therapy or in combination with a suitable carrier or excipient.
  • Techniques for the formulation and administration of compounds in the present formulations can be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes. .
  • compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the actives into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.
  • a compound of formula (1) may be formulated as an injectable preparation or an oral preparation and the like.
  • the components of the present invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • a non-invasive agent suitable for the barrier to pass through is used in the formulation.
  • Such non-invasive agents are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art.
  • Such carriers allow the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like.
  • accelerators, tablets, pills, powders and granules are possible, and especially accelerators and tablets are useful. Tablets and pills are preferably prepared with enteric agents.
  • Pharmaceutical preparations for oral use include mixing one or more compounds of the invention with one or more excipients, optionally grinding such a mixture, and if necessary
  • the mixture of granules can be treated after passing through the preparation to obtain a tablet or sugar core.
  • Suitable excipients include fillers such as lactose, sucrose, manny, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl salose, and / or polyvinylpyridone ( Cellulose-based materials such as PVP).
  • a disintergrinding agent such as cross-linked polyvinyl pyridone, butadiene, or a salt thereof such as alginic acid or sodium acrylate and a carrier such as a lubricant such as magnesium stearate, a binder, or the like may be added.
  • compositions that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbates, as well as pushable capsules made of gelatin.
  • the push-in capsules are fillers such as lactose, binders such as starch, and / or .
  • a lubricant such as talc or magnesium stearate
  • it may also contain active ingredients.
  • the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.
  • the compounds may be formulated for parenteral administration by injection, for example by large pill injection or continuous infusion.
  • injectable formulations may also be presented in unit dose form, eg, as a saline or multi-dos container with preservatives added.
  • the compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain formulation components such as suspensions, stabilizers and / or dispersants.
  • the active ingredient may also be in the form of a powder for constitution with a suitable vehicle, such as water of bacteriostatic material, before use.
  • the compounds may also be formulated in rectal dosage compositions such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in amounts effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of a subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
  • the compound of formula (1) as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg.
  • the dosage of the compound of formula (1) is according to the doctor's prescription according to the patient's weight, age and specific characteristics and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 1000 mg per day, depending on the frequency and intensity of administration.
  • a single daily dose will be divided up to a general dosage of about 1 to 500 mg per day, but for some patients a higher daily dose may be desirable.
  • the target disease is obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, retinopathy or renal failure,
  • Replacement Paper Rule 26 It may be Huntington's disease or inflammation, in particular fatty liver, diabetes or Huntington's disease, but is not limited thereto.
  • the present invention also provides a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, diastolic or pharmaceutically acceptable diastereomer thereof.
  • An effective amount of the isomers is used to provide a method for treating or preventing metabolic diseases.
  • “Therapeutic” means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of the disease, and “preventing” means stopping or manifesting the disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. Means to delay.
  • Example 1 is a graph showing the weight gain rate, weight change, and intake of obese rats (o6 / ob) for the compound according to Example 3 of Example 3-1 and Example 4 and the control group;
  • Example 2 is a graph showing the weight gain rate, weight change, and intake of obese rats (ob / ob) for the compound according to Example 7 of Example 3-2 and the compound according to Example 10 and the control group;
  • Figure 3 is a graph showing the body weight gain, weight change, and the intake of obese mice (0 6/0 b) for a compound to the control compound, and according to Example 13 according to Example 12 of Experimental Example 3-3;
  • Example 4 is a graph showing the weight gain rate, weight change, and intake of obese rats (o6 / oZ>) for the compound according to Example 16 of Experimental Example 3-4 and the control group;
  • Example 5 is a compound according to Example 12 and Example 13 of Experimental Example 4;
  • FIG. 6 is a graph showing weight gain rate, weight change, and intake of diabetic rats (dp / db) for the compound according to Example 12 of Example 5, the compound according to Example 13, and the control group.
  • Acetic acid (15 ml) is added to Compound B-3 (700 mg, 2.86 mrpol), and the mixture is stirred and refluxed for 3 hours. Acetic acid is removed by concentration under reduced pressure, and purified by silica gel column chromatography to obtain a compound (575 mg, 89%).
  • Enzyme reactions included 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQOl protein. Enzyme reaction is initiated by addition of NAPH and is performed at 37 degrees. At this time, the reaction rate was observed for 10 minutes at 550 nm to increase the absorbance as Cytochrome C 7 ⁇ reduction, NQOl activity is represented by the amount of reduced cytochrome C [nmol cytochrome C reduced / min / ug protein].
  • Paper rule Article 26 ORIENTBIO's Low fat diet (11.9 kcal% fat, 5053, Labdiet, USA) was purchased and fed freely. Drinking water was filtered and sterilized by using a filter and an oil sterilizer. (250 mL) was added to free intake.
  • the body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of the administration to the end of the test 3 ⁇ 4, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test.
  • the dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.
  • C57BU6J Lep ob / ob mice having the characteristics of genetic obesity from ORIENTBIO were prepared at 6.5 weeks of age, and the compounds according to Example 7 and the compounds according to Example 10 were respectively added to three C 57 BL / 0J Lep ob / ob mice. mg / kg and each control group was administered under the same conditions as Experimental Example 3-1 except that 0.1 mg of SLS was administered 10 mg / kg to 3 C57BIJ6J Lep ob / ob mice. By measuring the weight gain rate, weight change and intake over time administration is shown in £ 2 below.
  • C57BU6J Lep ob / ob mice having the characteristics of genetic obesity from ORIENTBIO were prepared at 6.5 weeks of age, and the compound according to Example 12 and the compound according to Example 13 were each 100 mg / in mouse C57BL / 6J Lep ob / ob.
  • the test was conducted in the same conditions as in Experiment 3-1, except that the control group was administered for 6 days with 10 mg / kg of 0.1% SLS administered to 3 C57B 6J Lep ob / ob mice as a control group.
  • the weight increase rate, weight change, and intake with time of administration are shown in Figure 3 below.
  • ORIENTBIO was prepared for 6.5 weeks of C57BL / 6J Lep ob / ob mice having genetic obesity, and the compounds according to Example 16 were administered to each of the C57BL / 6J Lep ob / ob mice at 100 mg / kg.
  • experiments were conducted under the same conditions as in Experimental Example 3-1 except that 0.1 mg of SLS was administered 10 mg / kg in three C57BL / 6J Lep ob / o6 mice for 14 days.
  • weight gain rate weight change and intake measured according to Figure 4 is shown. As shown in the graph of FIG.
  • ORIENTBIO's C57BLKS / 6 db / db mouse which possesses the characteristics of genetic obesity, is prepared for 10 weeks of age at a temperature of 22 to 24 degrees, a relative humidity of 50 to 30%, an illuminance of 150 to 300 lux, a contrast cycle of 12 hours, and an exhaust of 10 to 15 Polycarbonate Breeding Box (200Wx)
  • C57BLKS / 6 db / db mice with genetic diabetes characteristics are prepared for 6.5 weeks of age and have a degree of silver of 22 to 24 degrees, relative humidity of 50 to 30%, illuminance of 150 to 300 lux, a contrast cycle of 12 hours, and exhaust 10 to 15.
  • polycarbonate breeding box 200> ⁇ 2601 ⁇ ⁇ 13 ( «(mm), Three-shine), which maintained the breeding environment of ash / hr, two dogs were raised per breeding box and the feed was ORIENTBIO's low fat diet (11.9 kcal% fat, 5053 , Labdiet)
  • Example 12 The compound according to Example 12 synthesized in the present invention and the compound according to Example 13 were each administered 80 mg / kg to three C57BLKS / 6 db / db mice for 14 days, and as a control group, C57BLKS / 6 db Body weight increase rate, weight change and ⁇ according to administration time were tested in the same conditions as Experimental Example 3-1, except that 23 mice were administered with 10 mg / kg of 0.1% SLS in 3 / db mice. The amount of ⁇ was measured and shown in FIG. 6.
  • the body weight of the test animals was measured from the time of group separation (just before administration of the test substance) and from the time of administration to the end of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test.
  • the dietary intake was measured from the start of the administration of the test substance to the end of the test for each individual.
  • the novel 1,2-naphthoquinone derivative according to the present invention by increasing the NAD (P) + / NAD (P) H ratio through the NQ01 activity in vivo to change the energy environment in the cell AMPK activation, the energy consumption mechanism, mitochondria energy metabolism
  • Replacement Paper Rule 26 "Activate the body by improving calorie restriction such as expression of activating PGCla and systemic changes such as mitochondrial biosynthesis due to mitochondrial activation and endurance motility muscle induction by inducing genetic changes that appear during exercise. Since it has a therapeutic effect on exercise mimicking to increase physical activity, a drug using it as an active ingredient may be useful for treating or preventing metabolic diseases.

Abstract

The present invention relates to a compound represented by chemical formula (1) defined in claim 1, and a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, a tautomer, an enantiomer, or a pharmaceutically acceptable diastereomer thereof.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
1,2 나프토퀴논유도체 및 이의 제조방법  1,2 naphthoquinone derivatives and preparation method thereof
ί기술분야】  ί Technical field
본 발명은 1,2 나프토퀴논 유도체， 이의 제조방법 및 이를 함유하는 대사성 질환의 치료 및 예방효과를가지는조성물에 관한 것이다.  The present invention relates to 1,2 naphthoquinone derivatives, methods for preparing the same, and compositions having a therapeutic and prophylactic effect of metabolic diseases containing the same.
ί배경기술】  ί Background Technology]
대사성 질환 (Metabolic Syndrome)은고중성지방혈증,고혈압， 당대사 이 상， 혈액응고 이상 및 비만과 같은 위험인자가동시 나타나는 증후군을 지칭 하며， 심장마비， 허혈성심질환, 2형당뇨병， 고콜레스테를혈증, 암, 담석증, 관 절염， 관절통， 호홉기 질환， 수면성무호흡증， 전립선비대증, 월경불순등과 같 은 질병을 동반할 수 있기 때문에 현대인을 가장 크게 위협하는 질환이 되 고 있다, 20이년 공표된 미국 NCEP(National Cholesterol Education Program)의 기준에 따르면,①허리둘레가남자 40 인치 (102 cm), 여자 35 인치 (88 cm) 이 상인 복부 비만,② 증성지방 (triglycerides) 150 mg/dL이상,③ HDL콜레스테를 이 남자 40 mg/dL, 여자 50 mg/dL이하,④ 혈압 130/85 mmHg이상，⑤공복혈 당 (fasting glucose)이 110 mg/dL 이상 등의 다섯 가지 위험인자 중 한 환자가 세 개 이상을 나타낼 경우 대사성 질환으로 판정하게 된다. 동양인의 경우， 허리둘레가남자 90 cm, 여자 80 cm 이상일 때 복부비만으로 다소 조정되어 있으며， 이 규정을 적용할 때 한국인은 전 인구의 25% 정도가 대사성 질환 증상을 나타낸다는 최근의 연구보고도 있다.  Metabolic disease (Metabolic Syndrome) refers to syndromes that manifest simultaneously with risk factors such as hypertriglyceridemia, hypertension, abnormal metabolism, abnormal coagulation, and obesity. Heart failure, ischemic heart disease, type 2 diabetes, hypercholesterolemia, Cancer, gallstones, arthritis, arthralgia, staphylococcal disease, sleep apnea, prostatic hyperplasia, and menstrual irregularities are the most threatening conditions for modern people. According to the National Cholesterol Education Program (NCEP), ① waist circumference is 40 inches (102 cm) in men, 35 inches (88 cm) in women's stomach, obesity, ② triglycerides of 150 mg / dL or more, ③ HDL One of the five risk factors, including cholesterol, was below 40 mg / dL in men, 50 mg / dL in women, ④ above 130/85 mmHg in blood pressure, and ⑤ above 110 mg / dL in fasting glucose. If more than Metabolic disease is determined. In Asians, when waist circumference is more than 90 cm for males and 80 cm for females, abdominal obesity is somewhat adjusted. According to the recent study, Koreans have about 25% of the population with metabolic disease symptoms. have.
이러한 대사성 질환은 만성적인 장기간의 고칼로리 섭취가주요 위험 요소인  These metabolic disorders are chronic long-term high-calorie intake, the main risk factor
1 One
대체용지 규칙 제 26조 것으로 간주되고 있다. 과잉의 에너지 섭취， 운동 부족， 수명 연장 및 노화 의 진행 과정 등에서 대사 효율이 저하되고， 이것이 에너지 과잉의 문제를 심화시켜 비만， 당뇨 및 대사성 질환으로 이행되는 것으로 알려져 있다. Replacement Paper Rule 26 Is considered. It is known that metabolic efficiency decreases during excessive energy intake, lack of exercise, life extension, and aging, and this causes the problem of excess energy, which leads to obesity, diabetes and metabolic diseases.
치료방법으로 식사요법， 운동요법, 행동조절요법, 약물치료 등이 행해 지고 있으나, 원인이 정확히 밝혀지지 않았기 때문에 현재 효과는 미미하여 증상을 완화시키거나 질병의 진행을 늦추는 정도에 지나지 않는다. 치료제 개발을 위한 치료 target 역시 다양하게 제시되고 있으나 획기적인 치료 target이 보고되고 있지 않은 것도 현혁이다.  As a treatment method, diet therapy, exercise therapy, behavioral therapy therapy, drug therapy, etc. are being performed, but since the cause is not known precisely, the current effect is insignificant and only to relieve symptoms or slow the progression of the disease. Therapeutic targets for the development of therapeutics have also been proposed in various ways, but no breakthrough therapeutic targets have been reported.
한편， 생체 조건 (in vivo) 또는 시험관 조건 (in vitro)에서 NAD+/NADH 및 NADP+/NADPH 비율이 감소되어 ADH 및 NADPH가 잉여로 남아돌 때, 이들은 지방 생합성 과정에 사용될 뿐만 아니라， 과잉의 경우 반웅성 산소종 (ROS)을 생성시키는 주요기질로서 사윷되기도 하므로, ROS로 인한 염증질환 을 비롯한 중요한 질환의 원인이 되기도 한다. 이러한 이유로， NAD+/NADH 및 NADP+/NADPH 비율이 증가한 상태를 안정적으로 유지하도록 생체 조건 (in vivo) 또는 시험관 조건 (in vitro)의 환경을 조성할 수 있다면， NAD+ 및 NADP+에 의한 지방산화 및 다양한 에너지 소비대사가 활성화될 수 있다. 결과적으로， NAD(P)H의 농도를 지속 으로 낮게 유지하는 작용기전을 활성 화시킬 수 있다면, 과잉의 에너지가 φ진되도록 유도하여 비만을 포함한 다 양한 질환을 치료할 수 있을 것으로 판단된다. On the other hand, when the NAD + / NADH and NADP + / NADPH ratios are reduced in vivo or in vitro, and ADH and NADPH remain in excess, they are not only used in the fat biosynthesis process, but also in excess of In some cases, as a main substrate for generating semi-ungsung oxygen species (ROS), it is also a cause of important diseases including ROS-induced inflammatory diseases. For this reason, fats due to NAD + and NADP + can be generated in vivo or in vitro to ensure that the NAD + / NADH and NADP + / NADPH ratios remain stable. Oxidation and various energy metabolism can be activated. As a result, if it is possible to activate the mechanism of action to keep the concentration of NAD (P) H continuously low, it is determined that the excess energy is induced to treat various diseases including obesity.
이와 같은 다양한 기능을 하는 것으로 알려진 신호전달자인 NAD(P)+ 의 농도 Concentration of NAD (P) + , a known signal transducer
2 2
대체용지 규칙 제 26조 및 비율을 높이는 방법은， 첫째， NAD^P)+ 생합성 공정인 salvage 합성공정을 조절하는 방법， 둘째， NAD(P)H를 기¾ 또는 조효소로 사용하는 효소의 유전 자 또는 단백질을 활성화시켜 생체 내 NAD(P)+ 농도를 높이는 방법， 셋째， NAD(P)+또는 그의 유사체,유도체, 절구체와프로드럭을 외부로부터 공급하 여 NAD(P)+의 농도를 높이는 방법 등責고려할수 있다. Replacement Paper Rule 26 And the method of increasing the ratio, first, the method of adjusting the salvage synthesis process, NAD ^ P) + biosynthesis process, second, by activating the gene or protein of the enzyme using NAD (P) H as a base or coenzyme how to increase in NAD (P) + concentration, third, it can be considered NAD (P) + or an analogue, derivative, section sphere and how a prodrug to increase the concentration of W and supplied from the outside NAD (P) +, etc.責.
N AD(P)H： quinone oxidoreductas (EC 1.6.99.2)는 DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase,또는 azo-dye reductase등으로 불리고 있으며， 이러한 NQO는두 개 isoform,즉, NQ01과 NQ02로 존재한 다 (ROM. J. INTERN. MED. 2000-2001, yol. 38-39, 33-50). NQO는 플라보프로테 인 (flavoprotein)으로서， 퀴논 또는 퀴놓 유도체들의 쌍전자환원 (two electron reduction) 및 무독화를 촉매하는 작용윷 한다. NQO은 전자공여체로 NADH 및 NADPH를 모두사용한다. NQO의 활성은 반응성이 매우큰 퀴논 대사물 의 형성을 예방하고, benzo(d)pyrene, pinone을 무독화시키며， 크롬의 독성을 감소시킨다. Νςο의 활성은 모든 조직에 존재하지만, 활성은 조직에 따라 다르다. 일반적으로 암세포조직, 간， 위, 신장과 같은 조직에서 NQO의 발현 량이 높은 것으^ 확인되었다. NQO워 유전자 발현은 xenobiotics, 항산화제, 산화제, 중금속， 자외선， 방사선 등에 의해 유도된다. NQO는산화적 스트레 스에 의해 유도되는수많은 세포방어지작중의 일부이다. NQO을 포함한 이 러한 방어가작에 관여하는 유전자들의 연합된 발현은산화적 스트레스, 유리 기 및 종양형성 (neoplasia)에 대하여 세 를보호  N AD (P) H: quinone oxidoreductas (EC 1.6.99.2) are called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase, or azo-dye reductase, and these NQOs have two isoforms, NQ02 (ROM. J. INTERN. MED. 2000-2001, yol. 38-39, 33-50). NQO is a flavoprotein, which acts as a catalyst for the dielectron reduction and detoxification of quinones or quicule derivatives. NQO uses both NADH and NADPH as electron donors. NQO activity prevents the formation of highly reactive quinone metabolites, detoxifies benzo (d) pyrene and pinone, and reduces the toxicity of chromium. Νςο activity is present in all tissues, but activity varies from tissue to tissue. In general, high levels of NQO expression were found in tissues such as cancer cells, liver, stomach and kidneys. NQO gene expression is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet radiation and radiation. NQO is part of a number of cell defense mechanisms induced by oxidative stress. The combined expression of genes involved in these defenses, including NQO, protects against oxidative stress, free radicals and neoplasia.
3 3
대체용지 규칙 제 26조 하는 역할을 수행한다. NQO은 매우 넓은 기질 특이성을 갖고 있는데， 퀴논 이외에 quinone-imines, nitro 및 azo 화 "물이 기질로서 사용될 수 있다. Replacement Paper Rule 26 It plays a role. NQO is there have a very broad substrate specificity, in addition to quinone Chemistry quinone-imines, nitro and azo "water may be used as a substrate.
그중， NQ01은 주로 상피세포하 내피세포에 주로 분포해 있다. 이는 공기， 식도 또는 혈관을 통해 흡수된 화합물에 대한 방어기작으로 작용할 수 있음을 뜻한다. 최근， NQ01의 유전작 발현이 대사성 질환을 가지는 사람의 지방조직에서 매우 증가하는 것으로 나타났으며 특히 지방세포의 크기가 큰 지방세포에서 NQ01의 발현량이 통계적으로 유의하게 높은 것으로 나타났다. 식이를 통하여 체증감소흩 유도한 경우에 체중감소와 더불어 NQ01의 발현량이 비례적으로 감소하였다. I^QOl의 mRNA 양이 지방간의 정도와 관련된 지표로 알려진 GOT, GPT와 비례적으로 상관관계가 있는 것으로 나타났다. 따라서 지방조직에서의 ^QOl의 발현이 adiposity, 포도당내성， 간기능 지표와의 연관성을 고려할 때 비만 관련 대사성 질환에서 NQ01의 역할이 있을 것으로 판단된다 (The Journal of Clinical Endocrinology & Metabolism 92(6):2346. 2352).  Among them, NQ01 is mainly distributed in subepithelial endothelial cells. This means that it can act as a defense against compounds absorbed through air, esophagus or blood vessels. Recently, gene expression of NQ01 was found to be significantly increased in adipose tissue of humans with metabolic disease, and especially in adipose cells with large adipocyte size, the expression level of NQ01 was significantly higher. In the case of weight loss induction through diet, NQ01 expression was decreased proportionally with weight loss. MRNA levels of I ^ QOl correlated proportionally with GOT and GPT, which are known as markers of fatty liver. Therefore, the role of NQ01 in obesity-related metabolic diseases is considered to be related to the expression of ^ QOl in adipose tissue, adiposity, glucose tolerance, and liver function indices (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346. 2352).
【발명의 상세한 설명】  [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
이에 대해， 본 발명은 상기와 같은 종래기술의 문제점과 과거로부터 요청되어온 기술적 과제를 해결하는 을 목적으로 한다.  On the other hand, the present invention aims to solve the problems of the prior art as described above and the technical problem that has been requested from the past.
구체적으로, 본 발명은 새로운 구조의 1,2 나프토퀴논 유도체를 제공하는 것이다.  Specifically, the present invention provides a 1,2-naphthoquinone derivative having a novel structure.
본 발명워 다른 목적은 이 5]한 신규 화합물을 제조하는 방법을 제공하는 것이다.  Another object of the present invention is to provide a method for producing the new compound.
4 4
대체용지 규칙 제 26조 본 발명의 또 다른 목적은 성성분으로서 이러한 신규 화합물을 약리학적 유효 ¾으로 포함하는 대산성 질환의 치료 및 예방을 위한 조성물을 제공하는 것이다. Replacement Paper Rule 26 It is yet another object of the present invention to provide a composition for the treatment and prevention of acidic diseases comprising such novel compounds as constitutively effective ¾.
본 발명의 기타 목적은 이러한 신규 화합물을 활성성분으로 사용하여, 대사성 질환의 치료 및 예방을 위한 f법을 제공하는 것이다.  Another object of the present invention is to provide a method for the treatment and prevention of metabolic diseases using these novel compounds as active ingredients.
【기술적 해결방법】  Technical Solution
본 발명은 하기 화학식 (1)로 표시되는 화합물， 그것의 약제학적으로 허용되는 염， 수화물, 용매화물, 프로 ^럭， 토토머 (tautomer), 거울상 이성질체 生는 약학적으로 허용 가능한부분입 ᅵ 이성질체를 제공한다.  The present invention is a compound represented by the following formula (1), its pharmaceutically acceptable salts, hydrates, solvates, promers, tautomers, enantiomers are pharmaceutically acceptable moieties ᅵ Isomers To provide.
Figure imgf000007_0001
Figure imgf000007_0001
상기 식에서,  Where
Ri 및 R2^ 각각 독립적으로 宁소， 할로겐 원소， 치환 또는 비치환의 C1-C20 알콕시， 치환 또는 비치환의 C1-C6 알킬, 치환 또는 비치환의 C4- C10 안릴, 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C2- C10 헤테로아릴， -N02, -NR'!R'2,
Figure imgf000007_0002
- CO^R'u -C(0)NR'1R'2, -CN, Ri and R 2 ^ are each independently selected from a carbon atom, a halogen element, a substituted or unsubstituted C1-C20 alkoxy, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C4-C10 aryl, a substituted or unsubstituted C4-C10 aryloxy , Substituted or unsubstituted C2-C10 heteroaryl, -N0 2 , -NR '! R'2,
Figure imgf000007_0002
CO ^ R'u-C (0) NR ' 1 R' 2 , -CN,
대체용지 규칙 제 26조 -SO(0)R'i, -SO CONR'iR':!, -NR'i(SO(0)R'2), -CSNR'^^, 또는 Ri 및 R2는 상호 결합에 의해 치환 또는 비치환의 c4- io 아릴의 환형 구조, 또는 치환 또는 비치환의 C2-C10 헤테로아릴의 환형 구조를 이를 수 있으며， Replacement Paper Rule 26 -SO (0) R'i, -SO CONR'iR ': ! , -NR'i (SO (0) R ' 2 ), -CSNR' ^^, or Ri and R 2 are cyclic structures of substituted or unsubstituted c4-io aryl by mutual bonding, or substituted or unsubstituted C2- C10 heteroaryl may have a cyclic structure,
여기서 및 R'2는각각 독립적으로 수소， 치환 또는 비치환의 C1- C6 알킬, 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C4- C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C1-C8 헤테로아릴， 치환 또는 비치환의 -(CR'^R'^m'-C^ClO 아 또는 치환 또는 비치환의 Νβ Ι 2이고; 여기서 R"2는 각각 독립적으로 수소， C1-C3 알킬， 또는 Ι 'Ί 및 R"2는 상호 결확에 의해 치환 또는 비치환의 C4-C10 아릴의 환형 구조를 이를 수 있고; And R'2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted Or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR '^ R' ^ m'-C ^ ClO or substituted or unsubstituted Νβ Ι 2 ; wherein R ″ 2 are each independently hydrogen, C1- C3 alkyl, or Ι 'Ί and R " 2, can mutually lead to a cyclic structure of substituted or unsubstituted C4-C10 aryl;
R3, R4, R5, 및 R6은 각각 독 적으로 수소, 할로겐 원소, 치환 또는 비치환의 C1-C9 알킬, 치환 또는 ^ᅵ치환의 C1-C20 알콕시, 치환 또는 비치환의 C3-C8 시클로알킬, 치환 또는 비치환의 C2-C8 헤테로시클로알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C1-C10 헤테로아 1， 치환 또는 비치환의 -(CR'5R'6)m-C4- C10 아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 아릴옥시， 치환 또는 비치환의 -(CR'5 '6)m-C4-C10 헤테로아릴, 치환 또는 비치환의 -(CR'5R'6)m-C4- C10 행테로시클로알킬, 치환 또는 비치환의 -(CR'5R'6)m-NR'3R'4, 치환 또는 비치환의 -(CR'5R'6)m-OR'3, -CO(0)R'3, -CONR'3R'4, -NR'3R'4, -NR'3(C(0)R'4), - SO(0)R'3, -SO(0)NR'3R'4, -NR'3(SO(0)R'4), -CSNR'3R'4, R 3 , R 4, R 5 , and R 6 are each independently hydrogen, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, Substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroa 1, substituted or unsubstituted-(CR ' 5 R ' 6 ) m -C4-C10 aryl, substituted or unsubstituted-(CR' 5 R ' 6 ) m -C4-C10 aryloxy, substituted or unsubstituted-(CR' 5 '6) m -C4-C10 hetero Aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C 4 -C 10 hangterocycloalkyl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -NR ' 3 R'4, substituted or unsubstituted -(CR ' 5 R' 6 ) m -OR ' 3 , -CO (0) R' 3 , -CONR ' 3 R'4, -NR' 3 R ' 4 , -NR' 3 (C (0) R ' 4 ), -SO (0) R' 3 , -SO (0) NR ' 3 R'4, -NR' 3 (SO (0) R ' 4 ), -CSNR' 3 R ' 4 ,
6 6
대체용지 규칙 제 26조 화학식 (1)의 화합물이 "A"일 때 -CH2A, 또는 화학식 (1)워 화합물이 "A"일 때 -A이며; Replacement Paper Rule 26 -CH 2 A when the compound of formula (1) is "A", or -A when the compound of formula (1) is "A";
여기서， R'3, R'4는 각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C3-C8 시 로알킬， 치환 또는 비치환의 C4-C10 아릴, 치환또는 비치환의 -(CH2)m-C4-piO 아릴， 치환 또는 비치환의 -(CH2)m- C4-C10 아릴옥시, -CO(0)R"3, 또는 R'3 및 R'4는 상호 결합에 의해 치환 또는 비치환의 C4-C10 해테로시클로알킬의 환형 구조, 또는 치홧 또는 비치환의 C4-C10 헤테로아릴의 환형 구조를이骨 수 있고; Here, R'3, R '4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 during roal keel, a substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted - ( CH 2 ) m -C4-piO aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryloxy, -CO (0) R " 3 , or R'3 and R'4 are substituted by mutual bonds Or a cyclic structure of an unsubstituted C4-C10 heterocycloalkyl, or a cyclic structure of a chi or unsubstituted C4-C10 heteroaryl;
R'5, 및 R'6각각 독립적으로 순소 또는 C1-C3 알킬이며; R"3는 C1- C6알킬이며; R ' 5 , and R' 6 are each independently pure or C 1 -C 3 alkyl; R ″ 3 is C 1 -C 6 alkyl;
Q l COR7이고 Q2이 COR8일 Qi과 Q2는 이중 결합을 이루고 여기서 R7 및 R8은 각각 독립적으로 수소， 치환 또는 비치환의 C1- C20 알콕시， 차 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C2-C10 해테로아릴， -CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, -SO(0)NR'7R'8, -S03R'7, - P03R'7, -CSNR'7R'8, 또는 R7 및 R8는 상호 결합에 의해 치환 또는 비치환의 C3-C10 헤테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C3-C10 해테로아릴의 환형 구조를 이를 수 있으며， Q 1 COR 7 and Q 2 is a COR 8 day Qi and Q 2 are double bonds wherein R 7 and R 8 are each independently hydrogen, substituted or unsubstituted C1-C20 alkoxy, tea or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R '7 , -SO (0) NR' 7 R '8, -S0 3 R' 7, - P0 3 R '7, -CSNR' 7 R '8, or R 7 and R 8 May form a cyclic structure of a substituted or unsubstituted C3-C10 heterocycloalkyl by a mutual bond, or a cyclic structure of a substituted or unsubstituted C3-C10 heteroaryl,
여기서 R'7 및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬，  Wherein R'7 and R'8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl,
7 7
대체용지 규칙 제 26조 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시, 치환 또는 비치환의 C1-C8 헤테로아릴, 치환 또는 비치환의 -(CR"7R"8)m'-C4-C10 아릴이고; 여기서 R"7 및 R"8는 각각 독립적으로 수소， ci-q 알킬이고; Replacement Paper Rule 26 Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR " 7 R" 8 ) m'-C4-C10 aryl; Wherein R ″ 7 and R ″ 8 are each independently hydrogen, ci-q alkyl;
Q^l 치환 또는 비치환의 C3-C5 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는, Q l CO이고 Q2가 치환 또는 비치환의 C3-C5 헤테로시클로알킬의 환형 구조일 때， (^과 Q2는 단일 결합을 이루고 When Q ^ l substituted or unsubstituted C3-C5 heterocycloalkyl cyclic structure and Q 2 is CO or Q1 CO and Q 2 is cyclic structure of substituted or unsubstituted C3-C5 heterocycloalkyl, (^ and Q 2 is a single bond
여기서， 치환기는 히드록시， 할 S겐 원소, C1-C10 알킬， C2-C10 알케닐， C2-C10 알키닐， C1-C10 알콕시, C1-C10 알콕시카르보닐， C3-C8 시클로알킬， C2-C8 해테로시 "로알킬， C4-C10 아 ， 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 학나 이상이며;  Wherein the substituent is hydroxy, halogen element, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 Heterocythes "Hona, selected from the group consisting of roalkyl, C4-C10 ah, and C2-C10 heteroaryl;
m 와 m，은 각각독립적으로 1 내지 4의 자연수이고;  m and m are each independently a natural number of 1 to 4;
헤테로 원자는 Ν, Ο 및 S에서 선택된 하나 이상이며;  The hetero atom is at least one selected from Ν, Ο and S;
및 ¾는 각각 독립적으로 C(H) 또는 N이고;  And ¾ are each independently C (H) or N;
X5는 N또는 0이며 , X6는 Ν, Ο 또는 S이고; 및 X 5 is N or 0 and X 6 is Ν, Ο or S; And
η은 0 두는 1이며, η이 0인 경우에 그것의 인접 탄소원자들은 직접결합에 의해 환형 구조를 이룬다.  η is 0 to 1, and when η is 0, its adjacent carbon atoms form a cyclic structure by direct bonds.
또한， 상기 식에서 :는 단일결합 또는 이중결합이고， ᅳ" 는 단일 In addition, in the formula : is a single bond or a double bond, ᅳ " is a single
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대체용지 규칙 제 26조 ■· ··. Replacement Paper Rule 26 ■ · ··.
결합 또는 결합이 형성되지 않을 수 있으며， Λ'--...'·':는 이를 포함하는 환형 구조가 방향족 (arpmatic)일 수도 있고， 방향족이 아닐 수도 있음을 의미한다. 이하에서 별도의 설명이 없는 한， 치료제의 활성성분으로서 화학식 (1)의 화합물에는， 약제학적으로 허 "되는 그것의 염， 수화물， 용매화물， 프로드럭， 토토먹 (tautomer), 거울상 oj성질체 또는 약학적으로 허용 가능한 부분입체 이성질체가 모두 포함되명， 이들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다. 설명의 편의를 위하여， 본 명세서에서는 화학식 (1)의 화 ·물로 간단히 약칭하？ᅵ도 한다. A bond or a bond may not be formed, and Λ ' -...' · ': means that the cyclic structure including the same may or may not be aromatic. Unless otherwise stated below, the compound of formula (1) as an active ingredient of a therapeutic agent includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, and enantiomers thereof. Or pharmaceutically acceptable diastereomers, all of which are to be construed as being within the scope of the present invention, for convenience of description, are simply abbreviated herein as compounds of formula (1). Also
본 발명에 따른 상기 화학식 ,(1)의 화합물은 기존에 알려지지 않은 신규한 구조를 가지며， 이하의 실험맥에서도 볼 수 있는 바와 같이， 생체 내에서 운동 모밝 효과를 통해 대사 환의 치료 및 예방에 우수한 효과를 발휘한다. Formula (1) compound is As can have a novel structure unknown in the conventional, it can be seen in the experimental vein or less, a superior effect on metabolic ring treatment and prevention using the motion mobal effect in vivo in accordance with the present invention Exert.
구체적으로， 본 발명에 따른 삶기 화학식 (1)의 화합물은 산화환원 JL소로서 NAD(P)H:quinone oxidoreductase (NQ01)이 생체 내 NAD+/NADH의 비율을 증가하도록 유도하여 AMP/AT^의 비율을 증가시킬 수 있다. 이러한 세포 내의 AMP의 증가는 에너지 게 o지 (energy gauge) 역할을 하는 AMPK를 활성화시켜 미토콘드리아에서 에너지 대사를 활성화시키는 PGCla 발현으로 지방 대사를 촉진하여， 부족한 ATP 에너지를 보층하도록 한다. 또한 증가된 NAD+는 체내에서 포도당， 지방 대사 관련 효소의 보조인자 (cofactor)로 사용되어 대사 # 촉진시키며 NAD+가 분해되어 생성되는 cADPR은 endoplasmic reticulum (ER) 에서 Ca2+을 방출시켜 미토콘드리아 대사 작용을 상 Specifically, the boiling compound of formula (1) according to the present invention is a redox JL element to induce NAD (P) H: quinone oxidoreductase (NQ01) to increase the ratio of NAD + / NADH in vivo, the ratio of AMP / AT ^ Can be increased. The increase in AMP in the cell activates AMPK, which acts as an energy gauge, and promotes fat metabolism with PGCla expression that activates energy metabolism in the mitochondria, thereby compensating for insufficient ATP energy. In addition, increased NAD + is used as a cofactor for glucose and fat metabolism-related enzymes in the body to promote metabolism # and cADPR, which is produced by the breakdown of NAD + , releases Ca 2+ from endoplasmic reticulum (ER) to mitochondrial metabolism. Action
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대체용지 규칙 제 26조 승 작용 (synergistic activation)시키므로 생체 내 운동 모방 효과를 가져을 수 있다. Replacement Paper Rule 26 Synergistic activation can have imitation effects in vivo.
본 명세서에서 사용된 용어에 댕해 간략히 설명한다.  The terminology used herein is briefly described.
용어 "약제학적으로 허용되는 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 제형을 의밈한다.  The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
용어 "수환물"， "용매화물"， "프로드럭", "토토머"， "거울상 이성질체 또는 약학적으로 허용 가능한 부분입훼 이성질체" 역시 상기와 같은 의미를 가진다。  The terms "retainment", "solvate", "prodrug", "tautomer", "enantiomer or pharmaceutically acceptable diastereomer" also have the same meanings as above.
상기 "약제학적으로 허용되는 염，，은， 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 i 산， 예를 들어, 염산, 황산, 질산, 인산， 브롬화수소산， 요오드화수소산 등과 같은 무기산, 타타르산， 포름산， 시트르산, 아세트산， 트리클로로아세트산， 트리플로로아세트산， 글루콘산， 벤조산， 락트산， 푸마르산, 말레인산 살리신산 등과 같은 유기 카본산， 메탄설폰산, 에탄술폰산， 벤젠설폰산, p-를루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가 이 포함된다. 예를 들어， 약제학적으로 허용되는 카르복실산 염에는， 리튬， 나트륨， 칼륨， 칼슘， 마그네슘 등에 의해 형성된 금속염 또는 알 리 토금속 염， 라이신， 아르지닌， 구아니딘 등의 아미노산 염， 디시클로핵실아민， N-메틸 -D-글 "카민， 트리스 (히드록시메틸)메틸아민， 디에탄올아민， 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 (1)의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다. Said "pharmaceutically acceptable salts, silver, i acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like. , Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Acid moieties formed by sulfonic acids, such as toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or allitometal salts formed by lithium, sodium, potassium, calcium, magnesium, and the like. ， Amino acid salts such as lysine, arginine, guanidine, dicyclonuxylamine, N-methyl-D-letter "carmine, tris Organic salts such as (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like. The compounds of formula (1) according to the invention can also be converted to their salts by conventional methods.
용어 "수확물 (hydrate)"은 비공유적 분자간력 (non-covalent intermolecular  The term "hydrate" refers to non-covalent intermolecular
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대체용지 규칙 제 26조 force)에 의해 결합된 화학양론적 (sioichiometric) 또는 비화학양론적 (non- stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다ᅳ Replacement Paper Rule 26 means a compound of the invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by force.
용어 "용매화물 (solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양워 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성， 비독성, 및 /또는 인간에게 투여되기에 적합한 용매들이 있다.  The term “solvate” means a compound of the present invention or a salt thereof comprising a stoichiometric or non stoichiometric lifting solvent bound by non-covalent intermolecular forces. Preferred solvents therein are volatile, non-toxic, and / or solvents suitable for administration to humans.
용어 "프로드럭 (prodrug)"은 생체내에서 모 약제 (parent drug)로 변형되는 물질을 의미한다. 프로드럭은, 몇몇 경우에 있어서， 모 약제보다 투여하기 쉽기 때문에 종좋 사용된다. 예를 들;어, 이들은 구강 투여에 의해 생활성을 얻을 수 있음에 반하여， 모 약제는 그렇지 못할 수 있다. 프로드럭은 또한 모 약계보다 제약 조성물에서 향상된 용해도를 가질 수도 있다. 예를 들어， 프로드릭은, 수용해도가 이동성에 해가 되지만， 일단 수용해도가 이로운 세포에서는， 물질대사에 의해 활성체인 카르복실산으로 가수분해되는, 세포막의 통과胥 용이하게 하는 에스테르 ("프로드럭")로서 투여되는 화합물일 것이다. 프로드럭의 또다른 예는 펩티드가 활성 부위를 드러내도록 물¾대사에 의해 변환되는 산기에 결합되어 있는 짧은 펩티드 (폴리아미노 산)일 수 있다. The term "prodrug" refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example ; Uh, they can achieve bioactivity by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent system. For example, prodric is an ester that facilitates the passage of cell membranes, where the water solubility is detrimental to mobility, but once the water solubility is beneficial, it is hydrolyzed to the carboxylic acid, which is active by metabolism ("Pro" Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by water metabolism to reveal the active site.
용어 "토토머 "는 동일한 화학식 또는 분자식을 가지지만 구성원자들의 연결방식이 다른 구조이성질체의 한 종류로서， 예를 들어， 케토 -에놀 (keto- eno) 구조처럼 계속 양쪽 이성질체 사이를 왕복하며 그 구조가 변화는 것을 의미한다.  The term "tautomer" is a type of structural isomer that has the same chemical formula or molecular formula but differs in the way in which its members are linked, such as a keto-eno structure, which continues to reciprocate between both isomers. Means change.
용어 "거責상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체"는  The term "macro isomer or pharmaceutically acceptable diastereomer"
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대체용지 규칙 제 26조 동일한 화학식 또는 분자식을 가지지만 분자내 원자위 공간 배열이 달라짐에 따라 생기는 이성질체로, 용어 "거울상 이성질체"는 오른손과 왼손의 관계처럼 그 거울상과 서로 겹쳐지지 않는 이성질체를 의미하며, 또한， "부분입체 이성질체，，는 트랜스형, 시스형과 같이 거울상 관계가 아닌 입체이성질체로 본 발명에서는 약학적으로 허용 가능한 부분입체 이성질체로 한정한다. 이들의 모든 이성질체 및 그것의 흔합물들 역시 본 발명의 범위에 포함된다. Replacement Paper Rule 26 Isomers having the same chemical formula or molecular formula but resulting from a change in the arrangement of atomic spaces in the molecule, the term "enantiomer" means an isomer that does not overlap with its mirror image, such as the relationship between the right hand and the left hand, Isomers, are stereoisomers that are not enantiomeric, such as trans and cis, and are limited to pharmaceutically acceptable diastereomers in the present invention, all of their isomers and combinations thereof are also included in the scope of the present invention. .
용어 "알킬 (alkyl)"은 지방족 탄,화수소 그룹을 의미한다. ^ 발명에서 알킬은 어떠한 알켄이나 알킨 부위를 포함하고 있지 않음을 의미하는 "포화 알킬 (saturated alkyl)"과， 적어도 하나의 알켄 또는 알킨 부위를 포함하고 있음을 의미하는 "불포화 알킬 (unsaturated alkyl)"을 모두 포함하는 개념으로 사용되고 있으며, 상세하게는 어떠한 알켄이나 알킨 부위를 포함하고 있지 않음을 의미하는 "포화 알킬 (saturated ^kyl)"일 수 있다. 상기 알킬은 분지형， 직쇄형 또는 환형을 포함할 수 있 ， 또한 구조 이성질체를 포함하므로， 예를 ¾어, C3 알킬의 경우， 프로필， 이¾소 프로필을 의미할 수 있다. The term "alkyl" refers to aliphatic carbon , hydrogen group. ^ Alkyl in the invention means "saturated alkyl" which means that it does not contain any alkenes or alkyne moieties, and "unsaturated alkyl" which means that it contains at least one alkene or alkyne moieties. It is used in a concept that includes all, and in detail may be "saturated alkyl (saturated ^ kyl)" means that it does not contain any alkenes or alkyne sites. It said alkyl can include branched, straight-chain or cyclic, it also includes structural isomers, fish ¾ for example, may refer to the case of C3 alkyl, propyl, isopropyl is ¾.
용어 "알켄 (alkene)"은 적어도 두 개의 탄소원자가 적어도 하나의 탄소 -탄소 이중 결합으로 이루어진 그룹을 의미하며， "알킨 (alkyne)"은 적어도 두 개의 탄소원자가 적어도 하나의 탄소 -탄소 삼중 결합으로 이루어진 그룹을 의미한다.  The term "alkene" refers to a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and "alkyne" means at least two carbon atoms consisting of at least one carbon-carbon triple bond. Means a group.
용어 "헤테로시클로알킬 (heterocycloalky)"은 환 탄소가 산소, 질소， 황 등으로 치환되어 있는 치환체로이다.  The term "heterocycloalky" is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur or the like.
용어 "아릴 (aryl)"은 공유 파이 전자계를 가지고 있는 적어도 하나의 링을 가지고 있는 방향족치환체를 의미한다. 상기 용어는 모노시클릭 또는 융합 링 폴  The term "aryl" means an aromatic substituent having at least one ring having a shared pi electron system. The term monocyclic or fused ring pole
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대체용지 규칙 제 26조 리시클릭 (즉， 탄소원자들의 인접한 쌍들을 나눠 가지는 링들) 그룹들을 포함한다。 치환 경우, 치환기는 오쏘 (0)， 메타 (m), 파라 (p) 위치에 적절하게 결합될 수 있다. Replacement Paper Rule 26 Groups containing cyclic (ie, rings which divide adjacent pairs of carbon atoms). In the case of substitution, the substituents may be appropriately bonded at the ortho ( 0 ), meta (m) and para (p) positions.
용어 "헤테로아릴 (heteroaryl)"은 적어도 하나의 헤테로시클릭 환을 포함하고 있는 방향족 그룹을 의미한다.  The term "heteroaryl" refers to an aromatic group containing at least one heterocyclic ring.
상기 아릴 또는 헤테로아릴의 예로는 페닐, 퓨란， 피란, 피리딜, 피리미딜，트리아질 등을들수 있지만， 이들만으로 한정되는 것은 아니다. 용어 "할로겐"은 주기율표의 17족에 속하는 원소들로, 상세하게는 플루오르， 염소，본름，요오드일 수 있다.  Examples of the aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like. The term "halogen" is an element belonging to group 17 of the periodic table, specifically fluorine, chlorine, cobalt, and iodine.
용어 "아릴옥시"는 방향족치환체를 이루는 어느 하나의 탄소와산소와 결합된 그룹을 의미하며， 예를 들어， 페닐기에 산소가 결합되어 있는 경우 - 0-C6H5, -C6H4-0-로 표시할수 있다. The term "aryloxy" means a group bonded to any one of carbon and oxygen constituting an aromatic substituent, for example, when oxygen is bonded to a phenyl group-0-C 6 H 5 , -C 6 H 4- It can be displayed as 0-.
기타 용어들은 본 발명이 속하는 분야에서 통상적으로 이해되는 의미로서 해석될 수 있다.  Other terms may be interpreted as meanings commonly understood in the field to which the present invention belongs.
본 발명에 따른 바람직한 예에서,  In a preferred example according to the invention,
상기 화학식 (1)의 화합물은 하기 화학식 (2)의 화합물일 수 있다.  The compound of formula (1) may be a compound of formula (2).
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대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000016_0001
Figure imgf000016_0001
상기 식에서， ，！ ！^！^， 세：^： ，： 및 ¾는 제 1항에서 정의된 바와 다.  In the above formula,！！ ^！ ^ ， Tax ： ^ ： ， ： and ¾ are as defined in paragraph 1.
상기 화학식 (2)의 화합물은 하기 화학식 (2-1)의 화합물로 예시될 수 있으나, 하기 화¾물이 본 발명을 한 하는 것은 아니다.  The compound of formula (2) may be exemplified by the compound of formula (2-1), but the following compounds do not limit the present invention.
Figure imgf000016_0002
Figure imgf000016_0002
본 발명에 따른또 다른 예에서, 상기 화학식 (1)의 화합물은 하기 화학식 화학식 (4)의 화할물일 수 있다.  In another example according to the invention, the compound of formula (1) may be a compound of formula (4).
14 14
대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000017_0001
Figure imgf000017_0001
상기 식에서,  Where
상기 내지 ， R6, Ql5 Q2 X X2, X3, X4, X5및 X6은 제 1항에서 정의된 바와 같다. To the, R6, Q l5 Q 2 XX 2, X 3, X4, X 5 and X 6 are as defined in claim 1.
상기 화학식 (3)의 화합물과 화학식 (4)의 화합물에서，  In the compound of formula (3) and the compound of formula (4),
상세하게는， 상기 Ri 및 는 각각 독립적으로 H, F, CI, -N(CH3)2, - NHCOCH3, 또는 -NHCOC3H5이고, Xi 내지 X4는 각각 C(H)이고, X5 및 X6은 각각 N일 수 있고， 좀 더 상세하게는， 상기 및 ¾는 각각 H 이고， ¾ 내지 X4는 각각 C(H)이고， X5 및 X6은 각각 N일 수 있다. Specifically, Ri and are each independently H, F, CI, -N (CH 3 ) 2 ,-NHCOCH 3 , or -NHCOC 3 H 5 , Xi to X4 are each C (H), X 5 And X 6 may each be N, and in more detail, ¾ and ¾ are each H, ¾ to X4 are each C (H), and X 5 and X 6 may be each N.
또한, 상세하게는， R3 및 R6는 각각 독립적으로， H, 할로겐 원소， 치환 또는 비치환의 C1-C9 알킬, 치환 또는 비치환의 C3-C8 시클로알킬, 치환 또는 비치환의 -(CR'5R'6))m-C4-C10 아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4- C10 아릴옥시, 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로아릴, 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로시클로알킬， 치환 또는 비치환의 - (CHR'5)m-NR'3R'4, -CO(0)R'3> In detail, each of R 3 and R 6 independently represents H, a halogen element, a substituted or unsubstituted C1-C9 alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted-(CR ' 5 R' 6)) m -C4-C10 aryl, substituted or unsubstituted - (CR '5 R' 6 ) m -C4- C10 aryloxy, substituted or unsubstituted - (CR '5 R' 6 ) m -C4-C10 heteroaryl Aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted-(CHR ' 5 ) m -NR' 3 R ' 4 , -CO (0) R'3>
15 15
대체용지 규칙 제 26조 -CON '3R'4, -NR'3R'4, -NR'3(C(0)R'4), 또는 상기 화학식 (1)의 화합물이 "A"일 때 -CH2A이며; Replacement Paper Rule 26 -CON ' 3 R' 4 , -NR ' 3 R' 4 , -NR ' 3 (C (0) R' 4 ), or -CH 2 A when the compound of formula (1) is "A";
R4는 할로겐 원소， 치환 또는 비치환의 C2-C9 알킬， 치환 또는 비치환의 C1-C10 알콕시， 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C2-C8 헤테로시클로알킬, 치환 또는 비치환의 C4-C10 아릴, 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C1-C10 헤테로아릴, 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 아릴， 치환 또는 비치환의 - (CR, 5R,6)m-C4-C10 아릴옥시， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로아릴, 치환 또는 비치환의 -(CHR'5)m-NR'3-C4-C10 아릴， 치환 또는 비치환의 -(CR' R'6)m-C4-C10 헤테로시클로알킬， 치환 또는 비치환의 - (CR'5R'6)m-NR'3R'4, 치환 또는 비치환의 -(CR'5R'6)m-OR'3, -NR'3R'4, 또는 상기 화학식 (1)의 화합물이 "A"일 때 -A이고; R4 is halogen, substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4- C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 aryl, substituted or unsubstituted-(CR , 5 R , 6) m-C4-C10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heteroaryl, substituted or unsubstituted-(CHR ' 5 ) m -NR'3 -C4-C10 aryl, substituted or unsubstituted-(CR 'R'6) m -C4-C10 heterocycloalkyl, substituted or unsubstituted-(CR' 5 R ' 6 ) m -NR' 3 R ' 4 , substituted Or unsubstituted-(CR ' 5 R' 6 ) m -OR ' 3 , -NR' 3 R ' 4 , or -A when the compound of formula (1) is "A";
여기서， ，3， R'4는 각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬, 치환 또는 비치환의 C3-C8 시클로알킬, 치환 또는 비치환의 -(CH2)m- C4-C10 아릴, 치환 또는 비치환의 -(CH2)m-C4-C10 아릴옥시， -CO(0)R"3, 또는 R'3 및 R'4는 상호 결합에 의해 치환 또는 비치환의 C4-C10 해테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C4-C10 헤테로아릴의 환형 구조를 이를 수 있고;Where, 3, R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryl, substituted Or unsubstituted-(CH 2 ) m -C 4 -C 10 aryloxy, -CO (0) R " 3 , or R'3 and R'4 are substituted or unsubstituted by C4-C10 heterocycloalkyl Cyclic structures or cyclic structures of substituted or unsubstituted C4-C10 heteroaryl;
's, 및 R'6각각 독립적으로 수소 또는 C1-C3 알킬이며; R"3는 C1-
Figure imgf000018_0001
's, and R'6 are each independently hydrogen or C1-C3 alkyl; R " 3 is C1-
Figure imgf000018_0001
16 16
대체용지 규칙 제 26조 며; Replacement Paper Rule 26 ;
여기서， 치환기는 ' 히드록시， 할로겐 원소， C1-C10 알킬， C2-C10 알케닐， Wherein the substituent is hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl,
C2-C10 알키닐, C1-C10 알콕시， C1-C10 알콕시카르보닐， C3-C8 시클로알킬， C2-C8 헤테로시 "로알킬， C4-C10 아¾, 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 하나 이상이며; C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocylo " roalkyl, C4-C10 a¾, and C2-C10 heteroaryl One or more;
„!은 1 내지 4의 자연수이고;  „! Is a natural number from 1 to 4;
헤테로 원자는 O 및 S에서 선택된 하나 이상일 수 있다.  The hetero atom may be one or more selected from O and S.
더욱 상서)하게는，： R3 및 R6는 갉각 독립적으로, H, 할로겐 원소， 치환 또는 Hᅵ치환의 C1-C9 알킬이며; Moreover): R 3 and R 6 are each independently H, halogen, substituted or Hsubstituted C1-C9 alkyl;
는 할로겐 원소， 치환또는 비치환의 C2-C9 알킬일 수 있다. 또한， 상세하게는， 이 COR7이고 Q2이 COR8일 때， (^과 Q2는 이중 결합을 이루고 May be a halogen element, a substituted or unsubstituted C2-C9 alkyl. Also, in detail, when COR 7 and Q 2 is COR 8 , ( ^ and Q 2 form a double bond
R7 및 R8는 각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬, 치환 는 비치환의 C4-C10 아릴, 치환 또는 비치환의 C4-C10 아릴옥시， 치환 ^는 비치환의 C2-C10 헤테로아월， -CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, - SO(0)NR'7R'8, -S03R'7, -P03R'7, -CSNR'7R'8, 또는 R7 및 R8는 상호 결합에 의해 처환 또는 비치환의 C3-C10 헤테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C3-C10 헤테로아릴의 환형 구조를 이를 수 있으며, R 7 and R 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted is unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted ^ is unsubstituted C2-C10 heteroawall, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R' 7 , -SO (0) NR ' 7 R' 8 , -S0 3 R ' 7 ,- P0 3 R ' 7 , -CSNR' 7 R ' 8 , or R 7 and R 8 are mutually bonded to form a cyclic structure of a substituted or unsubstituted C3-C10 heterocycloalkyl, or a substituted or unsubstituted C3-C10 heteroaryl. Can have an annular structure,
여기서 R'7및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， Wherein R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl,
17 17
대체용지 규칙 제 26조 치환 또는 비치홧의 C3-C8 시클로알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아 옥시， 치환 또는 비치환의 C1-C8 헤테로아릴， 치환 또는 비치환의 -(CR"7R"8)m'-C4-C10 아릴이고; 여기서 R"7 및 R"8는 각각 독립적으로 수소， Cl-C^ 알킬이고; Replacement Paper Rule 26 Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aoxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR " 7 R " 8 ) m'-C4-C10 aryl; Wherein R ″ 7 and R ″ 8 are each independently hydrogen, Cl-C ^ alkyl;
Q^l 치환 또는 비치환의 C3 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는, 이 CO이: μ Q2가 치환 또는 비치환의 C3 헤테로시클로알킬의 환형 구조일 때， 과 Q2는 단일 결합을 이루고 And Q 2 is a single bond when Q ^ l substituted or unsubstituted C3 heterocycloalkyl cyclic structure and Q 2 is CO or this CO is: μ Q 2 is a cyclic structure of substituted or unsubstituted C3 heterocycloalkyl. Fulfilling
여기서, 치환기는 C1-C5이며; Wherein the substituent is C 1 -C 5 ;
m，은 각각독립적으로 1 내지 4의 자연수이고;  m, are each independently a natural number of 1 to 4;
헤테로 자는 Ν, Ο 및 S에서 선택된 하나 이상일 수 있다.  The hetero atom may be one or more selected from Ν, Ο and S.
더욱 상세하게는， 이 COR7이고 Q2이 COR8일 때， (^과 Q2는 이중 결합을 이루고 More specifically, when is COR 7 and Q 2 is COR 8 , (^ and Q 2 form a double bond
R7 및 ¾ 각각 독립적으로 수소, 치환 또는 비치환의 C1-C6 알킬， - CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, -SO(0)NR'7R'8, -CSNR'7R'8, 또는 R7 및 ¾는 살호 결합 의해 치환 또는 비치환의 C3-C5 헤테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C3-C5 헤테로아릴의 환형 구조를 이를 수 있으며, R 7 and ¾ each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R' 7 , -SO (0) NR ′ 7 R ′ 8 , —CSNR ′ 7 R ′ 8 , or R 7 and ¾ are cyclic structures of substituted or unsubstituted C3-C5 heterocycloalkyl by a salicylic bond, or substituted or unsubstituted C3-C5 hetero Can lead to the cyclic structure of aryl,
여기서 R'7및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬, 또는 치환 또는 비치환의 NR"7R"8이고; 여기서 R"7 및 R"8는 각각 독립적으로 수 Wherein R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted NR " 7 R"8; Where R " 7 and R" 8 are each independently
1β 1β
대체용지 규칙 제 26조 소， a-c3 알킬이고; Replacement Paper Rule 26 Bovine, a-c3 alkyl;
Qi이 비치환의 C3 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는, CO이고 Q2가 비치환의 헤테로시클로알킬의 환형 구조일 때， (^과 Q2는 단일 결합을 이루고 When Qi is a cyclic structure of unsubstituted C3 heterocycloalkyl and Q 2 is CO or CO and Q 2 is a cyclic structure of unsubstituted heterocycloalkyl, (^ and Q 2 form a single bond and
헤테로 원자는 Ν, Ο 및 S에서 선택된 하나 이상일 수 있다.  The hetero atom may be one or more selected from Ν, Ο and S.
좀 더 구체적으로， 상기 화학식 (3)의 화합물과 화학식 (4)의 화합물은 하기에서 표현된 화합물들 증 하나 이상으로 예시될 수 있으나, 하기 화합물들이 본 발명을 한정하는 것은 아니다.  More specifically, the compound of formula (3) and the compound of formula (4) may be exemplified by one or more of the compounds represented below, but the following compounds do not limit the present invention.
Figure imgf000021_0001
Figure imgf000021_0001
19 19
대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000022_0001
Figure imgf000022_0001
본 발명은또한화학식 (1)의 화합물을 제조하는 방법을 제공한다. 본 발명이 속한 분야에서 통상의 지식을 가진 자 ("당업자")라면， 화학식 (1)의 구조를 바탕으로 다양한 방법에 의해 화합물의 제조가 가능할 것이며， 이러한  The present invention also provides a process for preparing the compound of formula (1). Those skilled in the art to which the present invention pertains (“an authorized person”) will be able to prepare compounds by various methods based on the structure of formula (1), and
20 20
대체용지 규칙 제 26조 방법들은 모두 본 발명의 범주가 포함되는 것으로 해석되어야 한다. 즉， 본 명세서에 기재 5)어 있거나, 선행기专에 개시된 여러 합성법들을 임의로 조합하여， 본 발명의 범주내에서， 상기 화학식 (1)의 화합물의 제조가 가능하다. 따라서 본 발명의 범주가 이들만으로 한정되는 것은 아니다. 하나의 예로서， 상기 화학식 (1)의 화합물은 그 구조에 따라， Replacement Paper Rule 26 All methods should be construed as including the scope of the present invention. That is, within the scope of the present invention, it is possible to prepare the compound of formula (1) by arbitrarily combining various synthesis methods described in this specification or disclosed in the prior art. Therefore, the scope of the present invention is not limited only to these. As one example, the compound of formula (1) according to the structure,
A) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계; A) reacting a compound of formula (5) with a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
B) 단계 A)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합물에 -N02를 도입하 단계; B) reacting the compound produced in step A) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C) 단계 B)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C) reducing -N0 2 to -NH 2 through the reduction reaction of the compound produced in step B);
D) 단계 ς)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D) subjecting the compound produced in step ς) to cyclization reaction under acidic conditions;
Ε) 단계 D)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후， 선택적으로삼화 반웅을 하는 단계; 및 Ε) optionally reacting the compound produced in step D) under basic conditions, and then selectively reacting the trihydration; And
F) 단계 Ε)에서 생성된 화합물을 환원 반웅을 시켜 최종 생성물을 생성하는 단계; F) reacting the compound produced in step Ε) to produce a final product;
21 21
대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000024_0001
Figure imgf000024_0001
Figure imgf000024_0002
상기 식어!서,
Figure imgf000024_0002
Cool above!
Χ,, Χ2, Χ3, Χ4, Ri, R2, 및 R4는 제 1항에서 정의된 바와 같고; ?,? 2 ,? 3 ,? 4, Ri, R 2 , and R4 are as defined in claim 1;
Z，는 할로겐 원소 또는 R'COO-이며， 여기서 R，는 치환 또는 비치환의 C1-C9 알킬， 치환 또는 비치환의 -(CH2)m-C4-C10 아릴， 치환 또는 비치환의 -(CH2)m-C4-C10 아릴옥시 또는 치환 또는 비치환의 C4-C10 아릴이며， 여기서 치환기는 히드록시， 할로겐 원소， C1-C10 알킬, C2-C10 알케닐， C2-C10 알키닐， C1-C10 알콕시， C1-C10 알콕시카르보닐, C3-C8 시클로알킬， C3-C8 헤테로시클로알킬， C4-C10 아릴， 및 C5 Z is halogen or R'COO-, where R is substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryloxy or substituted or unsubstituted C4-C10 aryl, wherein the substituents are hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1 -C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5
22 22
대체용지 규칙 제 26조 -CIO헤테로아릴로 이루어진 군에서 설택된 하나 이상이고; 및 Replacement Paper Rule 26 -At least one selected from the group consisting of CIO heteroaryl; And
Y는 -NH2, -NH3Z또는 -N02이고， 여기서 Z는 할로겐 원소이다. Y is -NH 2 , -NH 3 Z or -N0 2 , where Z is a halogen element.
상기에서 정의하는 -NH3Z는 - ¾와 HZ이 배위 결합을 한상태일 수 있다. As defined above, -NH 3 Z may be in a coordination bond between -¾ and HZ.
. 본 발명에서 염기 조건은 트리에틸 아민， 다이아이소프로필에틸아민 또는 피리딘을사용하여 형성할수 있으나， 이들로 제한되는 것은 아니다. 본 발명에서 산 조건은 질산, 산, 아세트산 또는 아세트산 무수물을 사용하여 형성할수 있으나, 이들로 겨 j한되는 것은 아니다.  . Base conditions in the present invention can be formed using, but are not limited to, triethyl amine, diisopropylethylamine or pyridine. Acid conditions in the present invention can be formed using nitric acid, acid, acetic acid or acetic anhydride, but are not limited to these.
본 발명에서， 환원 반웅은 예를 들어， 수소화 반응을 통해 진행할 수 있고 수 있^며， 상기 수소화 반웅은 수소를 Pd/C, Zn등의 금속 촉매와 반웅시키는 과정으로 당업계에 널리 알려진 바 자세한 설명은 이하 생략한다.  In the present invention, the reduction reaction can be carried out, for example, through a hydrogenation reaction, the hydrogenation reaction is well known in the art as a process of reacting hydrogen with a metal catalyst such as Pd / C, Zn Description is omitted below.
또는， 좀 더 구체적으로 상기 단계 F)의 환원 반웅은 Na2S204와 같은 환원제를 이용하 진행할수 있다. Alternatively, more specifically, the reaction reaction of step F) may be performed using a reducing agent such as Na 2 S 2 0 4 .
본 발명에서, 고리화 반웅은 반웅물에서 고리를 형성하는 반웅을 의미한다.  In the present invention, cyclized reaction means a reaction that forms a ring in the reaction product.
본 발명에서 "선택적"이란 경우에 따라 해당 반웅이 포함될 수도 있고 포함되지 않을수도 있음을 의미한다.  In the present invention, "optional" means that the reaction may or may not be included in some cases.
상기 제조방법은，  The manufacturing method is
G) 상기 단계 F)에서 생성된 화합물을 R7COO R7C0C1, (R7)20, R7COOH, RgCOCl, 또는 (R8)20(단, 상기 R7 및 ¾은 각각 독립적으로 제 1항에서 정의한 바와 같다)과 염기 조건 또는 금속 촉매 하에서 반웅시켜 최종 생성물을 생성하는 단계; G) The compound produced in step F) is R 7 COO R 7 C0C1, (R 7 ) 2 0, R 7 COOH, RgCOCl, or (R 8 ) 2 0 (wherein R 7 and ¾ are each independently Reacting under basic conditions or a metal catalyst to produce the final product;
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대체용지 규칙 제 26조 를추가로 포함할수 있다. Replacement Paper Rule 26 You can additionally include
상기 금속 촉매는 당업계에 려진 것이라면 제한이 없으며， 예를 들어 Pd/C, Zn등밀 수 있다.  The metal catalyst is not limited as long as it is known in the art, and may be, for example, Pd / C, Zn.
상기 제조방법은，  The manufacturing method is
H) 상기 단계 G)에서 생성된 확합물을 NR"7R"8C(0)C1 (단， 상기 R"7 및 R"8은 각각 독립적으로 제 1항에서; 정의한 바와 같다)과 반웅시켜 최종 생성물을 생성하는 단계;를추가로 포梦할수 있다. H) reacting the resulting mixture in step G) with NR ″ 7 R ″ 8 C (0) C1 (wherein R ″ 7 and R ″ 8 are each independently defined in claim 1 as defined above) Producing a final product;
NR"7R"8C(0)C1은 상세하게는, 디메틸 카바모일 클로라이드 (dimetyl carbamoyl chloride) 일 수.있다. NR ″ 7 R ″ 8 C (0) C1 may be, in particular, dimethyl carbamoyl chloride.
본 발명은，다른 예로，  The present invention, as another example
화학식 (1)의 화합물을 제조하는 방법으로서,  Method for preparing a compound of formula (1),
A 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화한물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계;  A reacting a compound of formula (5) and a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
B 단계 에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합물에 -N02를도입하는 단계; Reacting the compound produced in step B with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C 단계 에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; Reducing -N0 2 to -NH 2 through a reduction reaction of the compound produced in step C;
D 단계 )에서 생성된 화합물을 산조건에서 고리화 반웅을 시키는 단계;  Subjecting the compound produced in step D) to cyclic reaction under acidic conditions;
대체용지 규칙 제 26조 E 단계 D,)에서 생성된 확합물을 선택적으로 염기 조건에서 반웅시킨 후, 선택적으로 산화 반웅을 하는 단계; 및 Replacement Paper Rule 26 Selectively reacting the resultant produced in step D,) under basic conditions, followed by selective oxidation reaction; And
F 단계 E!)에서 생성된 화합물을 고리화 반웅을 시켜 최종 생성물을 생성하는 단계; F step E ! Cyclization of the compound produced in) to produce the final product;
를 포함하는 것을 특징으로 하는 제조 방법:을 제공한다. It provides a manufacturing method comprising a.
화학식 (5)， 화학식 (6) 및 화학식 (7)의 화합물은 제 12항에 정의된 바와 같다.  Compounds of formula (5), formula (6) and formula (7) are as defined in claim 12.
상기 고릭화 반웅은 CHR9R10N92 또는 캄퍼서포닉산 (Camphorsulfonic cid)과 반응시키는 과정을 포함할 수 있고， 상기 식에서， R9, R10은 각각 독 ¾적으로 수소， 히드록시， 할로겐 원소， C1-C10 알킬, C2-C10 알케닐， C2-C10 알키닐， C1-C10 알콕시， C1-C10 알콕시카르보닐， C3-C8 시클로알킬， C2-C8 헤테로시클로알칼， C4-C10 아릴， 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 하나 이상이다. The cyclic reaction may include reacting with CHR 9 R 10 N92 or Camphorsulfonic cid, wherein R 9 and R 10 are each ¾ hydrogen, hydroxy and halogen elements. , C1-C10 Alkyl, C2-C10 Alkenyl, C2-C10 Alkynyl, C1-C10 Alkoxy, C1-C10 Alkoxycarbonyl, C3-C8 Cycloalkyl, C2-C8 Heterocycloalkali, C4-C10 Aryl, and C2 One or more selected from the group consisting of -C10 heteroaryl.
상세하게는， 상기 식에서， R9, R10은 각각 독립적으로 수소， 또는 C1-C 10 알킬일 수 있고, 더욱 상세하게는 수소, 메틸, 에틸， 또는 프로필일 수 있 다. Specifically, in the above formula, R 9 , R 10 may be each independently hydrogen, or C 1 -C 10 alkyl, more specifically hydrogen, methyl, ethyl, or propyl.
본 발명은， 다른 예로，  In another embodiment,
화학식 (1)의 화합물을 제조하는 방법으로서,  Method for preparing a compound of formula (1),
A2) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계;A 2 ) reacting a compound of formula (5) and a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
) 단계 A2)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 기 화학식 ) Reacting the compound produced in step A 2 ) with HN0 3 under acidic conditions
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대체용지 규칙 제 26조 (7)의 화합물에 -N02를 도입하는 단계; Replacement Paper Rule 26 Introducing -N0 2 to the compound of (7);
C2) 단계 B2)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 2 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step B 2 );
D2) 단계 C2)에서 생성된 화합물을 산 조건에서 고리화 반응을 시키는 단계;D 2 ) subjecting the compound produced in step C 2 ) to a cyclization reaction under acidic conditions;
) 단계 D2)에서 생성된 확합물을 선택적으로 염기 조건에서 반웅시킨 후, 선택적으로산화 반웅을 하는 단계; 및 ) Optionally reacting the resultant produced in step D 2 ) under basic conditions, followed by selective oxidation reaction; And
F2) 상기 단계 )에서 생성된 확합물을 ( )20， (¾)20， R3Z"또는 ¾Ζ" (여기서, R3 및 ¾은 각각 제 1항에서 정의한 바와 같고， Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; F 2 ) the condensate produced in step) () 2 0, (¾) 2 0, R 3 Z "or ¾" (wherein R 3 and ¾ are as defined in claim 1, respectively, and Z " Reacting with an elemental halogen) to produce a final product;
G2) 상기 단계 F2)에서 생성된 화합물을 R7COOH, R7C0C1, (R7)20, R7COQH, RsCOCl, 및 (R8)20(단， 상기 R7및 Rg은 각각 독립적으로 제 1항에서 정의한 바와 같다)에서 선택된 하나 이상을 금속 촉매 하에서 반웅시켜 최종 생성물을 생성하는 단계; 를 포함하는 것을 특징으로 하는 제조 방법. G 2 ) The compound produced in step F 2 ) is R 7 COOH, R 7 C0C1, (R 7 ) 2 0, R 7 COQH, RsCOCl, and (R 8 ) 2 0 (wherein R 7 and Rg are Reacting at least one selected from each independently as defined in claim 1 under a metal catalyst to produce a final product; Manufacturing method comprising a.
화학식 (5), 화학식 (6) 및 화학식 (7)의 화합물은 제 12항에 정의된 바와 같다.  Compounds of formula (5), formula (6) and formula (7) are as defined in claim 12.
본 발명은， 다른 예로，  In another embodiment,
화학식 (1)의 화합물을 제조하는 방법으로서，  As a method for preparing the compound of formula (1),
A3) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 A 3 ) A compound of formula (5) and a compound of formula (6)
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대체용지 규칙 제 26조 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계; Replacement Paper Rule 26 Reacting to synthesize a compound of formula (7);
B3) 단계 A3)에서 생성된 화합물과 HN03을 산 조건에서 반응시켜 하기 화학식 (7)의 화합물에 -N02를도입하는 단계; B 3 ) reacting the compound produced in step A 3 ) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C3) 단계 ¾)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 3 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step ¾);
D3) 단계 C3)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D 3 ) subjecting the compound produced in step C 3 ) to cyclization reaction in acid conditions;
¾) 단계 D3)에서 생성된 확합물을 선택적으로 염기 조건에서 반웅시킨 후, 선택적으로 산화 반웅을 하는 단계; 및 ¾) optionally reacting the resultant produced in step D 3 ) under basic conditions, followed by selective oxidation reaction; And
F3) 상기 단계 ¾)에서 생성된 화합물을 (R3)20, (¾)20， R3Z"또는 ¾Ζ" (여기서, R3 및 ¾은 각각 제 1항에서 정의한 바와 같고, Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; F 3 ) The compound produced in the step ¾) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or ¾" (wherein R 3 and ¾ are as defined in claim 1, respectively, Z is Reacting with " a halogen element " to produce the final product;
G3) 상기 단계 F3)에서 생성된 화합물을 NR"7R"8C(0)C1 (단, 상기 R"7 및 R"8은 각각 독립적으로 제 1항에서 정의한 바와 같다)과 반웅시키고 선택적으로 (R7)20, ( )20과 반웅시켜 (단， 상기 R7및 R8은 각각 독립적으로 제 1항에서 정의한 바와 같다) 최종 생성물을 생성하는 단계;를 포함하는 것을 특징으로 하는 제조 방법을 제공한다. G 3 ) reacting the compound produced in step F 3 ) with NR ″ 7 R ″ 8 C (0) C1, wherein R ″ 7 and R ″ 8 are each independently as defined in claim 1 and And optionally reacting with (R 7 ) 2 0, () 2 0 (wherein R 7 and R 8 are each independently as defined in claim 1) to produce a final product. It provides a manufacturing method.
상기 제조방법은,  The manufacturing method,
H3) 상기 단계 G3)에서 생성된 화합물을 수소화 환원 반옹시켜 최종 생성물을 H 3 ) reacting with hydrogenation reduction of the compound produced in step G 3 ) to give a final product
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대체용지 규칙 제 26조 생성하는 단계;를 추가로 포함할 수 있다. Replacement Paper Rule 26 Generating step; may further include.
본 발명은, 또 다른 예로，  As another example, the present invention
화학식 (1)의 화합물을 제조하 방법으로서,  As a process for preparing the compound of formula (1),
A4) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반응시켜 하기 화학식 (7)의 화합물을 합성하는 단계;  A4) synthesizing the compound of formula (7) by reacting a compound of formula (5) with a compound of formula (6) under basic conditions;
B4) 단계 A4)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합물에 -N02를 £입하는 단계; B 4 ) reacting the compound produced in step A4) with HN0 3 under acidic conditions to introduce -N0 2 into the compound of formula (7);
C4) 단계 B4)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 4 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step B 4 );
D4) 단계 C4)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D 4 ) subjecting the compound produced in step C 4 ) to cyclization reaction under acidic conditions;
E4) 단계 D4)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후， 선택적으로 산화 반웅을 하는 단계; 및 E 4 ) optionally reacting the compound produced in step D 4 ) under basic conditions, followed by selective oxidation reaction; And
F4) 상기 단계 E4)에서 생성된 화합물을 (R3)20, (¾)20, R3Z" 또는 ¾Ζ" (여기서, R3 및 R6은 각각 제 1항에서 정의한 바와 같고， Z"는 할로겐 원소이다)과 반응시켜 최종 생성물을 생성하는 단계; F 4 ) the compound produced in step E 4 ) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or ¾"", where R 3 and R6 are as defined in claim 1, Z ″ is a halogen element) to produce a final product;
G4) 상기 단계 F4)에서 생성된 화합물을 S03와 반웅시킨 후， 수소화 환원반웅을 시켜 최종 생성물을 생성하는 단계;를 추가로 포함할 수 있다. 본 발명은, 또 다른 예로， G 4 ) after reacting the compound produced in step F 4 ) with SO 3 , performing a hydrogenation reaction to produce a final product. As another example, the present invention
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대체용지 규칙 제 26조 화학식 (i)의 화합물을 제조하는 방법으로서， Replacement Paper Rule 26 As a method of preparing a compound of formula (i),
A5) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계; A 5 ) reacting a compound of formula (5) and a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
B5) 단계 A5)에서 생성된 화합물과 HN03을 산 조건에서 반응시켜 하기 화학식 (7)의 화합물에 -N02를 도입하는 단계; B 5 ) reacting the compound produced in step A 5 ) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C5) 단계 B5)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 5 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step B 5 );
D5) 단계 C5)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계;D 5 ) subjecting the compound produced in step C 5 ) to cyclization reaction under acidic conditions;
) 단계 D5)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후， 선택적으로 산화 반웅을 하는 단계; 및 ) Optionally reacting the compound produced in step D 5 ) under basic conditions, followed by selective oxidation reaction; And
F5) 상기 단계 )에서 생성된 화합물을 (R3)20, (¾)20， R3Z"또는 RiZ" (여기서， R3 및 Re은 각각 제 1항에서 정의한 바와 같고, Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; F 5 ) The compound produced in the step) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or RiZ" (wherein R 3 and Re are as defined in claim 1, respectively, Z " Is a halogen element) to produce a final product;
G5) 상기 단계 F5)에서 생성된 화합물을 R7NZ"' 또는 RgNZ'" (단， 상기 R7 및 Rg은 각각 독립적으로 계 1항에서 정의한 바와 같고, Z"，는 할로겐 원소이다)와 반웅시킨 후， 수소화 환원반웅을 시켜 최종 생성물을 생성하는 단계;를 제공한다. G 5) The compound produced in Step F 5) R 7 NZ "'orRgNZ'" (however, the R 7 and Rg are as defined in the system 1, each independently, Z ", is a halogen atom) After reacting with, reacting with hydrogenation to produce a final product.
상기한 본 발명에 따른 반웅이 완결된 후에 일반적인 흔합물의 분리는 통상적인 후처리 방법， 예를 들어 관크로마토그래피, 재결정， HPLC 을 통하여 분리할  After completion of the reaction according to the present invention described above, the separation of the general mixture may be separated by conventional post-treatment methods such as tube chromatography, recrystallization, and HPLC.
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대체용지 규칙 제 26조 수 있다. Replacement Paper Rule 26 Can be.
보다 자세한 내용은 이후 설명하는 다수의 실시예 및 실험예들에서 설명한다.  More details are described in a number of examples and experimental examples which will be described later.
본 발명은 또한, (a) 약리학적 유효량의 상기 화학식 (1)의 화합물， 그것의 약제학적으로 허용되는 염, 수화물， 용매화물， 토토머， 거을상 이성질체 및 /또는 약학적으로 허용 가능한 부분입체 이성질체; 및 (b) 약제학적으로 허용되는 담체， 회석제， 또는 부형제， 또는 이들의 조합;을 포함하는 것으로 구성된 대사성 질환 치료 및 예방을 위한 약제 조성물을 제공한다.  The present invention also provides a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate, tautomer, diastereomer and / or pharmaceutically acceptable diastereomer thereof. Isomers; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; provides a pharmaceutical composition for treating and preventing metabolic diseases.
용어 "약제 조성물 (pharmaceutical composition)"은 본 발명의 화합물과 희석제 또는 담체와 같은 다른 화학 성분들의 흔합물을 의미한다. 약제 조성물은 생물체내로 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술들이 존재하며, 여기에는 경구， 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만， 이들만으로 한정되는 것은 아니다. 약제 조성물은 염산， 브롬산， 황산， 질산, 인산， 메탄食폰산， P-를루엔술폰산， 살리실산 등과 같은 산 화합물 을 반웅시켜서 얻어질 수도 있다.  The term "pharmaceutical composition" means a mixture of a compound of the invention with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering a compound, including but not limited to oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may be obtained by reacting an acid compound such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methane couric acid, P-luenesulfonic acid, salicylic acid and the like.
용어 "약리학적 유효량 (therapeutically effective amount)"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 양을 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 (바람직하게  The term “therapeutically effective amount” refers to, to some extent, alleviate or reduce one or more symptoms of the disorder being treated, or delay the onset of a clinical marker or symptom of a disease that requires prevention. It means the amount of active ingredient effective to. Thus, the pharmacologically effective amount may be defined as (1) the effect of reversing the rate of progression of the disease, (2) the effect of inhibiting further progression of the disease to some extent, and / or (3) one or more symptoms associated with the disease. Relief (preferably
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대체용지 규칙 제 26조 는, 제거)하는 효과를 가지는 양을 의미한다. 약리학적 유효량은 치료를 요하는 질병에 대한 공지된 생채내 (in vivo) 및 생체외 (in vitro) 모델 시스템에서 화합물을 실험함으로써 경험적으로 결정될 수 있다. Replacement Paper Rule 26 Means an amount having the effect of removing). A pharmacologically effective amount can be determined empirically by experimenting with compounds in known in vivo and in vitro model systems for diseases in need of treatment.
용어 "담체 (carrier)"는 세포 또는 조직내로의 화합물의 부가를 용이하게 하는 화합물로 정의된다. 예를 들어， 디메틸 술폭사이드 (DMSO)는 생물체의 세포 또는 조직내로의 많은 유기 화합물들의 투입을 용이하게 하는 통상 사용되는 담체이다.  The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into living cells or tissues.
용어 "회석제 (diluent)"는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게 되는 물에서 회석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용뒤는 버퍼 용액은 포스페이트 버퍼 식염수이며， 이는 인간 용액의 염 상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에， 버퍼 회석제가 화합물의 생물학적 활성을 변형하는 은 드물다.  The term "diluent" is defined as a compound that is not only to stabilize the biologically active form of the compound of interest, but also to be soluble in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. After normal use, the buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents are rarely modifying the biological activity of a compound.
여기에 사용된 화합물들은 인간 환자에게 그 자체로서， 또는 결합 요법에서와 같이 다른 활성 성분들과 함께 또는 적당한 담체나 부형제와 함께 합된 약제 조성물로서, 투여될 수 있다. 본 웅용에서의 화합물의 제형 및 투여에 관한 기술은 "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PAᅳ， 18th edition, 1990에서 확인할수 있다.  The compounds used herein may be administered to a human patient as such or in combination with other active ingredients as in combination therapy or in combination with a suitable carrier or excipient. Techniques for the formulation and administration of compounds in the present formulations can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
본 발명의 약제 조성물은， 예를 들어， 통상적인 흔합， 용해， 과립화， 당제-제조， 분말화, 에멀션화， 캡슐화, 트래핑화 또는 동결건조 과정들의 수단에 의해， 공지 방식으로 제조될 수 있다.  The pharmaceutical compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes. .
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대체용지 규칙 제 26조 따라서, 본 발명에 따른 사용을 위한 약제 조성물은, 약제학적으로 사용될 수 있는 제형으로의 활성 화 물의 처리를 용이하게 하는 부형제들 또는 보조제들을 포함하는 것으로 구성되어 있는 하나 또는 그 이상의 약리학적으로 허용되는 담체를 사용하여 통상적인 방법으로 제조될 수도 있다. 적합한 제형은 선택된 투여 루트에 따라 좌우된다. 공지 가술들, 담체 및 부형제들 중의 어느 것이라도 적합하게， 그리고 당해 분야, 예를 들어, 앞서 설명한 Remingston's Pharmaceutical Sciences에서 이해되는 바와 같이 사용될 수 있다。 본 발명에서는 화학식 (1)의 화합물을 목적하는 바에 따라 주사용 제제 및 경구용 제제 등으로 제형화될 수 있다. Replacement Paper Rule 26 Thus, pharmaceutical compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the actives into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above. In the present invention, a compound of formula (1) And may be formulated as an injectable preparation or an oral preparation and the like.
주사를 위해서， 본 발명의 성분들은 액상 용액으로, 바람직하게는 Hank 용액， Ringer 용액， 또는 생리 숴염수 용액과 같은 약리학적으로 맞는 버퍼로 제형될 수 있다. 점막 투과 予여를 위해서， 통과할 배리어에 적합한 비침투성제가 제형에 사용된다. 그러한 비침투성제들은 당업계에 일반적으로 공지되어 있다.  For injection, the components of the present invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution. For mucosal permeation, a non-invasive agent suitable for the barrier to pass through is used in the formulation. Such non-invasive agents are generally known in the art.
경구 투여를 위해서， 화합물들은 당업계에 공지된 약리학적으로 허용되는 담체들을 활성 화합물들과 조합함으로써 용이하게 제형될 수 있다. 이러한 담체들은 본 발명의 화합물들이 정제， 알약， 산제， 입제, 당제， 캡슐， 액체, 겔， 시럽, 슬러리, 현탁액 등으로 제형화될 수 있도록 하여 준다. 바람직하게는 갑셀제， 정제， 환제, 산제 및 입제가 가능하고， 특히 갑셀제와 정제가 유용하다. 정제 및 환제는 장피제로 제조하는 것이 바람직하다. 경구 사용을 위한 약제 준비는 본 발명의 하나 또는 둘 이상의 화합물들과 하나 또는 둘 이상의 부형제를 흔합하고， 경우에 따라서는 이러한 흔합물을 분쇄하고, 필요하다면 적절한 보  For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Preferably, accelerators, tablets, pills, powders and granules are possible, and especially accelerators and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Pharmaceutical preparations for oral use include mixing one or more compounds of the invention with one or more excipients, optionally grinding such a mixture, and if necessary
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대체용지 규칙 제 26조 조제를 투과한 이후 과립의 혼합물을 처리하여 정제 또는 당체 코어를 얻을 수 있다. 적절한 부형제들은 락토스， 수크로즈, 만니를, 또는 소르비를과 같은 필러; 옥수수 녹말， 밀 녹말， 쌀 녹말， 감자 녹말， 겔라틴， 검 트래거켄스, 메틸 셀를로우즈， 히드록시프로필메틸-셀를로우즈, 소듐 카르복시메틸 샐를로우즈， 및 /또 폴리비닐피를리돈 (PVP)와 같은 셀를루오즈계 물질 등이다. 필 A하다면， 가교 폴리비닐 피를리돈， 우뭇가사리, 또는 알긴산 또는 알 산 나트륨과 같은 그것의 염 등의 디스인터그레이팅 에이전트와마그네 스테아레이트와 같은 윤활제, 결합제 등과같은 담체가 첨가될 수도 있다. Replacement Paper Rule 26 The mixture of granules can be treated after passing through the preparation to obtain a tablet or sugar core. Suitable excipients include fillers such as lactose, sucrose, manny, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl salose, and / or polyvinylpyridone ( Cellulose-based materials such as PVP). If necessary, a disintergrinding agent such as cross-linked polyvinyl pyridone, butadiene, or a salt thereof such as alginic acid or sodium acrylate and a carrier such as a lubricant such as magnesium stearate, a binder, or the like may be added.
경구에 사용될 수 있는 제약 준비물은， 겔라틴 및 글리콜 또는 소르비를과 같은 가소제로 만들어진 부드러운 밀봉 캡슐 뿐만 아니라， 겔라틴으로 만들어진 밀어 고정하는 캡슐을 포함할 수도 있다. 밀어 고정하는 캡슐은 락토오스와 같은 필러， 녹말과 같은 바인더， 및 /또는.활석 또는 마그네슘 스테아레이트와 같은 활제와의 흔합물로서, 활성 성분들을 포함할 수도 있다. 연질 캡슐에서， 활성 화합물들은 지방산， 액체 파라핀， 또는 액체 폴리에틸렌 글리콜과 같은 적합한 용체에 용해 또는 분산될 수도 있다. 또한， 안정화제가 포함될 수도 있다. 경구 투여를 위한 모든 조제들은 그러한투여에 적합한 함량으로 되어 있어야 한다. Pharmaceutical preparations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbates, as well as pushable capsules made of gelatin. The push-in capsules are fillers such as lactose, binders such as starch, and / or . As a combination with a lubricant such as talc or magnesium stearate, it may also contain active ingredients. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.
화합물들은，주사에 의해, 예를 들어， 큰 환약주사나 연속적인 주입에 의해， 비경구 투입용으로 제형화될 수도 있다. 주사용 제형은, 예를 들어， 방부제를 부가한 염플 또는 멀티 -도스 용기로서 단위 용량 형태로 제공될 수도 있다. 조성물은 유성 또는 액상 비히클상의 현탁액, 용액, 에멀션과 같은 형태를 취할 수도 있으며, 현탁제， 안정화제 및 /또는 분산제와 같은 제형용성분들을포함할수도 있  The compounds may be formulated for parenteral administration by injection, for example by large pill injection or continuous infusion. Injectable formulations may also be presented in unit dose form, eg, as a saline or multi-dos container with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain formulation components such as suspensions, stabilizers and / or dispersants.
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대체용지 규칙 제 26조 다. Replacement Paper Rule 26 All.
또한, 활성 성분은， 사용전에 균 무 발열물질의 물과 같은 적절한 비히클과의 구성을 위해 분말의 형태 수도 있다.  The active ingredient may also be in the form of a powder for constitution with a suitable vehicle, such as water of bacteriostatic material, before use.
화합물들은， 예를 들어, 코코아 버터나 다른 글리세라이드와 같은 통상적인 좌약 기재를 포함하고 있는 좌약 또는 정체관장과 같은 직장 투여 조성물로 제형될 수도 있다.  The compounds may also be formulated in rectal dosage compositions such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.
본 발명에서 사용에 적합한 약제 조성물에는， 활성 성분들이 그것의 의도된 목적을 달성하기에 유효한 양은로 함유되어 있는 조성물이 포함된다. 더욱 구체적으로, 치 ^적 유효량은 치료될 객체의 생존을 연장하거나， 질환의 증상을 방지， 경감 또는 완화시키는데 유효한 화합물의 양을 의미한다. 치료적 유효량의 결정은， 특히， 여기에 제공된 상세한 개시 내용 측면에서， 당업자의 능력 범위내에 있다.  Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in amounts effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of a subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
단위 용량 형태로 제형화하는 경우， 활성성분으로서 화학식 (1)의 화합물은 약 0.1 내지 1,000 mg의 단위 용량으로 함유되는 것이 바람직하다. 화학식 (1)의 화합물의 투여량은 환자의 체중， 나이 및 질병의 특수한 성질과 심각성과 같은 ^인에 따라 의사의 처방에 따른다. 그러나， 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 약 1 내지 1000 mg 범위 가 보통이다. 성인에게 근육내 또는 정맥내 투여시 일회 투여량으로 분리하여 하루에 보통 약 1 내지 500 mg의 전체 투여량이면 층분할 것이나， 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다.  When formulated in unit dose form, the compound of formula (1) as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound of formula (1) is according to the doctor's prescription according to the patient's weight, age and specific characteristics and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 1000 mg per day, depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to an adult, a single daily dose will be divided up to a general dosage of about 1 to 500 mg per day, but for some patients a higher daily dose may be desirable.
본 발명에서， 상기 대상성 질환은 비만， 지방간， 동맥경화, 뇌졸중， 심근경색, 심혈관 질환， 허혈성 질환， 당뇨병, 고지혈증, 고혈압， 망막증 또는 신부전증,  In the present invention, the target disease is obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, retinopathy or renal failure,
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대체용지 규칙 제 26조 헌팅턴 병 또는 염증일 수 있고, 상세하게는 지방간, 당뇨병 또는 헌팅턴 병일 수 있지만，그것만으로 한정되는 것은 아니다. Replacement Paper Rule 26 It may be Huntington's disease or inflammation, in particular fatty liver, diabetes or Huntington's disease, but is not limited thereto.
본 발명은, 또한 약리학적 유효량의 제 1 항에 따른 화학식 (1)의 화합물, 그것의 약제학적으로 허용되는 염， 수화물， 용매화물， 토토머， 거을상 이성질체 또는 약학적으로 허용 가놓한 부분입체 이성질체를 유효량으로 사용하여， 대사성 질환을 치료하거냐 예방하는 방법을 제공한다. "상기 "치료 "란 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단 또는 지연시키는 것을 의미하며, 상기 "예방 "이란 발병 증상을 보이지는 않지만 그러한 위험성이 높은 객체에 사용될 때 발병 징후를 중단 또는 지연시키는 것을 의미한다.  The present invention also provides a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, diastolic or pharmaceutically acceptable diastereomer thereof. An effective amount of the isomers is used to provide a method for treating or preventing metabolic diseases. "Therapeutic" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of the disease, and "preventing" means stopping or manifesting the disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. Means to delay.
【도면의 간단한 설명】  [Brief Description of Drawings]
도 1은 실험예 3-1의 실시예 3에 따른 화합물 및 실시예 4과 대조군 에 대한 비만 쥐 (o6/ob)의 체중 증가율， 체중 변화， 및 섭취량을 나타낸 그래 프이다；  1 is a graph showing the weight gain rate, weight change, and intake of obese rats (o6 / ob) for the compound according to Example 3 of Example 3-1 and Example 4 and the control group;
도 2는 실험예 3-2의 실시예 7에 따른 화합물 및 실시예 10에 따른 화합물과 대조군에 대한 비만 쥐 (ob/ob)의 체중 증가율， 체중 변화, 및 섭취 량을 나타낸그래프이다;  2 is a graph showing the weight gain rate, weight change, and intake of obese rats (ob / ob) for the compound according to Example 7 of Example 3-2 and the compound according to Example 10 and the control group;
도 3는 실험예 3-3의 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물과 대조군에 대한 비만 쥐 (06/0b)의 체중 증가율， 체중 변화， 및 섭취량을 나타낸 그래프이다; Figure 3 is a graph showing the body weight gain, weight change, and the intake of obese mice (0 6/0 b) for a compound to the control compound, and according to Example 13 according to Example 12 of Experimental Example 3-3;
도 4은 실험예 3-4의 실시예 16에 따른 화합물과 대조군에 대한 비만 쥐 (o6/oZ>)의 체중 증가율， 체중 변화， 및 섭취량을 나타낸 그래프이다;  4 is a graph showing the weight gain rate, weight change, and intake of obese rats (o6 / oZ>) for the compound according to Example 16 of Experimental Example 3-4 and the control group;
도 5는 실험예 4의 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물과  5 is a compound according to Example 12 and Example 13 of Experimental Example 4;
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대체용지 규칙 제 26조 대조군에 대한 당뇨쥐 (db/db)의 Gluco e Level를 나타낸 그래프이다; 및 도 6은 실험예 5의 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물과 대조군에 대한 당뇨 쥐 (dp/db)의 체중 증가율, 체중 변화， 및 섭취량을 나타낸 그래프이다. Replacement Paper Rule 26 It is a graph showing the glucose level of the diabetic rats (db / db) compared to the control group; And FIG. 6 is a graph showing weight gain rate, weight change, and intake of diabetic rats (dp / db) for the compound according to Example 12 of Example 5, the compound according to Example 13, and the control group.
【발명의 실시를 위한 형태】  [Form for implementation of invention]
본 발명을 이하 실시예 및 실험예들을 참조하여 상세히 설명하지만， 본 발명의 범주가 그것에 의해 한정되는 것은 아니다. 하기에서， 실시예들에는 최종 화합물을 만들기 위한 중간체의 합성방법 및 실시예의 화합물을 사용한 최종 화합물의 합성 법에 관한 내용이 기재되어 있다. 실시예 1. [화합물 1의 합성]  The present invention will be described in detail with reference to Examples and Experimental Examples below, but the scope of the present invention is not limited thereto. In the following, the examples describe the synthesis of intermediates to make the final compounds and the synthesis of the final compounds using the compounds of the examples. Example 1. [Synthesis of Compound 1]
Figure imgf000038_0001
Figure imgf000038_0001
1) IStep  1) IStep
compound A (4-amino- 1 -naphthol hydrochloride, 500 mg, 2.55 inmol))에 Pyridine (5 ml)을 넣은 후, Ice bath를 데고 cooling시킨다. 뒤이어 Isobutyric  Pyridine (5 ml) is added to Compound A (4-amino-1 -naphthol hydrochloride, 500 mg, 2.55 inmol), and the ice bath is dehydrated and cooled. Following Isobutyric
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대체용지 규칙 제 26조 anhydride (1.7 ml, 10.2 mmol)를 dropw^se한다. 반웅물은동일온도에서 2.5 시 간 동안 교반한다. 반웅물은 메탄 로 quenching한 후, 감압 농축하면서 pyridine을 어느정도 제거한다. EA와증류수를 넣은 뒤 , 1 N HC1수용액으로 pH 6.5정도를 맞춘 다음， 유기층을 여렁 번 씻어주므로써 남아있는 Pyridine을 제거한다. 유기층은 Na2S04로 건조， 여과후， 감압농축 한다. 농축된 반응 물은 silica gel column chromatography으 정제하여 compound B-1 (686 mg, 90%) 를 얻었다. Replacement Paper Rule 26 Dropw ^ se anhydride (1.7 ml, 10.2 mmol). The reactant is stirred for 2.5 hours at the same temperature. The reaction product is quenched with methane and concentrated under reduced pressure to remove some pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 solution, and wash the organic layer several times to remove the remaining pyridine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound B-1 (686 mg, 90%).
2) 2Step 2) 2Step
Compound B-1 (300 mg, LOO mmoj)에 Acetic anhydride (3 ml)를 넣고，섭씨 0도에서 Fuming nitric acid (0.20 ml, 2.Q0 mmol)를 dropwise한다. 반: § "물은 1 시간 ^안 교반한 후, 여과한다. 이때 걸러진 고체는 compound B-2 로써 Hexane으로 여러 번 씻어주어 얻는다. compound B-2 (217 mg, 63%).  Add Acetic anhydride (3 ml) to Compound B-1 (300 mg, LOO mmoj) and dropwise fuming nitric acid (0.20 ml, 2.Q0 mmol) at 0 ° C. PART: § “Water is stirred for 1 hour and then filtered. The filtered solid is washed several times with Hexane with compound B-2. Compound B-2 (217 mg, 63%).
1H NMR (300 MHz, Acetone-d6) δ 9.55(s, IH), 8.33 (d, J= 6.6 Hz, IH), 8.06 (d, J = 6.2 Hz, IH), 7.86 (s, IH), 7.81-7.73(m, 2H), 3.16-3.07 (m, IH), 2.96-2.87(m, 1 H), 1.41 (d, J = 7.0 Hz, 6H), 1.25 (d, J = 7.0 Hz, 6H) 1 H NMR (300 MHz, Acetone-d 6 ) δ 9.55 (s, IH), 8.33 (d, J = 6.6 Hz, IH), 8.06 (d, J = 6.2 Hz, IH), 7.86 (s, IH), 7.81-7.73 (m, 2H), 3.16-3.07 (m, IH), 2.96-2.87 (m, 1H), 1.41 (d, J = 7.0 Hz, 6H), 1.25 (d, J = 7.0 Hz, 6H )
3) 3 Step 3) 3 Step
Compound B-2 (500 mg, 1.45 mmol)를 에탄올 (5 ml)에 녹인 후，. Pd/C (50 mg)과 Hydrazine (0.29 ml, 5.81 mmol)를순서대로 넣는다. 반웅물은섭씨 70도 에서 1 시간동안 반웅한다. 반웅물은실은으로 cooling, celite filter하여 Pd/C  Compound B-2 (500 mg, 1.45 mmol) was dissolved in ethanol (5 ml). Add Pd / C (50 mg) and Hydrazine (0.29 ml, 5.81 mmol) in order. The reaction is stirred for 1 hour at 70 degrees Celsius. The reaction water is cooled by celite filter by Pd / C
37 37
대체용지 규칙 제 26조 제거한다, 여과액은 압농축하고， silica gel column chromatography로 정제하 여 compound B-3 (232 mg, 51%)를 얻는다. Replacement Paper Rule 26 The filtrate is concentrated under pressure and purified by silica gel column chromatography to give compound B-3 (232 mg, 51%).
1H NMR (300 MHz, CD3OD) δ 8.Q2 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, IH), 7.35 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.47 (s, 1H), 2.85-2.83 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H) 1 H NMR (300 MHz, CD 3 OD) δ 8.Q2 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, IH), 7.35 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.47 (s, 1H), 2.85-2.83 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H)
LC-MS m/z 245.1 (M+l)  LC-MS m / z 245.1 (M + l)
4) 4Step 4) 4Step
Compound B-3 (700 mg, 2.86 mrpol)에 아세트산 (15 ml)을 넣고, 3 시간 동안 교반, 환류한다. 아세트산을 감압 농축하여 제거하고， silica gel column chromatography로 정제하여 compound (575 mg, 89%)를 얻는다  Acetic acid (15 ml) is added to Compound B-3 (700 mg, 2.86 mrpol), and the mixture is stirred and refluxed for 3 hours. Acetic acid is removed by concentration under reduced pressure, and purified by silica gel column chromatography to obtain a compound (575 mg, 89%).
1H NMR (300 MHz, CD3OD) δ 8.30 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 8.0 Hz, IH), 7.47 (t, J= 8.1 Hz, IH), 6.99 (s, IH), 3.35-3.28 (m, IH), 1.46 (d, J = 7.0 Hz, 6H)1 H NMR (300 MHz, CD 3 OD) δ 8.30 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 8.0 Hz, IH), 7.47 (t, J = 8.1 Hz, IH), 6.99 (s , IH), 3.35-3.28 (m, IH), 1.46 (d, J = 7.0 Hz, 6H)
LC-MS m/z 227.0 (M+l) LC-MS m / z 227.0 (M + l)
5) 5Step 5) 5Step
Compound B-4 (50 mg, 0.22 mmol)에 DMF(2.5 ml)을 넣어 녹인 뒤， IBX (159 mg, 0.26 mmol)을 넣는다. 반웅물은 실온에서 1 시간 동안 반웅한다. Dissolve DMF (2.5 ml) in Compound B-4 (50 mg, 0.22 mmol), and add IBX (159 mg, 0.26 mmol). The reaction product is reacted for 1 hour at room temperature.
EA를 EA
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대체용지 규칙 제 26조 넣은 후 유기층을 NaHC03 포화 수 액으로 씻어준다. 분리한 육기층은 MgS04로 건조시킨 뒤 여과한다. 여과액은 감압 농축한 뒤 column chromatography로정제하여 compound B-5 (47 mg, 89%)# 얻는다. Replacement Paper Rule 26 After washing, wash the organic layer with saturated NaHC0 3 sap. The separated meat layer was dried over MgS0 4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound B-5 (47 mg, 89%) #.
1H NMR (300 MHz, CDC13) δ 9.96 (N-H, s, IH), 8.06 (d, J= 7.7 Hz, IH), 7.99 (d, J= 7.7 Hz, IH), 7,65 (t, J= 7.7Hz, IH), 7.44 (t, J= 7.7 Hz, IH), 3.26-3.17 (m, IH), 1.45 (d, J= 7.0 Hz, 6H)
Figure imgf000041_0001
1 H NMR (300 MHz, CDC1 3 ) δ 9.96 (NH, s, IH), 8.06 (d, J = 7.7 Hz, IH), 7.99 (d, J = 7.7 Hz, IH), 7,65 (t, J = 7.7 Hz, IH), 7.44 (t, J = 7.7 Hz, IH), 3.26-3.17 (m, IH), 1.45 (d, J = 7.0 Hz, 6H)
Figure imgf000041_0001
B-5 com. 1  B-5 com. One
6) 6Step 6) 6Step
Compound B-5 300mg에 EA와 H20를 5:1의 비율로 총 6 ml 넣은 후， N S204를 넣고 실온에서 3 시간 동0 교반한다. 반응액은 붉은색에서 밝은 분흥색으로 변한다. 반응이 완료되면,바로 filter하여 solid를 얻는다. To Compound B-5 300mg EA and H 2 0 5: Insert total 6 ml at a ratio of 1: 1, into the NS 2 0 4 0 and the mixture was stirred for 3 hours at room temperature. The reaction solution changes from red color to bright red color. When the reaction is complete, immediately filter to obtain a solid.
IH NMR: IH NMR (300 MHz, DMSO) δ 8.25-8.19 (m, IH), 8.14-8.04 (m, IH), 7.39-7.31 (m, 2H), 3.14-3.03 (m, IH), 1.40 (d, J = 6.9 Hz, 6H) IH NMR: IH NMR (300 MHz, DMSO) δ 8.25-8.19 (m, IH), 8.14-8.04 (m, IH), 7.39-7.31 (m, 2H), 3.14-3.03 (m, IH), 1.40 ( d, J = 6.9 Hz, 6H)
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대체용지 규칙 제 26조 실시예 2. [화합 ^ 2의 합성] Replacement Paper Rule 26 Example 2. [Synthesis of Compound ^ 2]
Figure imgf000042_0001
Figure imgf000042_0001
Compound B-5 (0.2 g, 0.832 mmpl)을 Ether (17 ml), H20 (4 ml)에 녹인 뒤 10 분간 교반 시킨다. 반웅 용액을 감앓농축한 뒤 Pyridine (8 ml)과 Ac20 (8 ml)를 넣고 24 시간 동안 교반 시킨다. 반웅 용액에 와 NaHC03 포화수용 액을 넣고 여러 번 씻어준다. 유기 충은 MgS04로 건조， 여과한 뒤 column chromatography로 분리 후 재결정으로 정제한다 Compound B-5 (0.2 g, 0.832 mmpl) is dissolved in Ether (17 ml), H 2 0 (4 ml) and stirred for 10 minutes. After concentrating the reaction solution, Pyridine (8 ml) and Ac 2 0 (8 ml) were added and stirred for 24 hours. Add NaHC0 3 saturated aqueous solution to the reaction solution and rinse several times. Organic worms are dried over MgS0 4 , filtered, separated by column chromatography and purified by recrystallization.
Ivory solid  Ivory solid
1H NMR (300 MHz, CDC13) δ 11.15 (br, 2H), 8.15 (d, 1H), 7.72 (d, 1H, J= 8.8 Hz), 7.34 (t, 1H), 7.17 (t, 1H), 2.83 (m, 1H), 2.46 (s, 3H), 0.99 (d, 6H, J= 5.9 Hz) 1 H NMR (300 MHz, CDC1 3 ) δ 11.15 (br, 2H), 8.15 (d, 1H), 7.72 (d, 1H, J = 8.8 Hz), 7.34 (t, 1H), 7.17 (t, 1H), 2.83 (m, 1H), 2.46 (s, 3H), 0.99 (d, 6H, J = 5.9 Hz)
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대체용지 규칙 제 26조 실시예 3, 4. [화 물 3， 4의 합성] Replacement Paper Rule 26 Examples 3 and 4. [Synthesis of Compounds 3 and 4]
Figure imgf000043_0001
Figure imgf000043_0001
com.3 com.4 com.3 com.4
1) lstep (확합물 3): 1) lstep (compound 3):
SM (500 mg, 2.08 mmol)에 AcO (0.2 M, 10.4 ml)를 넣고， 60 °C로 교반한 다, 이때 Zn(680 mg, 10.405 mmol)를 넣고 100 °C로 을린다 . 100 °C에서 Ac20 를 넣: jl 7 시간 동안 반웅한다. 감압 류후， EA로 묽힌 후, NaHC03 수용액 보로씻어준다. EA층은분리 후， MgS04로 처리하고, celite를 이용하여 filter한 다. 여액은 감압증류하여 Hex/EA로 재결정한다. Add AcO (0.2 M, 10.4 ml) to SM (500 mg, 2.08 mmol) and stir at 60 ° C. At this time, add Zn (680 mg, 10.405 mmol) and lower to 100 ° C. Add Ac 2 0 at 100 ° C: jl React for 7 hours. After distillation under reduced pressure, dilute with EA and wash with NaHC0 3 aqueous solution. The EA layer is separated, treated with MgS0 4 , and filtered using celite. The filtrate is distilled under reduced pressure and recrystallized from Hex / EA.
White solid: 621mg(92%)  White solid: 621 mg (92%)
화합물 3: 1H NMR (300 MHz, CDC13) δ 7.86-7.80 (m, 1H), 7.49-7.30 (m, 3H), 7.30-7.18 (m, 1H), 2.49 (s, 3H), 2.23 (s, 3H), 1.36 (d, J = 6.0 Hz, 6H) Compound 3: 1H NMR (300 MHz, CDC1 3 ) δ 7.86-7.80 (m, 1H), 7.49-7.30 (m, 3H), 7.30-7.18 (m, 1H), 2.49 (s, 3H), 2.23 (s , 3H), 1.36 (d, J = 6.0 Hz, 6H)
2) 2step(화합물 4): 2 step 2 (compound 4):
화합물 3 (439 mg, 1.345 mmol)에 ACN을 넣은 뒤， K2C03(372 mg, 2.69 mmol)와 dimethylcarbamylchloride (320 mg, 2.96 mmol)를 넣고, 21 시간동안교 반환 Add ACN to compound 3 (439 mg, 1.345 mmol), add K 2 C0 3 (372 mg, 2.69 mmol) and dimethylcarbamylchloride (320 mg, 2.96 mmol) and return to bridge for 21 hours.
44 44
대체용지 규칙 제 26조 류한다. Aq.Na iC03로 중화 후, EA^ 추출한다. 분리한 유기층은 MgS04를 넣어 건조, 여과， 감압증류, 실리카겔 컬럼 하고, 마지막으로 Hex/EA로 재결 정 하 목적 화합물을 얻는다. Replacement Paper Rule 26 Ryu. After neutralization with Aq.Na iC0 3 , EA ^ extraction. The separated organic layer was dried over MgS0 4 , filtered, distilled under reduced pressure, silica gel column, and finally recrystallized with Hex / EA to obtain the target compound.
Ivory solid: 290 mg (61 %)  Ivory solid: 290 mg (61%)
화합물 4: IH NMR: IH NMR (300 MHz, DMSO) δ 8.42-8.35 (m, IH), 7.89 (d, J = 8.4 Hz, IH), 7.62 (s, IH), 7.50 (t, J; = 7.5 Hz, IH), 3.33-3.23 (m, IH), 3.21 (s, 3H), 3.10 (s, 3H), 2.44 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H) 실시예 5. [화합 5의 합성] Compound 4: IH NMR: IH NMR (300 MHz, DMSO) δ 8.42-8.35 (m, IH), 7.89 (d, J = 8.4 Hz, IH), 7.62 (s, IH), 7.50 (t, J ; = 7.5 Hz, IH), 3.33-3.23 (m, IH), 3.21 (s, 3H), 3.10 (s, 3H), 2.44 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H) Example 5 [Synthesis of Compound 5]
Figure imgf000044_0001
Figure imgf000044_0001
1) lstep  1) lstep
SM(500 mg, 2.081 mmol)을 THF(0.2 M, 10 ml)에 녹인 후， TEA(0.44 ml, 3.121 mmol)와 Di-ter-butyldicarbonate(0.52 ml, 2.289 mmol), DMAP(50 mg)을순서 대로 넣고， 실은에서 15 시간 동안 교반한다. 감압 증류 후, short column(Hex:EA=5:l)하여, 밝은주황색 solid 594 mg(84%)을 얻었다.  Dissolve SM (500 mg, 2.081 mmol) in THF (0.2 M, 10 ml), TEA (0.44 ml, 3.121 mmol), Di-ter-butyldicarbonate (0.52 ml, 2.289 mmol), and DMAP (50 mg) in this order. Put in and stir for 15 hours at room temperature. After distillation under reduced pressure, a short column (Hex: EA = 5: l) was obtained to give 594 mg (84%) of a bright orange solid.
42 42
대체용지 규칙 제 26조
Figure imgf000045_0001
Replacement Paper Rule 26
Figure imgf000045_0001
2) 2step  2) 2step
1 step의 생성물 (ί 00 mg, 0.294 mmol)에 AcOH(1.45 ml, 0.2 M)를 넣은 뒤, 60 °C로 가온한다. 은도가 60 °C에 도 :하면， Zn powder(96 mg, 1.47 mmol)를 가한다ᅳ 다시 온 £를 120 °C로 을린 ， Ac2O(0.4 ml)을 넣고 7 시간동안교 반환류한다. Aq.NaHC03를 넣고 중화한 뒤， ΈΑ로 추출한다. 분리된 유기층 은 MgS04로 건조， EA로 silicagel filter한후， 감압증류， Hex/EA로 재결정 하 여 목적화합물을 얻는다. AcOH (1.45 ml, 0.2 M) was added to the product of 1 step (ί 00 mg, 0.294 mmol) and warmed to 60 ° C. If the silver is also at 60 ° C, add Zn powder (96 mg, 1.47 mmol). Add £ 2 at 120 ° C and add Ac 2 O (0.4 ml). Add Aq.NaHC0 3 , neutralize, and extract with ΈΑ. The separated organic layer was dried with MgS0 4 , silicagel filtered with EA, distillation under reduced pressure, and recrystallized with Hex / EA to obtain the target compound.
White solid: 82 mg, 76% White solid: 82 mg, 76%
1H NMR:  1 H NMR:
1H NMR (300 MHz, CDC13) δ 8.17-8.13 (m, 1H), 7.81-7.77 (m, 1H), 7.41-7.36 (m, 2H), 3.26-3.16 (m, 1H), 2.49 (S, 3H), 2.28 (s, 3H), 1.32 (d, J = 5.1 Hz, 6H) 1 H NMR (300 MHz, CDC1 3 ) δ 8.17-8.13 (m, 1H), 7.81-7.77 (m, 1H), 7.41-7.36 (m, 2H), 3.26-3.16 (m, 1H), 2.49 (S, 3H), 2.28 (s, 3H), 1.32 (d, J = 5.1 Hz, 6H)
43 43
대체용지 규칙 제 26조 실시예 6. [화합 # 6의 합성] Replacement Paper Rule 26 Example 6. [Synthesis of Compound # 6]
Figure imgf000046_0001
Figure imgf000046_0001
1) Istep:  1) Istep:
SM(0.5 g, 2.08 ηψιοΐ)을 CH3C (10 ml)에 녹인다. K2C03 (0.9 g, 6.24 mmol)# 넣어준 후, 실온에서 10 분 ：동안 교반 시킨다. Benzyl chloroformate (0.36 ml, 1.2 mmol)을넣어 준후 21 시간동안환류 시킨다. EA와증류수를 넣은 뒤， 여러 번 씻어낸다. 분리할 유기 층을 MgS04로 건조시킨 뒤 여과한다. 여과 액은 감압 농축한 퀴, Silica gel column chromatography로 정제한다, Dissolve SM (0.5 g, 2.08 ηψιοΐ) in CH 3 C (10 ml). K 2 CO 3 (0.9 g, 6.24 mmol) # was added and stirred at room temperature for 10 minutes. Benzyl chloroformate (0.36 ml, 1.2 mmol) was added and refluxed for 21 hours. Add EA and distilled water and rinse several times. The organic layer to be separated is dried over MgSO 4 and filtered. The filtrate is purified by distillation under reduced pressure, silica gel column chromatography,
Red solid 0.44 g (56 %) Red solid 0.44 g (56%)
1H NMR (300 MHz, CDC13) δ 8.04-8.01 (m, 2H), 7.61 (t, J = 7.7 Hz, 8.2 Hz, 1H), 7.41-7.15 (m, 6H), 5.59 (s, 2H), 3.08-3.04 (m, 1H), 1.31 (d, J= 6.8 Hz, 6H) 1 H NMR (300 MHz, CDC1 3 ) δ 8.04-8.01 (m, 2H), 7.61 (t, J = 7.7 Hz, 8.2 Hz, 1H), 7.41-7.15 (m, 6H), 5.59 (s, 2H), 3.08-3.04 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H)
44 44
대체용지 규칙 제 26조
Figure imgf000047_0001
Replacement Paper Rule 26
Figure imgf000047_0001
2) 2step: 2) 2step:
1번 화합 (100 mg, 0.267 mmol)에 dry.Pyridine (1.3 ml, 0.2 M)을 넣고, Zn을 가한 후， 40 °C로 가온한다. 40 °C에서 Pyridine-Sulfer trioxide(213 mg, 1.337 mmol)을 넣고, 20분 동안교반함다. 반웅물은 evaporation후，실리카겔 컬럼하여 목적화합물을 얻는다. White solid: 110 mg(77%) To 1 compound (100 mg, 0.267 mmol) add dry.Pyridine (1.3 ml, 0.2 M), add Zn, and warm to 40 ° C. Add Pyridine-Sulfer trioxide (213 mg, 1.337 mmol) at 40 ° C and stir for 20 minutes. The reaction product is subjected to silica gel column after evaporation to obtain the target compound. White solid: 110 mg (77%)
3) 3 step: 3) 3 step:
2번 화합 " (89 mg, 0.166 mmol) 에 MeOH(1.6 ml, 0.1M)과 Pd/C을 넣고， degassing후, ¾^ 치흰:한다. 실온에서 24 시간동안교반후, edit 여과한다. 여액은 감압증류한 뒤， prep TLC로 분리하여 목적 화합물을 얻는다.  Add MeOH (1.6 ml, 0.1M) and Pd / C to 2 compound "(89 mg, 0.166 mmol), degassing, ¾ ^ white. After stirring for 24 hours at room temperature, filter the filtrate. After distillation under reduced pressure, the mixture was purified by prep TLC to obtain the title compound.
1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 8.28-8.20 (m, 1H), 8.03-7.96 (m, 1H), 7.42-7.35 (m, 1H), 1.40 (d, J = 6.9 Hz, 6H)  1 H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 8.28-8.20 (m, 1H), 8.03-7.96 (m, 1H), 7.42-7.35 (m, 1H), 1.40 (d, J = 6.9 Hz, 6H)
45 45
대체용지 규칙 제 26조 실시예 7. [화합 7의 합성] Replacement Paper Rule 26 Example 7. [Synthesis of Compound 7]
Figure imgf000048_0001
Figure imgf000048_0001
1) lstep:  1) lstep:
SM(300 mg, 1.249 mmol)에 ACN(6.2 ml, 0.2 M)과 K2C03(518 mg, 3.747 mmol)를 넣고 실은에서 15 분 동안 H반한다. 그 후， PMB-C1을 넣고， 15시간 동안 교반환류한다. 반웅물은 물을 넣은 후 EA로 추출한다. 분리한 유기층 은 MgS04로 건조시킨 뒤 여과액은 감압농축한다. Hex/EA로 재결정하여 주 황색 solid 400 mg(89%)을 얻었다. Add ACN (6.2 ml, 0.2 M) and K 2 CO 3 (518 mg, 3.747 mmol) to SM (300 mg, 1.249 mmol) and incubate for 15 minutes at room temperature. Thereafter, PMB-C1 was added thereto, followed by stirring under reflux for 15 hours. The reaction water is extracted with EA after adding water. The separated organic layer was dried over MgS0 4 and the filtrate was concentrated under reduced pressure. Recrystallization from Hex / EA gave 400 mg (89%) of a yellowish yellow solid.
Figure imgf000048_0002
Figure imgf000048_0002
2) 2step:  2) 2step:
lstep 생성물 (100 mg, 0.277 mmol)에 AcOH(0.1 M, 3 ml)와 Zn(91 mg, 1.385 mmol)를 넣고，실온에서 20분동안교반한다. Ac20(l ml)를 넣고 100 °C 에서 2시간 AcOH (0.1 M, 3 ml) and Zn (91 mg, 1.385 mmol) were added to the lstep product (100 mg, 0.277 mmol) and stirred at room temperature for 20 minutes. Add ac 2 0 (l ml) at 100 ° C for 2 hours
4i 4i
대체용지 규칙 제 26조 동안 반웅한다. ^압증류;후, EA와 NaHC03수용액으로중화후, EA층은추출 한다. 분리한 유기층은 MgS04로 처리하고， filter후， 감압증류하여 Hex/EA로 재결정한다. 99 mg(80%) Replacement Paper Rule 26 Respond while. ^ Distillation ; After neutralization with EA and NaHC0 3 aqueous solution, the EA layer is extracted. The separated organic layer was treated with MgSO 4 , filtered, distilled under reduced pressure and recrystallized with Hex / EA. 99 mg (80%)
IH NMR OO MHz, CDC13) δ 8.69 (d, J = 8.4 Hz, IH), 7.79 (d, J = 8.7 Hz, IH), 7.64-7.58 (m, IH), 7.53-7.47 (m, IH), 6.89-6.80 (m, 4H), 5.52 (s, 2H), 3.76 (s, 3H); 3.16-3.12 (m, IH), 2.41 (s 3H), 1.99 (s, 3H), 1.41 (d, J = 6.9 Hz, 6H) IH NMR OO MHz, CDC1 3 ) δ 8.69 (d, J = 8.4 Hz, IH), 7.79 (d, J = 8.7 Hz, IH), 7.64-7.58 (m, IH), 7.53-7.47 (m, IH) , 6.89-6.80 (m, 4H), 5.52 (s, 2H), 3.76 (s, 3H) ; 3.16-3.12 (m, IH), 2.41 (s 3H), 1.99 (s, 3H), 1.41 (d, J = 6.9 Hz, 6H)
실서예 8. [화합물 8의 합성] Example 8 Synthesis of Compound 8
Figure imgf000049_0001
Figure imgf000049_0001
1) Istep:  1) Istep:
SM (120 mg, 0.283 mmol)을 DMF(1.4 ml, 0.2 M)에 녹인 후， Zn(92 mg, 1.415 mmol), K2C03(195 mg, 1.415 mmol), Ν,Ν-dimethylcarbamyl chloride(65 ul, 0.708 mmol)를 넣고， 80oC에서 2시간 동안 반웅한다. 여액은 celite filter, ac.NaHC03로 중화 후, EA로 추출한다. 분리한 유기충은 MgS04로 건조시킨 뒤 여과한다. 여과액은 감압 농축한 뒤 column으로 분리하여 화합물을 얻는 다. 22 mg (15%) SM (120 mg, 0.283 mmol) was dissolved in DMF (1.4 ml, 0.2 M), then Zn (92 mg, 1.415 mmol), K 2 CO 3 (195 mg, 1.415 mmol), Ν, Ν-dimethylcarbamyl chloride (65 ul, 0.708 mmol) and reacted at 80 ° C. for 2 hours. The filtrate is neutralized with celite filter, ac.NaHC03 and extracted with EA. The separated organic insects are dried with MgS04 and filtered. The filtrate is concentrated under reduced pressure and separated by column to obtain a compound. 22 mg (15%)
47 47
대체용지 규칙 제 26조 2step) Replacement Paper Rule 26 2step)
lstep 생성물 (22 mg, 0.053 mmol)에 Ac20 (0.8 ml, 0.07 M)를 넣고, 40분 동안교반환류 한다. 반웅이 완료되 , 감압증류후， EA와 aq.NaHC03로 중 화한다. 분리한유기층은 MgS04로 건조, 여과， 감압농축후, Hex/EA로 재결 정한다. Ac 2 0 (0.8 ml, 0.07 M) was added to the lstep product (22 mg, 0.053 mmol) and stirred for 40 minutes. The reaction is complete and neutralized with EA and aq.NaHC0 3 after distillation under reduced pressure. The separated organic layer was dried over MgSO 4 , filtered, concentrated under reduced pressure, and recrystallized with Hex / EA.
16 mg(67%)  16 mg (67%)
1H NMR,(300 MHz, CDC13) δ 8.67 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 6.88-6.79 (m, 4H), 5.54 (s, 2H), 3.75 (s, 3H), 3.19 (s, 3H), 3.17-3.12 (m, 1H), 3.05 (s, 3H), 1.96 (s, 3H), 1.41 (d, J = 6.6 Hz, 6H) 1 H NMR, (300 MHz, CDC1 3 ) δ 8.67 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t , J = 7.5 Hz, 1H), 6.88-6.79 (m, 4H), 5.54 (s, 2H), 3.75 (s, 3H), 3.19 (s, 3H), 3.17-3.12 (m, 1H), 3.05 ( s, 3H), 1.96 (s, 3H), 1.41 (d, J = 6.6 Hz, 6H)
실시예 9， 10. [화합물 9， 10의 합성] Examples 9 and 10. Synthesis of Compounds 9 and 10
Figure imgf000050_0001
Figure imgf000050_0001
com.9 Corn- 10 화합물 9  com.9 Corn-10 Compound 9
SM(100 mg, 0.277 mmol)에 CHC13(1.4 ml, 0.2 M)을 넣고， Pyridine(67 ul, 0.831 mmol), Ν,Ν-dimethylcarbamyl chloride(77 ul, 0.831 mmol), Zn(181 mg, 2.77 mmol)을순서대로 넣은후， 3 시간동안교반환류한다 , EA와 ¾0로 중화후, CHC1 3 (1.4 ml, 0.2 M) was added to SM (100 mg, 0.277 mmol), Pyridine (67 ul, 0.831 mmol), Ν, Ν-dimethylcarbamyl chloride (77 ul, 0.831 mmol), Zn (181 mg, 2.77) After the addition of mmol), the mixture was stirred under reflux for 3 hours, neutralized with EA and ¾0, and
48 48
대체용지 규칙 제 26조 ^리한유기층은 MgS04로 건조， 여과 (silicagel filter), 감압농축후， Hex/EA로 재결정한다. 65 mg(46%) Replacement Paper Rule 26 ^ The organic layer was dried over MgSO 4 , filtered (silicagel filter), concentrated under reduced pressure, and recrystallized from Hex / EA. 65 mg (46%)
IH NMR (300 MHz, CDC13) δ 8.66 (d, J = 7.8 Hz, IH), 7.87 (d, J = 7.8 Hz, IH), 7.57 (t, J = 7.2 Hz, IH), 7.47 (t, J = 7.2 Hz, IH), 6.95 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.48 (s, 2H), 3.75 (s, 3H), 3.19-3.11 (m, 4H), 3.04 (s, 3H), 2.87 (s, 3H), 2.85 (s, 3H), 1.40 (s, J = 6.6 Hz, 6H) IH NMR (300 MHz, CDC1 3 ) δ 8.66 (d, J = 7.8 Hz, IH), 7.87 (d, J = 7.8 Hz, IH), 7.57 (t, J = 7.2 Hz, IH), 7.47 (t, J = 7.2 Hz, IH), 6.95 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.48 (s, 2H), 3.75 (s, 3H), 3.19-3.11 ( m, 4H), 3.04 (s, 3H), 2.87 (s, 3H), 2.85 (s, 3H), 1.40 (s, J = 6.6 Hz, 6H)
화합물 1Q Compound 1q
화합물 9 (50 mg, 0.1 mmol) 에 IyIeOH(l ml, 0.1 M)과 MC(0.5 ml, 0.2 M)를 넣는다. 20wt% Pd(OH)2 21 mg(0,03 mn l)을 넣고 ¾로 치환후，실온에서 2.5 days ^안 반웅 한다. Celite filter후， 여액은 감압증류， short column하여 화합 물을 얻는다 . 29 ^lg (76%) To compound 9 (50 mg, 0.1 mmol) was added IyIeOH (l ml, 0.1 M) and MC (0.5 ml, 0.2 M). Add 21 wt (0,03 mn l) of 20wt% Pd (OH) 2 , replace with ¾, and react at 2.5 days at room temperature. After Celite filter, the filtrate is distilled under reduced pressure and short column to obtain the compound. 29 ^ lg ( 76 %)
IH NMR (300 MHz, DMSO) δ 8.40-8.28 (m, IH), 7.86 (d, J = 8.1 Hz, IH), 7.65-7.60 (m, IH), 7.60-7.48 (m, IH), 3.27-3.22 (m, IH), 3.15 (s, 3H), 3.09 (s, 3H), 2.96 (s, 6H), 1.39 (d, J = 6.9 Hz, 6H)  IH NMR (300 MHz, DMSO) δ 8.40-8.28 (m, IH), 7.86 (d, J = 8.1 Hz, IH), 7.65-7.60 (m, IH), 7.60-7.48 (m, IH), 3.27- 3.22 (m, IH), 3.15 (s, 3H), 3.09 (s, 3H), 2.96 (s, 6H), 1.39 (d, J = 6.9 Hz, 6H)
49 49
대체용지 규칙 제 26조 실시예 11. [화합물 11의 합성] Replacement Paper Rule 26 Example 11. Synthesis of Compound 11
Figure imgf000052_0001
Figure imgf000052_0001
l) stepl :  l) stepl:
화합물 1 (0.2 g, 0.83 mmol)을 CH3CN (8.5 ml)에 녹인다. K2C03 (0.35 g, 2.5 mmol)를 넣고， 실온에서 10 분 간 교반 시킨다. lodomethane (65 ul, 1.0 mmol)을 넣은 뒤， 섭씨 80도 에서 2 시간 동안 교반 시킨다. EA와 증류수를 넣고， 여러 번 씻어낸다. 분리한 유기 층을 MgS04로 건조시킨 뒤 여과한다. 여과 액은 감압 농축한 뒤， Silica gel co}umn chromatography로 정제한다. Compound 1 (0.2 g, 0.83 mmol) is dissolved in CH 3 CN (8.5 ml). Add K 2 CO 3 (0.35 g, 2.5 mmol) and stir at room temperature for 10 minutes. Add lodomethane (65 ul, 1.0 mmol) and stir at 80 ° C for 2 hours. Add EA and distilled water and rinse several times. The separated organic layer was dried over MgS0 4 and filtered. The filtrate is concentrated under reduced pressure, and then purified by silica gel co-umn chromatography.
Red solid 0.13 g (62 %)  Red solid 0.13 g (62%)
1H NMR (300 MHz, CDC13) δ 8.00-7.94 (m, 2H), 7.58 (t, J= 7.5 Hz, 1H), 7.36 (t, J= 7.5 Hz, 1H), 3.94 (s, 3H), 3.11-3.06 (m, 1H), 1.42 (d, J= 6.8 Hz, 6H) 1 H NMR (300 MHz, CDC1 3 ) δ 8.00-7.94 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 3.94 (s, 3H), 3.11-3.06 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H)
50 50
대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000053_0001
Figure imgf000053_0001
2) step2:  2) step2:
Step2 생성물 (0.6 g, 2.36 mmol), Zn (0.8 g, 11.8 mmol)에 AcOH (24 ml)를 넣고 실온에서 20 분간 교반 시킨다. Ac20 (2.4 ml)를 넣고 1 시간 동안 환류 시킨다. 반웅 용액을 농축한 뒤 EA≤ NaHC03 포화수용액을 넣고 여러 번 씻어준다. 유기 층은 MgS04로 건조， 여과한 뒤 재결정으로 정제한다. Add AcOH (24 ml) to Step2 product (0.6 g, 2.36 mmol) and Zn (0.8 g, 11.8 mmol) and stir at room temperature for 20 minutes. Add Ac 2 0 (2.4 ml) and reflux for 1 hour. After concentrating the reaction solution, add saturated solution of EA≤ NaHC0 3 and wash several times. The organic layer is dried over MgSO 4 , filtered and purified by recrystallization.
White solid (0.73 g, 92 %)  White solid (0.73 g, 92%)
lH NMR (300 MHz, CDC13) δ 8.64 (d, IH, J= 8.0 Hz), 7.79 (d, IH, J= 8.4 Hz), 7.56 (t, IH, J= 7.0 Hz), 7.49 (t, IH, J= 6.9 Hz), 3.88 (s, 3H), 3.26-3.21 (m, IH), 2.47 (s, 3H), 2.44 (s, 3H), 1.47 (d, 6H, J= 7.0 Hz) 실시예 12. 화합물 12의 합성] l NMR (300 MHz, CDC1 3 ) δ 8.64 (d, IH, J = 8.0 Hz), 7.79 (d, IH, J = 8.4 Hz), 7.56 (t, IH, J = 7.0 Hz), 7.49 (t, IH, J = 6.9 Hz), 3.88 (s, 3H), 3.26-3.21 (m, IH), 2.47 (s, 3H), 2.44 (s, 3H), 1.47 (d, 6H, J = 7.0 Hz) Example 12. Synthesis of Compound 12]
Figure imgf000053_0002
Figure imgf000053_0002
대체용지 규칙 제 26조 SM(0.1 g, 0.42 mmol)을 Carbonate buffer [Na2C03 (0.35 g, 3.33 mmol/CH3CN: THF: H20=1:1:1, 8.4 ml!]에 녹인 후 질소 분위기 하에서 교반 시킨다. 2-Nitropropane (0.4 ml, 4.16 πψιοΐ)을 천천히 넣어준 후, 55 °C에서 58 시간 동안 교반 시킨다. EA와 NaGl 포화 수용액를 넣은 뒤, 여러 번 씻어낸다. 분리한 유기 4층을 MgS04론 건조시킨 뒤 여과한다. 여과 액은 감압농축한 뒤, ' Silica gel column chron^tography로 정제한다. Replacement Paper Rule 26 SM (0.1 g, 0.42 mmol) was dissolved in Carbonate buffer [Na 2 C0 3 (0.35 g, 3.33 mmol / CH 3 CN: THF: H 2 0 = 1: 1: 1, 8.4 ml!] And stirred under nitrogen atmosphere. thereby. 2-Nitropropane (0.4 ml, 4.16 πψιοΐ) then gave put slowly, at 55 ° C and the mixture was stirred for 58 hours. back into saturated suyongaekreul EA and NaGl, and wash several times. MgS0 the separated organic 4F 4 INTRODUCTION After drying, the filtrate is concentrated under reduced pressure and purified by ' silica gel column chron ^ tography.
Ivory solid 21 mg (18 %)  Ivory solid 21 mg (18%)
1H NMR (300 MHz, DMSO) δ 12.86 (br, s, 1H), 8.28 (m, 1H), 7.74-7.71 (m, 1H), 7.41-7.37 (m, 2H), 3.26-3.17 (m, 1H), 1.76 (s, 6H), 1.38 (d, J= 7.0 Hz, 6H)  1 H NMR (300 MHz, DMSO) δ 12.86 (br, s, 1H), 8.28 (m, 1H), 7.74-7.71 (m, 1H), 7.41-7.37 (m, 2H), 3.26-3.17 (m, 1H ), 1.76 (s, 6H), 1.38 (d, J = 7.0 Hz, 6H)
LC-MS m/z 283.0 (M+l) 실시예 [화합물 13의 합성]  LC-MS m / z 283.0 (M + 1) Example [Synthesis of Compound 13]
Figure imgf000054_0001
Figure imgf000054_0001
SM(0.1 g, 0.42 mmol)을 Carbonate buffer [Na2C03 (0.35 g, 3.33 SM (0.1 g, 0.42 mmol) was added to Carbonate buffer [Na 2 CO 3 (0.35 g, 3.33).
대체용지 규칙 제 26조 mmol/CH3CN: THF: H20=1:1:1, 8.4 ml ]에 녹인 후 질소 분위기 하에서 교반 시킨다. 2-Nitroe¾iane (0.3 ml, 4.16 mmol)을 천천히 넣어준 후， 55 °C에서 15 시간 동안 교반 시킨다. EA와 NaC!l 포화 수용액를 넣은 뒤, 여러 번 씻어낸다. 분리한 유기 층을 MgS04로 건조시킨 뒤 여과한다. 여과 액은 감압농축한 뒤， lica gel. column chromatography로 정제한다 . Replacement Paper Rule 26 mmol / CH 3 CN: THF: H 2 0 = 1: 1: 1, 8.4 ml] and stirred under nitrogen atmosphere. Slowly add 2-Nitroe¾iane (0.3 ml, 4.16 mmol) and stir at 55 ° C for 15 hours. Add saturated aqueous solution of EA and NaC! L and rinse several times. The separated organic layer was dried over MgS0 4 and filtered. The filtrate was concentrated under reduced pressure, and then lica gel. Purify by column chromatography.
Ivory solid 28 mg (25 %)  Ivory solid 28 mg (25%)
1H NMR (300 MHz, DMSO) δ 12,91 (br, s, IH), 8.30 (m, IH), 7.76-7.73 (m, IH), 7.43-7.40 (m, 2H), 6.56-6.54 (m, IH), 3.25-3.20 (m, IH), 1.74 (d, J= 4.8 Hz, 3H), 1.38 (d, J = 7.0 Hz, 6H)  1 H NMR (300 MHz, DMSO) δ 12,91 (br, s, IH), 8.30 (m, IH), 7.76-7.73 (m, IH), 7.43-7.40 (m, 2H), 6.56-6.54 (m , IH), 3.25-3.20 (m, IH), 1.74 (d, J = 4.8 Hz, 3H), 1.38 (d, J = 7.0 Hz, 6H)
LC-MS m/z 269.0 (M+l) 실시예 14. [화합물 14의 합성]
Figure imgf000055_0001
LC-MS mlz 269.0 (M + 1) Example 14. Synthesis of Compound 14
Figure imgf000055_0001
1) lstep:  1) lstep:
SM 200 mg(0.555 mmol), BmNBr 45 mg(0.139 mmol), 85% Na2S204 511 mg(2.5 mmol)에 THF 1.85 ml(0.3 M)와 H20 0.6 ml(l M)을 넣고 실온에서 교반한다. 뒤이어 SM 200 mg (0.555 mmol), BmNBr 45 mg (0.139 mmol), 85% Na 2 S 2 0 4 THF 1.85 ml (0.3 M) to 511 mg (2.5 mmol) and H 2 0 0.6 ml (l M ) into the Stir at room temperature. Subsequently
53 53
대체용지 규칙 제 26조 Me2S04와 4.5 M NaOH 1.3 ml(0.38 M) - 순서대로 넣고실온에서 1 시간동안 교반한다, EA와 ¾0로 중화후， 분리한 유기층은 MgS04로 건조， 여과， 감압 농축후， column한다. 212 mg(98%) Replacement Paper Rule 26 1.3 ml (0.38 M) of Me 2 S0 4 and 4.5 M NaOH-Add sequentially and stir at room temperature for 1 hour. After neutralization with EA and ¾0, the separated organic layer is dried over MgS0 4 , filtered, concentrated under reduced pressure, and columned. . 212 mg (98%)
IH NMR (300 MHz, DMSO) δ 8.31-8.24 (m, IH), 8.03 (d, J = 7.2 Hz, IH), 7.49-7.40 (m, 2H), 4.25 (s, 2H), 4.06 (s, IH), 3.87 (s, 3H), 3.25-3.20 (m, IH), 1.39 (d, J = 6.9 Hz, 6H)  IH NMR (300 MHz, DMSO) δ 8.31-8.24 (m, IH), 8.03 (d, J = 7.2 Hz, IH), 7.49-7.40 (m, 2H), 4.25 (s, 2H), 4.06 (s, IH), 3.87 (s, 3H), 3.25-3.20 (m, IH), 1.39 (d, J = 6.9 Hz, 6H)
2) 2step: 2) 2step:
위 물질 (220 mg, 0.563 mmol) 에 MeOH(2.8 ml, 0.2 M)을 넣는다. 20 wt% Pd(OH)2 118 mg을 넣고 로 치환 乎, 실온에서 2.5 days 동안 반웅 한다. Celite filter후， 역액은 감압증류， colui n하여 화합물을 얻는다 . 60 mg (39%) 실시예 15, 16. [화합물 15， 16의 합성] Add MeOH (2.8 ml, 0.2 M) to the above substance (220 mg, 0.563 mmol). Add 118 mg of 20 wt% Pd (OH) 2 , replace with, and react at room temperature for 2.5 days. After Celite filter, the backwash is distilled under reduced pressure and colui n to obtain the compound. 60 mg (39%) Examples 15, 16. [Synthesis of Compounds 15, 16]
Figure imgf000056_0001
Figure imgf000056_0001
com. 15 com. 16 com. 15 com. 16
SM(150 mg, 0.624 mmol), Camphorsulfonic acid(22 mg, 0.094 mmol)에 Glycol:MeOH 0.7 ml: 3.5 ml을 넣고 120 °C에서 6시간동안 반웅한다. 반웅물 Add SM (150 mg, 0.624 mmol) and Camphorsulfonic acid (22 mg, 0.094 mmol) to 0.7 ml of Glycol: MeOH 3.5 ml and react at 120 ° C for 6 hours. Banungmul
54 54
대체용지 규칙 제 26조 감압증류후， column한다. Replacement Paper Rule 26 After distillation under reduced pressure, column is used.
화합물 15: 18mg(ll%)  Compound 15: 18 mg (ll%)
IH NMR (300 MHz, CDC13) δ 10.93 (s, IH), 8.00 (d, J = 7.2 Hz, IH), 7.58 (d, J = 7.5 Hz, IH), 7.46-7.34 (m, 2H), 4.58-4.50 (m, 2H), 4.43-4.40 (m, 2H), 3.29-3.19 (m, IH), 1,44 (d, J = 6.9 Hz, 6H) 화합물 16: 15mg(8.5%)  IH NMR (300 MHz, CDC13) δ 10.93 (s, IH), 8.00 (d, J = 7.2 Hz, IH), 7.58 (d, J = 7.5 Hz, IH), 7.46-7.34 (m, 2H), 4.58 -4.50 (m, 2H), 4.43-4.40 (m, 2H), 3.29-3.19 (m, IH), 1,44 (d, J = 6.9 Hz, 6H) Compound 16: 15 mg (8.5%)
IH NMR (300 MHz, CDC13) δ 7.93 ( d, J = 6.9 Hz, IH), 7.74 (brs, IH), 7.57- 7.50 (m, IH), 7.28-7.19 (m, IH), 4.49 (s, 2H), 4.28 (s, 2H), 3.18-3.13 (m, IH), 1.36 (d, J = 6.9 Hz, 6H) 실험예 1: N001 활성 측정  IH NMR (300 MHz, CDC13) δ 7.93 (d, J = 6.9 Hz, IH), 7.74 (brs, IH), 7.57-7.50 (m, IH), 7.28-7.19 (m, IH), 4.49 (s, 2H), 4.28 (s, 2H), 3.18-3.13 (m, IH), 1.36 (d, J = 6.9 Hz, 6H) Experimental Example 1 Determination of N001 Activity
효소 반웅액은 25 mM Tris/HCl(pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C그리고 5 ng의 NQOl protein 이 포함된다. 효소 반웅은 NAPH 첨가로 개시되며, 37도에서 시행한다. 이때 반응속도는 Cytochrome C 7} 환원되면서 흡광도가 증가됨을 550 nm 에서 10 분 동안 관찰하고， NQOl 활성은환원되는 cytochrome C 량 [nmol cytochrome C reduced / min / ug protein]으로 나타낸다.  Enzyme reactions included 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQOl protein. Enzyme reaction is initiated by addition of NAPH and is performed at 37 degrees. At this time, the reaction rate was observed for 10 minutes at 550 nm to increase the absorbance as Cytochrome C 7} reduction, NQOl activity is represented by the amount of reduced cytochrome C [nmol cytochrome C reduced / min / ug protein].
Extinction coefficient for cytochrome C： 21.1mmol/L/cm = 21.1umol / ml / cm  Extinction coefficient for cytochrome C ： 21.1mmol / L / cm = 21.1umol / ml / cm
그 결과를 하기 표 1에 나타내었다.  The results are shown in Table 1 below.
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대체용지 규칙 제 26조 [표 1】 Replacement Paper Rule 26 TABLE 1
Figure imgf000058_0001
Figure imgf000058_0001
상기 표 에서 보는 바와 같이， 본 발명에 따른 화합물은 NQOl 활성을 나타내는 것을 알 수 있다. 실험예 2: 세포내의 Lactate 변화량 측정  As shown in the table, it can be seen that the compound according to the present invention exhibits NQOl activity. Experimental Example 2: Measurement of Lactate Change in Cells
Cell 에 400 ul 6% PCA 처리하여 회수 및 추출한다. 원심분리 (13,000 rpm, 10 min)한다. 침전물은 speed-vac 으로 건조하여 건조하여 세포의 건조 무게를 측정한다. 상등액은 400 ul 1 M KOH 를 이용하여 중화하고， 0.33 M KH2P04/K2HP04, pH 7.5을 이용하여 최종량을 1 ml로 맞춘다. 원심분리 (13,000 rpm, 10 min)하여， 상등액으로 lactate의 양 (Megazyme, K-LATE) 측정한다. 그 결과를 하기 표 2에 나타내었다. 400 ul 6% PCA treatment on the cells to recover and extract. Centrifuge (13,000 rpm, 10 min). The precipitate is dried by speed-vac and dried to measure the dry weight of the cells. The supernatant is neutralized with 400 ul 1 M KOH and the final amount is adjusted to 1 ml using 0.33 M KH 2 P0 4 / K 2 HP0 4 , pH 7.5. Centrifuge (13,000 rpm, 10 min) and measure the amount of lactate (Megazyme, K-LATE) in the supernatant. The results are shown in Table 2 below.
【표 2】  Table 2
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대체용지 규칙 제 26조 Replacement Paper Rule 26
Figure imgf000059_0001
실시예에 따른 세포내의 Lactate 활성을 낙타내는 것을 알 수 있다. Cytosol 내의 NAD/NADH 비율은 pyruvate/lactate의 비율와 유사하게 변화하기 때문에 pyruvate/lactate 비율로 cytosol 내의 NAD/NADH 비율 측정할 수 있다. 따라서 lactate의 량이 감소하면 세포내의 NAD/NADH 비가 증가하게 된다. 실험예 3-1 : 실시예 3에 따른 화합물 및 실시예 4에 따른 화합물에 대한 비만 쥐 (o6/ob)에서의 체중 감량 효과
Figure imgf000059_0001
It can be seen that camel Lactate activity in the cell according to the embodiment. Since the NAD / NADH ratio in the cytosol changes similarly to the pyruvate / lactate ratio, the pyruvate / lactate ratio can be used to measure the NAD / NADH ratio in the cytosol. Therefore, decreasing lactate amount increases the intracellular NAD / NADH ratio. Experimental Example 3-1: Weight loss effect in obese mice (o6 / ob) on the compound according to Example 3 and the compound according to Example 4
ORIENTBIO사의 유전적 비만의 특성을 갖고 있는 C57BL/6J Lep o6/ob 마우스 10 주령을 준비하여 온도 20~24 °C , 상대 습도 35~65 %, 조도 150-300 lux, 명암주기 12 시간, 배기 10-15 회 /hr의 사육환경이 유지된 폴리카보네이트 사육상자 (200Wx260Lx 130H (mm), Three-shine)에서 사육상자당 2 마리씩 사육하였고 사료는  10 weeks old C57BL / 6J Lep o6 / ob mouse with ORIENTBIO genetic obesity, temperature 20-24 ° C, relative humidity 35-65%, light intensity 150-300 lux, contrast cycle 12 hours, exhaust 10 Two animals per breeding box were bred in a polycarbonate breeding box (200Wx260Lx 130H (mm), Three-shine) maintained at -15 times / hr.
5757
용지 규칙 제 26조 ORIENTBIO사의 Low fat diet (11.9 kcal% fat, 5053, Labdiet, 미국)을 구입하여 급이기에 넣고 자유섭취 시켰으며 음용수는 필터와 유수살균기를 이용하여 여과 ·살균된 정젝수를 폴리카보네이 ^제 음수병 (250 mL)에 넣어 자유섭취 시켰다. Paper rule Article 26 ORIENTBIO's Low fat diet (11.9 kcal% fat, 5053, Labdiet, USA) was purchased and fed freely. Drinking water was filtered and sterilized by using a filter and an oil sterilizer. (250 mL) was added to free intake.
본 발명에서 합성한 실시예 3에 따른 하합물 및 실시예 4에 따른 화합물을 각각 C57BL/6J Lep ob/ob 마우스 3 마리에 100 mg/kg의 투여 용량으로 매일 1 회씩 총 1 주간 경구투여용 존데가 부착된 일회용 주사기를 이용하여 위 내에 강제 경구 투여하였다. 대조군으로는 C57B 6J Lep ob/ob 마우스 3마리 ᅵ 0.1%의 SLS (소듐 라우릴 설페이트: Soudium Lauryl Sulfate)을 10 mg/kg의 투여 용량으早 총 2 주간 같은 방법을 이용하여 투여하였다. 투여 시간에 따른 체중 증가율, 체중 변화 및 섭취량을 측정하여 하기 도 1에 나타내었다.  Sonde for oral administration once a day for a total of 1 week at a dose of 100 mg / kg of the compound according to Example 3 and the compound according to Example 4 synthesized in the present invention to each of three C57BL / 6J Lep ob / ob mice Forced oral administration into the stomach was performed using a disposable syringe to which was attached. As a control group, three C57B 6J Lep ob / ob mice ᅵ 0.1% SLS (Soudium Lauryl Sulfate) were administered using the same method for a total of 2 weeks at a dose of 10 mg / kg. The weight gain rate, weight change, and intake measured with administration time are shown in FIG. 1.
시험동물의 체중은 군 분리시 (시험물질 투여직전) 및 투여 개시일부터 시험 종료 ¾까지 측정하였고， 전체 체중 증가량은 종료 전일에 측정한 체중에서 실험 개시시의 체중을 빼어 산출하였다. 식이섭취량은 개체별로 시험물질 투여 개시일부터 시험 종료일까지 주 2 회 사료공급량 및 잔량을 측정하였다.  The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of the administration to the end of the test ¾, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test. The dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.
하기 도 1의 그래프에서 보는 바와 같이 실시예 3에 따른 화합물 및 실시예 4에 따른 화합물을 각각 투여한 C57BIV6J Lep ob/ob 마우스의 7일 후 체중 증가율, 및 체중 변화가 대조군과 비교하여 유의성 있게 감소하며， 실시예 3에 따른 화합물을 투여한 7일 후 C57BL/6J Lep ob/ob 마우스의 섭취량이 대조군과 비교하여 유의성 있게 감소하는 것을 알 수 있다.  As shown in the graph of FIG. 1, the body weight gain and body weight change after 7 days of C57BIV6J Lep ob / ob mice administered the compound according to Example 3 and the compound according to Example 4 were significantly decreased compared with the control group. In addition, it can be seen that the intake of C57BL / 6J Lep ob / ob mice was significantly reduced compared to the control group after 7 days of administering the compound according to Example 3.
실험예 3-2: 실시예 7에 따른 화합물 및 실시예 10에 따른 화합물에 대한 비 Experimental Example 3-2: Ratios to the compound according to Example 7 and the compound according to Example 10
58 58
대체용지 규칙 제 26조 만쥐 (ob/0b)에서의 체중 감량효과 Replacement Paper Rule 26 Weight loss effect in rats (ob / 0 b)
ORIENTBIO사의 유전적 비만의 특성을 갖고 있는 C57BU6J Lep ob/ob 마우스 6.5 주령을 준비하여 실시예 7에 따른 화합물 및 실시예 10에 따른 화합물을 각각 C57BL/0J Lep ob/ob 마우스 3 마리에 100 mg/kg씩 투여하고， 대조군으로는 C57BIJ6J Lep ob/ob마우스 3 마리에 0.1%의 SLS을 10 mg/kg씩 투여하여 총 1 주간 설험한 것을 제외하고는 실험예 3-1과 동일한 조건에서 실험을 하여 투여 시간에 따른 체중 증가율， 체중 변화 및 섭취량을 측정하여 하기 £ 2에 나타내었다. C57BU6J Lep ob / ob mice having the characteristics of genetic obesity from ORIENTBIO were prepared at 6.5 weeks of age, and the compounds according to Example 7 and the compounds according to Example 10 were respectively added to three C 57 BL / 0J Lep ob / ob mice. mg / kg and each control group was administered under the same conditions as Experimental Example 3-1 except that 0.1 mg of SLS was administered 10 mg / kg to 3 C57BIJ6J Lep ob / ob mice. By measuring the weight gain rate, weight change and intake over time administration is shown in £ 2 below.
하기 도 2의 그래프에서 보는 바와 같이 상기 방법으로 실시예 7에 따른 화합물 및 실시예 10에 따른 화합물을각각투여한 C57BL/6J Lep ob/ob 마우스의 7일 후 체중 증가율, 및 처)중 변화가 대조군과 비교하여 유의성 있게 감소하는 것을 알수 있다. 실험예 3-3: 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물에 대한 비만쥐 (o6/obᅵ에서의 체중 감량효과  As shown in the graph of FIG. 2 below, after 7 days of the C57BL / 6J Lep ob / ob mice to which the compound according to Example 7 and the compound according to Example 10 were administered by the above method, the weight gain rate and the change during treatment were It can be seen that the decrease significantly compared to the control. Experimental Example 3-3: Weight Loss Effect in Obese Rats (o6 / ob ᅵ) on Compounds according to Example 12 and Compounds according to Example 13
ORIENTBIO사의 유전적 비만의 특성을 갖고 있는 C57BU6J Lep ob/ob 마우스 6.5 주령을 준비하여 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물을 각각 C57BL/6J Lep ob/ob 마우스 3 마리에 100 mg/kg씩 투여하고, 대조군으로는 C57B 6J Lep ob/ob마우스 3마리에 0.1%의 SLS을 10 mg/kg씩 투여하여 총 6 일간 실험한 것을 제외하고는 실험예 3-1과.동일한 조건에서 실험을 하여 투여 시간에 따른 체중 증가율， 체중 변화， 및 섭취량을 측정하여 하기 도 3에 나타내었다.  C57BU6J Lep ob / ob mice having the characteristics of genetic obesity from ORIENTBIO were prepared at 6.5 weeks of age, and the compound according to Example 12 and the compound according to Example 13 were each 100 mg / in mouse C57BL / 6J Lep ob / ob. The test was conducted in the same conditions as in Experiment 3-1, except that the control group was administered for 6 days with 10 mg / kg of 0.1% SLS administered to 3 C57B 6J Lep ob / ob mice as a control group. By measuring the weight increase rate, weight change, and intake with time of administration are shown in Figure 3 below.
하기 도 3의 그래프에서 보는 바와 같이 상기 방법으로 실시예 12에 따른화  According to Example 12 in this manner as shown in the graph of Figure 3 below
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대체용지 규칙 제 26조 합물 실시예 13에 따른 화합물을 각각 투여한 C57BL/6J Lep ob/ob 마우스의 6일 후 체중 증가율, 체중 변화， 및 섭취량이 대조군과 비교하여 유의성 있게 감소한 것을 알수 있다. 실험예 3-4: 실시예 16에 따른 화합물에 대한 비만 쥐 (ob/ob)에서의 체중 감량효과 Replacement Paper Rule 26 The body weight gain, body weight change, and intake of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 13, respectively, were significantly reduced compared to the control group. Experimental Example 3-4: Weight loss effect in obese rats (ob / ob) on the compound according to Example 16
ORIENTBIO사희 유전적 비만의 특성을 갖고 있는 C57BL/6J Lep ob/ob 마우스 6.5 주령윷 준비하여 실시예 16에 따른 화합물을 각각 C57BL/6J Lep ob/ob 마우스 3 마리에 100 mg/kg씩 투여하고， 대조군으로는 C57BL/6J Lep ob/o6마우스 3마리에 0.1%의 SLS을 10 mg/kg씩 투여하여 총 14 일간실험한 것을 ^외하고는 실험예 3-1과 동일 조건에서 실험을 하여 투여 시간에 따른 체중 증가율, 체중 변화 및 섭취량을측정하여 하기 도 4에 나타내었다. 하기 도 4의 그래프에서 보는 바와 같이 상기 방법으로 실시예 16에 따른 합물을 각각 투여한 C57BL/6J Lep ob/ob마우스의 체중 증가율, 체중 변화 섭취가 대조군과 비교하여 일부 구간에서 유의성 있게 감소한 것을 알수 있다. 실험예 4: 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물에 대한 당뇨 쥐 0 ^에서의 Glucose Level측정 결과  ORIENTBIO was prepared for 6.5 weeks of C57BL / 6J Lep ob / ob mice having genetic obesity, and the compounds according to Example 16 were administered to each of the C57BL / 6J Lep ob / ob mice at 100 mg / kg. As a control group, experiments were conducted under the same conditions as in Experimental Example 3-1 except that 0.1 mg of SLS was administered 10 mg / kg in three C57BL / 6J Lep ob / o6 mice for 14 days. In accordance with the weight gain rate, weight change and intake measured according to Figure 4 is shown. As shown in the graph of FIG. 4, the weight gain rate and the weight change intake of the C57BL / 6J Lep ob / ob mice respectively administered the compound according to Example 16 by the above method were found to be significantly reduced in some sections compared to the control group. have. Experimental Example 4: Glucose Level Measurement Results in Diabetic Rat 0 ^ for the Compound According to Example 12 and the Compound According to Example 13
ORIENTBIO사의 유전적 비만의 특성을 갖고 있는 C57BLKS/6 db/db 마우스 10 주령을 준비하여 온도 22~24 도， 상대 습도 50~30 %， 조도 150-300 lux, 명암주기 12 시간, 배기 10-15 회 /hr의 사육환경이 유지된 폴리 카보네이트사육상자 (200Wx  ORIENTBIO's C57BLKS / 6 db / db mouse, which possesses the characteristics of genetic obesity, is prepared for 10 weeks of age at a temperature of 22 to 24 degrees, a relative humidity of 50 to 30%, an illuminance of 150 to 300 lux, a contrast cycle of 12 hours, and an exhaust of 10 to 15 Polycarbonate Breeding Box (200Wx)
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대체용지 규칙 제 26조 260Lxl30H (mm), Three-shine)에서 사육상자당 2 마리씩 사육하였고 사료는 ORIENTBIO사의 Low fat diet (11.9 kca /0 fat, 5053， Labdiet)을구입하여 급이기 에 넣고 자유섭취 시켰으며 음용수는 필터와유수살균기를 이용하여 여과 -살 균된 정제수를 폴리카보네이트제 음수병 (250 mL)에 넣어 자유섭취 시켰다. 본 발명에서 합성한 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물을 각각 C57BLKS/6 db/db마우^ 3 마리에 80 mg/kg의 투여 용량으로 경구투여용 존데가 부착된 일회용 주사기를 이용하여 위 내에 강제 경구 투여하였다. 대조군으로는 C57BLKS db/db 마우스 3마리에 0.1%의 SLS을 10 mg/kg의 투여 용량으로 같은 방법을 이용하여 투여하였다. 14일 동안 Glucose Level을측정하아하기 도 5에 나타내었다. Replacement Paper Rule 26 260Lxl30H (mm), two dogs per breeding box were bred in the box, feed was fed ORIENTBIO's Low fat diet (11.9 kca / 0 fat, 5053, Labdiet) into the feeder and freely ingested. Filtration-sterilized purified water was added to a polycarbonate drinking bottle (250 mL) using an oil sterilizer and was freely ingested. The compound according to Example 12 synthesized in the present invention and the compound according to Example 13 were used for each C57BLKS / 6 db / db Mau ^ three disposable syringes with oral administration of the sonde at a dosage of 80 mg / kg Forced oral administration into the stomach. As a control group, 0.1% SLS was administered to three C57BLKS db / db mice using the same method at a dose of 10 mg / kg. Glucose Level was measured for 14 days, and is shown in FIG. 5.
하기 도 5의 그래프에서 보는 마와 같이 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물을 각각투여한 C57BLKS/6 마우스 의 Glucose Glucose of C57BLKS / 6 mice to which the compound according to Example 12 and the compound according to Example 13 were respectively administered as shown in the graph of FIG. 5.
Level 이 대조군과 비교하여 유의성 게 감소하는 것을 알수 있다. 실험예 5: 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물에 대한 당뇨 쥐 ( /b// 에서의 체중감량 효과 It can be seen that the level is significantly decreased compared to the control. Experimental Example 5: Weight loss effect in diabetic rats (/ b // on the compound according to Example 12 and the compound according to Example 13
ORIENTBIO사 유전적 당뇨의 특성을 갖고 있는 C57BLKS/6 db/db 마우스 6.5 주령을 준비하여 은도 22~24 도， 상대 습도 50~30 %, 조도 150-300 lux, 명암주기 12 시간， 배기 10-15 회/ hr의 사육환경이 유지된 폴리카보네이트 사육상자(200 ><2601^< 13(« (mm), Three-shine)에서 사육상자당 2마리씩 사육하였고사료는 ORIENTBIO사의 Low fat diet (11.9 kcal% fat, 5053， Labdiet)을구입하여 급이기  ORIENTBIO Co., Ltd. C57BLKS / 6 db / db mice with genetic diabetes characteristics are prepared for 6.5 weeks of age and have a degree of silver of 22 to 24 degrees, relative humidity of 50 to 30%, illuminance of 150 to 300 lux, a contrast cycle of 12 hours, and exhaust 10 to 15. In the polycarbonate breeding box (200> <2601 ^ <13 («(mm), Three-shine), which maintained the breeding environment of ash / hr, two dogs were raised per breeding box and the feed was ORIENTBIO's low fat diet (11.9 kcal% fat, 5053 ， Labdiet)
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대체용지 규칙 제 26조 에 넣고 자유섭취 시켰으며 음용수는 필터와 유수살균기를 이용하여 여과。살균된 정제수를 폴리카보네이론제 음수병 (250 mL)에 넣어 자유섭취 시켰다. Replacement Paper Rule 26 Drinking water was filtered using a filter and an oil sterilizer. The sterilized purified water was freely added to polycarbonate bottle (250 mL).
본 발명에서 합성한 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물을 각각 C57BLKS/6 db/db 마우스 3 마리에 80 mg/kg씩 투여하여 총 14 일간 실험하고， 대조군으로는 C57BLKS/6 db/db 마우스 3마리에 0.1%의 SLS을 10 mg/kg씩 투여하여 총 23 간실험한 것을 제외하고는 실험예 3- 1과 동일한 조건에서 질험을 하여 투여 시간에 따른 체증 증가율, 체중 변화 및 섟 ^량을 측정하여 하기 도 6에 나타내었다.  The compound according to Example 12 synthesized in the present invention and the compound according to Example 13 were each administered 80 mg / kg to three C57BLKS / 6 db / db mice for 14 days, and as a control group, C57BLKS / 6 db Body weight increase rate, weight change and 섟 according to administration time were tested in the same conditions as Experimental Example 3-1, except that 23 mice were administered with 10 mg / kg of 0.1% SLS in 3 / db mice. The amount of ^ was measured and shown in FIG. 6.
시험동물의 체중은 군 분리시 (시험물질 투여직전) 및 투여 71]시일부터 시험 종료일까지 측정하 ^고， 전체 체중 증가량은 종료 전일에 측정한 체중에서 실험 개시시의 체중을 빼어 산출하였다. 식이섭취량은 개체별로 시험물질 투여 개시일부터 시험 종료일까지 사료공급량 및 잔량을 측정하였다.  The body weight of the test animals was measured from the time of group separation (just before administration of the test substance) and from the time of administration to the end of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test. The dietary intake was measured from the start of the administration of the test substance to the end of the test for each individual.
하기 도 의 그래프에서 보는 바와 같이 상기 방법으로 실시예 12에 따른 화합물 및 실시예 13에 따른 화합물을 각각 투여한 C57BLKS/6 db/db 마우스의 체중 증기；율， 체중 변화 및 섭취가 대조군과 비교하여 일부 구간에서 유의성 있게 감소한 것을 알수 있다.  As shown in the graph of the following figure, the body weight steam, rate, weight change and intake of the C57BLKS / 6 db / db mice to which the compound according to Example 12 and the compound according to Example 13 were respectively administered by the above method were compared with those of the control group. It can be seen that there was a significant decrease in some intervals.
【산업상 이용가능성】  Industrial Applicability
이상에서 설명한 바와 같이， 본 발명에 따른 신규한 1,2-나프토퀴논 유도체는， 생체 내 NQ01 활성을 통해 NAD(P)+/NAD(P)H 비율을 높임으로써 세포 내 에너지 환경변화에 대한 에너지 소비기전인 AMPK 활성화， 미토콘 드리아의 에너지 대사를  As described above, the novel 1,2-naphthoquinone derivative according to the present invention, by increasing the NAD (P) + / NAD (P) H ratio through the NQ01 activity in vivo to change the energy environment in the cell AMPK activation, the energy consumption mechanism, mitochondria energy metabolism
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대체용지 규칙 제 26조 ί "성화시키는 PGCla 발현 등 장기간 칼로리 제한 (calorie restriction)과 운동 시에、나타나는 유전적 변화를 유도하여 미토콘드리아 활성화로 인한 미토콘 드리아 생합성， 지구력 운동성 근섬육로의 변화와 같은 시스템의 개선으로 신체의 활동성 (physical activity)를 높이는 운동모방 치료효과를 가져오므로, 이를 유효성분으로 사용하는 약제는 대사성 질환을 치료 또는 예방하는데 유용하게 사용할수 있다. Replacement Paper Rule 26 ί "Activate the body by improving calorie restriction such as expression of activating PGCla and systemic changes such as mitochondrial biosynthesis due to mitochondrial activation and endurance motility muscle induction by inducing genetic changes that appear during exercise. Since it has a therapeutic effect on exercise mimicking to increase physical activity, a drug using it as an active ingredient may be useful for treating or preventing metabolic diseases.
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대체용지 규칙 제 26조  Replacement Paper Rule 26

Claims

【청구의 범위】  [Range of request]
【청구항 1】  [Claim 1]
하기 화 식 (1)로 표시되는 攀합물, 그것의 약제학적으로 허용되는 염， 수화물， 용맥화물， 프로드럭， 토토머 (tautomer), 거울상 이성질체 또는 약 학적으로 허용 가능한 부분입체 이성질체  A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate, a hemohydrate, a prodrug, a tautomer, an enantiomer or a pharmaceutically acceptable diastereomer thereof
Figure imgf000066_0001
Figure imgf000066_0001
상기 식에서，  In the above formula,
¾ 및 R2fe 각각 ;독립적으로 수소， 할로겐 원소， 치환또는 비치환의¾ and R 2 fe are each independently hydrogen, halogen, substituted or unsubstituted
C1-C20 알콕시, 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C4-C1 0 아릴， 치환 또^ 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C2-C10 헤테로아릴, -N02, -NR'!R'2, -NR'i(CO(0)R'2), -NR'i(C(0)NR'1R'2), -CO(0)R'!,
Figure imgf000066_0002
-CSNR'iR'2, 또는 및 R2는 상호 결합에 의해 치환 또는 비치환의 C4-C10 아릴의 환형 구조, 또는 치환또는 비치환의 C2-C10 헤테로아릴의 환형 구조를 이를 수 있으며， C1-C20 alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C1 0 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -N0 2 ,- NR '! R'2, -NR'i (CO (0) R' 2 ), -NR'i (C (0) NR ' 1 R' 2 ), -CO (0) R '!,
Figure imgf000066_0002
-CSNR'iR ' 2 , or R 2 may lead to a cyclic structure of substituted or unsubstituted C4-C10 aryl or a cyclic structure of substituted or unsubstituted C2-C10 heteroaryl by mutual bonding,
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대체용지 (규칙 제 26조) 여기서 및 R'2는각각 독립적으로 수소， 치환 또는 비치환의 C1-Alternative Site (Article 26) And R ' 2 are each independently hydrogen, substituted or unsubstituted C1-
C6 알킬， 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C4- C10 아릴, 치환 또는 비치환의 C4-C1Q 아릴옥시， 치환 또는 비치환의 C1-C8 헤테로아릴, 치환 또는 비치환의 -(CR^R'^m'-C^ClO 아릴 또는 치환 또는 비치환의 Νβ Ι "2이고; 여기서 R"j 및 R"2는 각각 독립적으로 수소, C1-C3 알킬， 또는 R"i 및 R"2는 상호 결합에 의해 치환 또는 비치환의 C4-C10 아릴의 환형 구 ^를 이를 수 있고; C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C1Q aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR ^ R '^ m'-C ^ ClO aryl or substituted or unsubstituted Νβ Ι " 2 , wherein R" j and R " 2 are each independently hydrogen, C1-C3 alkyl, or R" i and R " 2 are mutually By bonding, a substituted or unsubstituted C4-C10 aryl cyclic ^ can be followed;
R3, R4, R5, 및 Re은 각각 독혁적으로 수소， 할로겐 원소， 치환 또는 비치환의 C1-C9 알킬, 치환 또는 비치환의 C1-C20 알콕시, 치환 또는 비치환의 C3-C8 시클호알킬， 치환 또는 비치환의 C2-C8 헤테로시클로알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치환 ^는 비치환의 C1-C10 헤테로아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4- C10 아릴, 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 아릴옥시， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4- C10 혜테로시클로알킬， 치환 또는 비치환의 -(CR'5R'6)m-NR'3R'4, 치환 또는 비치환의 -(CR'5R'6)m-OR'3, -CO(0)R'3, -CONR'3R'4, -NR'3R'4, -NR'3(C(0)R'4), - SO(0)R'3, -SO(0)NR'3R'4, -NR'3(SO(0)R'4), -CSNR'3R'4, 화학식 (1)의 화합물이 "A"일 때 -CH2A, 또는 화학식 (1)의 화합물이 "A"일 때 -A이며; R 3 , R 4, R 5 , and Re are each independently hydrogen, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cyclohoalkyl, substituted Or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted ^ is unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' 5 R ' 6 ) m -C4-C10 aryl, substituted or unsubstituted-(CR' 5 R ' 6 ) m -C4-C10 aryloxy, substituted or unsubstituted-(CR' 5 R ' 6 ) m -C4-C10 hetero Aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -NR ' 3 R'4, substituted or unsubstituted -(CR ' 5 R' 6 ) m -OR ' 3 , -CO (0) R' 3 , -CONR ' 3 R'4, -NR' 3 R ' 4 , -NR' 3 (C (0) R ' 4 ), -SO (0) R' 3 , -SO (0) NR ' 3 R'4, -NR' 3 (SO (0) R ' 4 ), -CSNR' 3 R ' 4 , chemical formula ( 1) -CH 2 a, or when the compound is "a" Learning (1) -A compound and when the "A"of;
여기서， R'3, R'4는 각각 독립적으로 수소, 치환 또는 비치환의 C1-C6 알킬，  Here, R'3, R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl,
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대체용지 (규칙 제 26조) 처환 또는 비치 ¾의 C3-C8 시클로알킬, 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치 ¾의 -(CH2)m-C4-C10 아릴， 치환 또는 비치환의 -(C¾)m-C4- C10 아릴옥시， -CO(0)R"3, 또는 R'3 및 R'4는 상호 결합에 의해 치환 또는 비치환의 C4-C1( 헤테로시클로알킬의 환형 구조, 또는 치환 또는 비치환의 C4-C10 헤테로아릴의 환형 구조를 이 Ϊ " 수 있고; Alternative Site (Article 26) Substituted or unsubstituted ¾ C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryl, substituted or unsubstituted-(C¾) m -C4-C10 Aryloxy, -CO (0) R " 3 , or R'3 and R'4 are substituted or unsubstituted C4-C1 (cyclic structure of heterocycloalkyl, or substituted or unsubstituted C4-C10 heteroaryl by mutual bonding) Can have a cyclic structure of;
R'5, 및 R'6각각 독립적으로 수소 또는 C1-C3 알킬이며; R"3는 C1- 。6알¾이며; R ' 5 , and R' 6 are each independently hydrogen or C1-C3 alkyl; R " 3 is C1-.6 al¾;
COR7이고 Q2이 COR8일 때， (^과 Q2는 이중 결합을 이루고 여기서 R7 및 ¾은 각각 독립적으로 수소， 치환 또는 비치환의 C1- C20 알콕시， 치환 또는 비치환의 C1-C6 알킬, 치환 또는 비치환의 C4-C10 아릴, 치환 또는 비치환의 C4-C10 아릴옥시, 치환 또는 비치환의 C2-C10 테로아릴, -CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, -SO(0)NR'7R'8, -S03R'7, - P03R'7, -CSNR'7R'8, 또는 R7 및 Rg는 상호 결합에 의해 치환또는 비치환의 C3-C10 헤테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C3-C10 헤테로아릴의 환형 구조를 이를 수 있으며， When COR 7 and Q 2 is COR 8 (^ and Q 2 form a double bond where R 7 and ¾ each independently represent hydrogen, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 teraryl, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R '7, -SO (0) NR' 7 R '8, -S0 3 R' 7, - P0 3 R '7, -CSNR' 7 R '8, or R 7 and Rg are mutually Cyclic structure of substituted or unsubstituted C3-C10 heterocycloalkyl by a bond, or cyclic structure of substituted or unsubstituted C3-C10 heteroaryl,
여기서 R'7및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C3-C8 시클로알킬, 치환 또는 비치환의 C4-C10 아릴, 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C1-C8 헤테로아릴， 치환 또는 비치환의 -(CR"7R"8)m'-C4-C10 아릴아고; 여기서 R"7 및 R"8는 각각 독립적으로 Wherein R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy , Substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR " 7 R" 8 ) m'-C4-C10 arylago; Where R " 7 and R" 8 are each independently
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대체용지 (규칙 제 26조) 수소, C1-C3 알킬이고; 이 치환 또는 비치환의 C3-C5 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는， (^이 CO이고 Q2가 치환 또는 비치환의 C3-C5 헤테로시클로알 의 환항구조일 때， 9,과 Q2는 단일 결합을 이루고 여기서， 칩환기는 히드록시, 할로겐 원소, C1-C10 알킬, C2-C10 알케닐， C2-C10 알키닐, C1-C10 알콕시, C1-C10 알콕시카르보닐, C3-C8 시클로알킬, C2-C8 헤테로시 로알 ¾， C4-C10 아릴， 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 하나 이상이며; m 와 m' r 각 4독립적으로 1 내지 4의 자연수이고; 헤테로 원자는 H O 및 S에서 선택된 하나 이상이며; 및 X4는 각각 독립적으로 C(H) 또는 N이고; Alternative Site (Article 26) Hydrogen, C1-C3 alkyl; 9, and Q when the cyclic structure of this substituted or unsubstituted C3-C5 heterocycloalkyl and Q 2 is CO or (^ is CO and Q 2 is a cyclic structure of substituted or unsubstituted C3-C5 heterocycloal 2 is a single bond wherein the chip ring group is hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cyclo At least one selected from the group consisting of alkyl, C2-C8 heterocyloal, C4-C10 aryl, and C2-C10 heteroaryl; each of m and m'r is independently a natural number of 1 to 4; And at least one selected from S and X 4 are each independently C (H) or N;
X5는 N두는 0이며， X6는 Ν, Ο 또는 S이고; 및 η은 0 또는 1이며, η이 0인 경우에 그것의 인접 탄소원자들은 직접결합에 의해 환형 구조를 이루며； 및 '는 단일결합 또는 이중결합이고， -" -는 단일결합 또는 결합이 X 5 is N is 0 and X 6 is Ν, Ο or S; And η is 0 or 1, and when η is 0, its adjacent carbon atoms form a cyclic structure by direct bond; and 'is a single bond or a double bond, and-"-is a single bond or a bond.
,····'··.  , ···· '··.
형성되지 않을 수 있으며， U 는 이를 포함하는 환형 구조가 방향촉 (aromatic)일 수도 있고, 방향족이 아닐 수도 있음을 의미한다. It may not be formed, U means that the cyclic structure containing it may be aromatic, may not be aromatic.
【청구항 2】 [Claim 2]
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대체용지 (규칙 제 26조) 제 1 항에 있어서， 상기 화학식 (1)의 화합물은 하기 화학식 (2)의 화합물인 것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염， 수화물, 용매화물， 프로드릭， 토토머， 거울상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체: Alternative Site (Article 26) The compound according to claim 1, wherein the compound of formula (1) is a compound of formula (2), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer thereof Or pharmaceutically acceptable diastereomers:
Figure imgf000070_0001
Figure imgf000070_0001
상기 식에서， R5, Qh 및 ¾는 제 1항에서 정의된 바와 같다. Wherein R 5 , Q h and ¾ are as defined in claim 1.
【청구항 3】  [Claim 3]
제 2 항에 있어서, 상기 화학식 (2)의 화합물은 하기 화학식 (2-1)의 ¼합물인 것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염, 수화물， 용매화물， 프로드럭， 토토머, 거을상 이성질체 또는 약학적으로 허용 가능한부분입체 이성질체:  3. A compound according to claim 2, wherein the compound of formula (2) is a ¼ compound of formula (2-1), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer thereof , Sieving or pharmaceutically acceptable diastereomers:
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대체용지 (규칙 제 26조) Alternative Site (Article 26)
Figure imgf000071_0001
Figure imgf000071_0001
상기 식에서 및 Q2는 제 1항에서 정의한 바와 같다. Wherein Q 2 is as defined in claim 1.
【청구항 4】  [Claim 4]
제 1 항에 있어서， 상기 화학식 (1)의 화합물은 하기 화학식 (3)의 화합물 및 /또는 화학식 (4)의 화합물인 것을 특징으로 하는 화합물， 그것의 약제학적으로 허용돠는 염， 수화물， 용매화물, 프로드럭, 토토머， 거울상 이성질체 또는 약학적으로 허용 가능한부분입체 이성질체:  A compound according to claim 1, wherein the compound of formula (1) is a compound of formula (3) and / or a compound of formula (4), pharmaceutically acceptable salts, hydrates, solvents thereof Cargo, prodrugs, tautomers, enantiomers or pharmaceutically acceptable diastereomers:
Figure imgf000071_0002
Figure imgf000071_0002
상기 식에서,  Where
상기 내지 ¾， Re, Ql5 Q2. X!, ¾， X3, ¾, X5및 X6은 제 1항에서 정의된 바와 같다. Said to ¾, Re, Ql5 Q2. X !, ¾, X 3 , ¾, X 5 and X 6 are as defined in claim 1.
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대체용지 (규칙 제 26조) 【청구항 5】 Alternative Site (Article 26) [Claim 5]
제 4 항에 있어서，  The method of claim 4,
상기 ¾ 및 R2는 각각 독립적으로 H, F, CI, -N(CH3)2, -NHCOCH3, 또는 -NHCOC3H5이고， Xi 내지 X4는 각각 C(H)이고， X5 및 ¾은 각각 N인 것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염， 수화물, 용매화물， 프로드릭， 토토머， 거을상 이성질체 는 약학적으로 허용 가능한 부분입체 이성질체. ¾ and R 2 are each independently H, F, CI, -N (CH 3 ) 2 , -NHCOCH 3 , or -NHCOC 3 H 5 , Xi to X4 are each C (H), and X 5 and ¾ Are each N, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, and isomers of the pharmaceutically acceptable diastereomers.
【청구항 6】  [Claim 6]
제 5 항에 있어서，  The method of claim 5,
상기 ¾ 및 R2는 각각 H 이고， 내지 X4는 각각 C(H)이고, Xs 및 X6은 각각 N인 것을 ?특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염， 수화물， 용맥화물， 프로드력， 토토머, 거울상 이성질체 또는 약학적으로 허용 가능한 부북입체 이성질체. Wherein ¾ and R 2 are each H, to X4 are each C (H), and X s and X 6 are each N ? Characterized compounds, pharmaceutically acceptable salts thereof, hydrates, hemolysates, prodrugs, tautomers, enantiomers or pharmaceutically acceptable diastereomers.
【청구항 7]  [Claim 7]
제 4 항에 있어서，  The method of claim 4,
R3 및 ¾는 각각 독립적으로， H, 할로겐 원소, 치환 또는 비치환의 C1-C9 알킬, 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 - (CR'5R'6))m-C4-C10 아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 아릴옥시， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로아릴， 치환 또는 비치환의 - (CR'5R'6)m-C4-C10 헤테로시클 R 3 and ¾ are each independently H, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted-(CR ' 5 R' 6 )) m -C4 -C10 aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heteroaryl, substituted or unsubstituted -(CR ' 5 R'6) m-C4-C10 heterocycle
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대체용지 (규칙 제 26조) 로알킬， 치환 또는 비'치환의 -(CHR'5)m-NR'3R'4, -CO(0)R'3) -CONR'3R'4, - NR'3R'4, -NR'3(C(0)R'4), 또는 상기 화학식 (1)의 화합물이 "A"일 때 - CH2A이며; Alternative Site (Article 26) "Substituted - (CHR 'roal keel, a substituted or non-5) m -NR' 3 R ' 4, -CO (0) R' 3) -CONR '3 R' 4, - NR '3 R' 4, - NR ' 3 (C (0) R' 4 ), or when the compound of formula (1) is "A"-CH 2 A;
¾는 할로겐 원소, 치환 또 비치환의 C2-C9 알킬， 치환 또는 비치환의 C1-C1Q 알콕시， 치환 또는 치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C2-C8 해테로시클로알킬， 칙환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치 또는 비치환의 C1-C10 헤테로아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 아릴， 치환 또는 비치환의 - (CR'5R'6)m-C4-C10 아릴옥시， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로아릴, 치환 또는 비치환의 -(CHR'5)m-NR'3-C4-C10 아릴， 치환 또는 비치환의 -(CR'5R'6)m-C4-C10 헤테로시클로알킬, 치환 또는 비치환의 - (CR'5R'6)m-NR'3R'4, 치환 또는 비치환의 -(CR'5R'6)m-OR'3, -NR'3R'4, 또는 상기 화학식 (1)의 화합물이 "A"일 때 -A이고; ¾ is a halogen element, substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C1Q alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, disubstituted or unsubstituted C4 -C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 aryl, substituted or unsubstituted-( CR ' 5 R' 6 ) m-C4-C10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heteroaryl, substituted or unsubstituted-(CHR ' 5 ) m -NR' 3 -C4-C10 aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heterocycloalkyl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -NR ' 3 R'4 , Substituted or unsubstituted — (CR ′ 5 R ′ 6 ) m —OR ′ 3 , —NR ′ 3 R ′ 4 , or —A when the compound of Formula (1) is “A”;
여기서， R'3, R'4는 각각 독립적 <으로 수소， 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 -(C¾)m- C4-C10 아릴， 치환 또는 비치환의 -(CH2)m-C4-C10 아릴옥시, -CO(0)R"3, 또는 R'3 및 R'4는 상호 결합에 의해 치환 또는 비치환의 C4-C10 헤테로시클로알킬의 환형 구조, 또는 치환 또는 비치환의 C4-C10 헤테로아릴의 환형 구조를 이를 수 있고； Wherein R'3 and R'4 are each independently < hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted-(C¾) m -C4-C10 aryl, Substituted or unsubstituted-(CH 2 ) m -C 4 -C 10 aryloxy, -CO (0) R " 3 , or R'3 and R'4 are mutually bonded to form a substituted or unsubstituted C4-C10 heterocycloalkyl Cyclic structure or cyclic structure of substituted or unsubstituted C4-C10 heteroaryl;
R'5, 및 R'6각각 독립적으로 수소 또는 C1-C3 알킬이며; R"3는 C1- C6알킬이 R'5, and R'6 are each independently hydrogen or C1-C3 alkyl; R " 3 is C1-C6 alkyl
71 71
대체용지 (규칙 제 26조) 며; Alternative Site (Article 26) ;
여기서， 치환기는 히드록시， 할로겐 원소， C1-C10 알킬， C2-C10 알케닐， C2-C10 알키닐， C1-C10 알콕시, C1-C10 알콕시카르보닐, C3-C8 시클로알킬， C2-C8 헤테로시#로알킬， C4-C10 아릴， 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 한나 이상이며;  Wherein the substituent is hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocy At least one selected from the group consisting of #roalkyl, C4-C10 aryl, and C2-C10 heteroaryl;
m은 1 내지 4의 자연수이고;  m is a natural number of 1 to 4;
헤테로 원자는 Ν, Ο 및 S에서 선택된 하나 이상인;  The hetero atom is at least one selected from Ν, Ο and S;
것을 특징으로 하는 화합물， 그것의; 약제학적으로 허용되는 염, 수화물, 용매화물, 프로드럭, 토토머, 거울상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체. Compounds, characterized in that; Pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers or pharmaceutically acceptable diastereomers.
【청구항 8】  [Claim 8]
제 7 항 있어서， The method of claim 7 ,
R3 및 Re는 각각 독립적으로， H, 할로겐 원소, 치환 또는 비치환의 C1-C9 알킬이며; R 3 and Re are each independently H, a halogen element, a substituted or unsubstituted C 1 -C 9 alkyl;
는할로겐 원소， 치환또는 비치환의 C2-C9 알킬인;  Is a halogen element, a substituted or unsubstituted C2-C9 alkyl;
것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염， 수화물, 용매화물, 프로드럭， 토토머， 거을상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체. Compounds, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, diastereomers or pharmaceutically acceptable diastereomers thereof.
【청구항 9】  [Claim 9]
제 4 항에 있어서，  The method of claim 4,
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대체용지 (규칙 제 26조) Q l COR7이고 Q2이 COR8일 때, Qi과 Q2는 이중 결합을 이루고 R7 및 ¾는 각하 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치확의 C4-C10 아릴， 침환 또는 비치환의 C4-C10 아릴옥시， 치환또는 비치환의 C2-C10 헤테로아 , -CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, - SO(0)NR'7R'8, -S03R'7, -P03R'7, -CSNR'7R'8, 또는 R7 및 R8는 상호 결합에 의해 치환 또는 바치환의 C3-C10 헤 ᅵ로시클로알킬의 환형 구조, 또는 치환 또는 비치환의 C3-C10 헤테로아릴의 형 구조를 이를 수 있으며， Alternative Site (Article 26) When Q l COR 7 and Q 2 is COR 8 , Qi and Q 2 form a double bond and R 7 and ¾ are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unexpanded C4-C10 aryl , Substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 heteroa, -CO (0) R ' 7 , -C (0) NR' 7 R ' 8 , -SO (0) R' 7 , -SO (0) NR ' 7 R' 8 , -S0 3 R ' 7 , -P0 3 R' 7 , -CSNR ' 7 R' 8 , or R 7 and R 8 are substituted or substituted by a mutual bond The C3-C10 he may be the cyclic structure of the cyclocycloalkyl, or substituted or unsubstituted C3-C10 heteroaryl structure,
여기서 R'7및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， 치환 또는 비치환의 C3-C8 시클로알킬， 치환 또는 비치환의 C4-C10 아릴， 치환 또는 비치환의 C4-C10 아릴옥시， 치환 또는 비치환의 C1-C8 헤테로아릴, 치환 또는 비치환의 -(CR"7R"8)m'-C4-C10 아릴이고; 여기서 R"7 및 1 "8는 각각 독립적으로 수소， Cl-C 알킬이고; Wherein R'7 and R ' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy Substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR " 7 R" 8 ) m'-C4-C10 aryl; Wherein R " 7 and 1" 8 are each independently hydrogen, Cl-C alkyl;
Q,o) 치환 또는 비치환의 C3 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는, Q l CO이고 Q2가 치환 또는 비치환의 C3 헤테로시클로알킬꾀 환형 구조일 때， (^과 Q2는 단일 결합을 이루고 Q, o) when a substituted or unsubstituted C3 heterocycloalkyl cyclic structure and Q 2 is CO or Q 1 CO and Q 2 is a substituted or unsubstituted C3 heterocycloalkyl cyclic structure, (^ and Q 2 are In a single bond
여기서， 치환기는 C1-C5이며;  Wherein the substituent is C 1 -C 5;
m，은 각각 독립적으로 1 내지 4의 자연수이고;  m ， are each independently a natural number of 1 to 4;
헤테로 원자는 Ν, Ο 및 S에서 선택된 하나 이상인;  The hetero atom is at least one selected from Ν, Ο and S;
73 73
대체용지 (규칙 제 26조) 것을 특징으로 하는 화합물, 그것의 약제학적으로 허용되는 염， 수화물, 용매화물， 프로드럭， 토토머， 거울상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체. Alternative Site (Article 26) Compounds, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof.
【청구항 10】  [Claim 10]
제 9 항에 있어서，  The method of claim 9,
Q^l CO&7이고 Q2이 CORs일 때, (^과 Q2는 이중 결합을 이루고 When Q ^ l CO & 7 and Q 2 is CORs, (^ and Q 2 form a double bond
R7 및 R8fe 각각 ,독립적으로 수소, 치환 또는 비치환의 C1-C6 알킬, - CO(0)R'7, -C(0)NR'7R'8, -SO(0)R'7, -SO(0)NR'7R'8, -CSNR'7R'8, 또는 R7 및 R8는 상호 결합에 의해 치환또는 비치환의 C3-C5 헤테로시클로알킬의 환형 구조， 또는 치환 또는 비치환의 C3-C5 헤테로아릴의 환형 구조를 이를 수 있으며， R 7 and R 8 fe are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -CO (0) R ' 7 , -C (0) NR' 7 R'8, -SO (0) R ' 7 , -SO (0) NR ' 7 R' 8 , -CSNR ' 7 R' 8 , or R 7 and R 8 are cyclic structures of C3-C5 heterocycloalkyl substituted or unsubstituted by mutual bonding, or substituted or unsubstituted The cyclic structure of the C3-C5 heteroaryl of the ring,
여기서 R'7및 R'8각각 독립적으로 수소， 치환 또는 비치환의 C1-C6 알킬， 또는 치환 또는 비치환의 NR"7R"8이고; 여기서 R"7 및 R"8는 각각 독립적으로수소, C1-C3 알킬이고; Wherein R ' 7 and R' 8 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted NR " 7 R"8; Wherein R ″ 7 and R ″ 8 are each independently hydrogen, C 1 -C 3 alkyl;
Qi이 비치환의 C3 헤테로시클로알킬의 환형 구조이고 Q2가 CO이며 또는, CO이고 Q2가 비치환의 C3 헤테로시클로알킬의 환형 구조일 때,When Qi is a cyclic structure of unsubstituted C3 heterocycloalkyl and Q 2 is CO or CO and Q 2 is a cyclic structure of unsubstituted C3 heterocycloalkyl,
( 과 는 단일 결합을 이루고 (And form a single bond
헤테로 원자는 Ν, Ο 및 S에서 선택된 하나 이상인;  The hetero atom is at least one selected from Ν, Ο and S;
것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염， 수화물， 용매화물， 프로드럭， 토토머, 거을상 이성질체 또는 약학적으로 허용 가능한 부분입 Compounds, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, diastereomers or pharmaceutically acceptable moieties thereof
74 74
대체용지 (규칙 제 26조) 체 이성질체. Alternative Site (Article 26) Isomer.
ί청구항 11】  ί claim 11】
제 4 항에 있어서， 상기 화학식 (3)의 화합물 또는 화학식 (4)의 화합물은 하기에서 표 된 화합물들 중 하나인 것을 특징으로 하는 화합물， 그것의 약제학적으로 허용되는 염, 수화물， 용매화물， 프로드럭， 토토머， 거울상 이성질체 또는 약학적으로 허용 가능한 부분입체 이성질체:  The compound of formula (3) or the compound of formula (4) is one of the compounds listed below, a pharmaceutically acceptable salt, hydrate, solvate, Prodrugs, tautomers, enantiomers or pharmaceutically acceptable diastereomers:
Figure imgf000077_0001
Figure imgf000077_0001
75 75
대체용지 (규칙 제 26조) Alternative Site (Article 26)
Figure imgf000078_0001
Figure imgf000078_0001
【청구항 12]  [Claim 12]
제 1 항에 따른화학식 (1)의 화합물을 제조하는 방법으로서， A) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 조건에서  A process for preparing the compound of formula (1) according to claim 1, wherein A) a compound of formula (5) and a compound of formula (6)
76 76
대체용지 (규칙 제 26조) 반웅사켜 하기 화학식 (7)의 화합물을 합성하는 단계; Alternative Site (Article 26) Step by step to synthesize a compound of formula (7);
B) 단계 A)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화 "물에 -N02를도입하^ 단계; B) to banung to the compound and HN0 3 produced in step A) in the acid conditions Chemistry of formula (7), "the -N0 2 in water also in stock ^ step;
C) 단계 B)에서 생성된 화합물퓌 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C) reducing -N0 2 to -NH 2 through the compound pu reduction reaction produced in step B);
D) 단계 C)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계;  D) subjecting the compound produced in step C) to cyclic reaction in acid conditions;
E) 단계 D)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후, 선택적으로산화 :반웅을 하는 단계; 및 E) optionally reacting the compound produced in step D) under basic conditions, followed by selective oxidation : reaction; And
F) 단계 E)에서 생성된 화합물을 환원 반웅을 시켜 최종 생성물을 생성하는 단계; F) reacting the compound produced in step E) to form a final product;
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대체용지 (규칙 제 26조) 를 포함하는 것을특징으로 하 ¾ 제조 방법: Alternative Site (Article 26) ¾ manufacturing method comprising:
Figure imgf000080_0001
Figure imgf000080_0001
상기 식에서,  Where
Xi, X2, X3, X4, i, R2, 및 R4는 제 1항에서 정의된 바와 같고; Xi, X 2 , X 3 , X4, i, R2, and R4 are as defined in claim 1;
Z，는 할로겐 원소 또는 R'COO-이며， 여기서 R，는 치환 또는 비치환의 C1-C9 알킬, 치환 또는 비치환의 -(C¾)m-C4-C10 아릴, 치환 또는 비치환의 -(CH2)m-C4-C10 아릴옥시 또는 치환 또는 비치환의 C4-C10 아릴이며, 여기서 치환기는 히드록시, 할로겐 원소， C1-C10 알킬, C2-C10 알케닐, C2-C10 알키닐， C1-C10 알콕시, C1-C10 알콕시카르보닐, C3-C8 시클로알킬, C3-C8 헤테로시클로알킬， C4-C10 아릴， 및 C5- Z is halogen or R'COO-, where R is substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted-(C¾) m -C4-C10 aryl, substituted or unsubstituted-(CH 2 ) m -C4-C10 aryloxy or substituted or unsubstituted C4-C10 aryl, wherein the substituents are hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1- C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-
78 78
대체용지 (규칙 제 26조) CIO 혜테로아릴로 이루어진 군에서 선;택된 하나 이상이고; 및Alternative Site (Article 26) At least one selected from the group consisting of CIO heteroaryl; And
Y는 -NH2, -N¾Z또는 -N02이^ 1， 여기서 Z는 할로겐 원소이다. Y is -NH 2 , -N¾Z or -N0 2 I 1, where Z is a halogen element.
【청구항 13]  [Claim 13]
제 12 항에 있어서， 상기 단계 F)의 환원 반웅은 Na2S204, Zn 및 Fe로 이루어진 군에서 선택되는 하나 >ᅵ상의 환원제를 반응시키는 단계를 포함하는 것을 ^징으로 하는 제조 방법. 13. The method according to claim 12, wherein the reducing reaction of step F) comprises reacting a reducing agent of one &gt; phase selected from the group consisting of Na 2 S 2 O 4 , Zn and Fe.
【청구항 14】  [Claim 14]
제 12항에 있어서，  The method of claim 12,
G) 상기 단계 F)에서 생성된 화합물을 R7COOH, R7COCI, (R7)20, RsCOOH, R8COCl, 또는 (R8)20(단， 상기 R7 및 은 각각 독립적으로 체 1항에서 정의한 바와 같다)과 염기 조건 또는 금속 촉매 하에서 반웅시켜 촤종 생성물을 생성하는 단계;를포함하는 것을 특징으로하는 제조 방법. ί청구항 15】 G) the compound produced in step F) is R 7 COOH, R 7 COCI, (R 7 ) 2 0, RsCOOH, R 8 COCl, or (R 8 ) 2 0 (wherein R 7 and are each independently Reacting under basic conditions or a metal catalyst to produce a boson product. ί claim 15]
제 14 항에 있어서，  The method of claim 14,
Η) 상기 단계 G)에서 생성된 화합물을 NR"7R"8C(0)C1 (단， 상기 R"7 및 R"8은 각각 독립적으로 제 1항에서 정의한 바와 같다)과 반웅시켜 최종 생성물을 생성하는 단계;를 포함하는 것을특징으로 하는 제조 방법. Η) The compound produced in step G) is reacted with NR ″ 7 R ″ 8 C (0) C1 (wherein R ″ 7 and R ″ 8 are each independently as defined in claim 1) to give the final product. Producing a; characterized in that it comprises a.
【청구항 16】  [Claim 16]
제 1 항에 따른 화학식 (1)의 화합물을 제조하는 방법으로서，  A process for preparing the compound of formula (1) according to claim 1,
79 79
대체용지 (규칙 제 26조) A 하기 화학식 (5)의 화합 과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계; Alternative Site (Article 26) A step of synthesizing the compound of formula (7) by reacting the compound of formula (5) and the compound of formula ( 6 ) under basic conditions;
B 단계 )에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합물에 -N02를 독입하는 단계; Reacting the compound produced in step B) with HN0 3 under acidic conditions to read -N0 2 into the compound of formula (7);
d) 단계 B!)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -N¾로 환원하는 단계; d) step B ! Reducing -N0 2 to -N¾ through the reduction reaction of the compound produced in
D 단계 CO에서 생성된 화합록을 산 조건에서 고리화 반웅을 시키는 단계;  Subjecting the compound produced in step D CO to cyclization reaction in acidic conditions;
Ε,) 단계 D,)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후， 선택적으 산화 반웅을 하는 단계; 및  Ε,) optionally reacting the compound produced in step D,) under basic conditions, followed by selective oxidation reaction; And
F 단계 Ε0에서 생성된 화합물을 고리화 반웅을 시켜 최종 생성물을 생성하는 단계;  Subjecting the compound produced in step F EO to cyclization to produce the final product;
를 포함하는 것을 특징으로 하는 제조 방법: Manufacturing method characterized in that it comprises:
화학식 (5)， 화학식 (6) 및 화학식 (7)의 화합물은 제 12항에 정의된 바와.같다.  The compounds of the formulas (5), (6) and (7) are as defined in claim 12.
【청구항 17】  [Claim 17]
제 16 항에 있어서， 상기 고리화 반웅은 CHR9R10NO2 또는 캄퍼서포닉산 (Camphorsulfonic acid)과 반웅시키는 과정을 포함하는 것을 특징으로 하는 제조 방법: The method of claim 16, wherein the cyclized reaction comprises reacting with CHR 9 R 10 NO 2 or Camphorsulfonic acid.
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대체용지 (규칙 제 26조) 상기 식에서, R9, R10은 각각 독립적으로 수소， 히드록시， 할로겐 원소，Alternative Site (Article 26) Wherein R 9 and R 10 are each independently hydrogen, hydroxy, halogen,
C1-C10 알킬， C2-C10 알케닐， C2-C10 알키닐, C1-C10 알콕시， C1-C10 알콕시카르보닐， C3-C8 시클로알킬, C2-C8 헤테로시클로알킬， C4-C10 아릴， 및 C2-C10 헤테로아릴로 이루어진 군에서 선택된 하나 이상이다. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2- One or more selected from the group consisting of C10 heteroaryl.
【청구항 18】  [Claim 18]
제 1 항에 따른 화학식 (1)의 화합물을 제조하는 방법으로서，  A process for preparing the compound of formula (1) according to claim 1,
A2) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반응시켜 하기 화학식 (7)의 화합물을 합성하는 단계; A 2 ) synthesizing a compound of formula (7) by reacting a compound of formula (5) with a compound of formula (6) under basic conditions;
B2) 단계 A2)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합 에 -N02를 도입하는 단계; B 2 ) reacting the compound produced in step A 2 ) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C2) 단계 ¾)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 2 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step ¾);
D2) 단계 C2)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D 2 ) subjecting the compound produced in step C 2 ) to cyclization reaction under acidic conditions;
¾) 단계 D2)에서 생성된 화합물을 선택적으로 염기 조건에서 반웅시킨 후， 선택적으로 산화 반응을 하는 단계; 및 ¾) optionally reacting the compound produced in step D 2 ) under basic conditions, followed by a selective oxidation reaction; And
F2) 상기 단계 E2)에서 생성된 화합물을 (R3)20, (¾)20， R3Z"또는 ¾Ζ" (여기서， R3 및 ¾은 각각 제 1항에서 정의한 바와 같고， Z"는 할로겐 원소이다)과 반응시켜 최종 생성물을 생성하는 단계; F 2 ) the compound produced in step E 2 ) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or ¾"", where R 3 and ¾ are as defined in claim 1, Z ″ is a halogen element) to produce a final product;
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대체용지 (규칙 제 26조) G2) 상기 단계 F2)에서 생성된 화합물을 R7COOH, R7C0C1, (R7)20, RgCOOH, RgCOCl, 및 (¾)20(단， 상기 R7및 ¾은 각각독립적으로 제 1항에서 정의한 바와 같다)에서 선택된 하나 이상을 금속 촉매 하에서 반웅시켜 최종 생성물을 생성하는 단계; 를 포함하는 것을 특징으로 하는 제조 방법. Alternative Site (Article 26) G 2) The compound produced in Step F 2) R 7 COOH, R 7 C0C1, (R 7) 2 0, RgCOOH, RgCOCl, and (¾) 2 0 (however, the R 7 and ¾ are each independently Reacting at least one selected from the group as defined in claim 1 under a metal catalyst to produce a final product; Manufacturing method comprising a.
화학식 (5)， 화학식 (6) 및 화학식 (7)의 화합물은 제 12항에 정의된 바와 갈다.  Compounds of formula (5), formula (6) and formula (7) are as defined in claim 12.
【청구항 19]  [Claim 19]
제 1 항에 따른 화학식 (1)의 합물을 제조하는 방법으로서,  A process for preparing the mixture of formula (1) according to claim 1,
A3) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계; A 3 ) reacting a compound of formula (5) and a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
Β3) 단계 Α3)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화힙1물에 -Ν02를 도입하는 단계; Β 3 ) reacting the compound produced in step A 3 ) with HN0 3 under acidic conditions to introduce -Ν0 2 into the compound 1 of Formula (7);
C3) 단계 B3)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -N¾로 환원하는 단계; C 3 ) reducing -N0 2 to -N¾ through reduction reaction of the compound produced in step B 3 );
D3) 단계 C3)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D 3 ) subjecting the compound produced in step C 3 ) to cyclization reaction in acid conditions;
¾) 단계 D3)에서 생성된 화합물을 선택적으로 염기 조건에서 반응시킨 후， 선택적으로 산화 반웅을 하는 단계; 및 ¾) optionally reacting the compound produced in step D 3 ) under basic conditions, followed by selective reaction reaction; And
F3) 상기 단계 ¾)에서 생성된 화합물을 (R3)20, (¾)20, R3Z"또는 ¾Ζ" F 3 ) the compound produced in the above step ¾) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or ¾Ζ"
(여 (female
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대체용지 (규칙 제 26조) 기서， R3및 R6은 각각 제 1항에서 정의한 바와 같고 , Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; Alternative Site (Article 26) Where R 3 and R 6 are each as defined in claim 1 and Z ″ is a halogen element) to produce a final product;
G3) 상기 단계 F3)에서 생성된 ]·합물을 NR"7R"8C(0)C1 (단， 상기 R"7 및 R8 "은 각각 독립적으로 제 1항에서 정의한 바와 같다)과 반웅시키고 선택적으로 (R7)20, (R8)20과 반웅시켜 (단， 상기 R7 및 R8은 각각 독립적으로 제 1항에서 정의한 바와 같다) 최종 생성물을 생성하는 단계；를 포함하는 것을 특징으로 하는 제조 방법. G 3 ) the mixture produced in step F 3 ) is NR ″ 7 R ″ 8 C (0) C1, wherein R ″ 7 and R 8 ″ are each independently as defined in claim 1. Reacting and optionally reacting with (R 7 ) 2 0, (R 8 ) 2 0 (wherein R 7 and R 8 are each independently as defined in claim 1) to produce a final product; The manufacturing method characterized by the above-mentioned.
【청구항 20】  [Claim 20]
제 19 항에 있어서，  The method of claim 19,
H3) 상기 단계 G3)에서 생성된 화합물을 수소화 환원 반응시켜 최종 생성물을 생성하는 단계;를 포함하는 것을 특징으로 하는 제조 방법. H 3 ) producing a final product by hydrogenation of the compound produced in step G 3 ).
【청구항 21】  [Claim 21]
제 1 항에 따른 화학식 (1)의 화합물을 제조하는 방법으로서，  A process for preparing the compound of formula (1) according to claim 1,
A4) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반웅시켜 하기 화학식 (7)의 화합물을 합성하는 단계;  A4) reacting a compound of formula (5) and a compound of formula (6) under basic conditions to synthesize a compound of formula (7);
B4) 단계 A4)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하기 화학식 (7)의 화합물에 -N02를 도입하는 단계; B 4 ) reacting the compound produced in step A4) with HN0 3 under acidic conditions to introduce -N0 2 to the compound of formula (7);
C4) 단계 B4)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 C 4 ) reducing -N0 2 to -NH 2 through the reduction reaction of the compound produced in step B 4 )
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대체용지 (규칙 제 26조) 단계; Alternative Site (Article 26) step;
D4) 단계 C4)에서 생성된 화합 을 산 조건에서,고리화 반웅을 시키는 단계; D 4 ) subjecting the compound generated in step C 4 ) to acidic conditions, subjecting the ring reaction;
E4) 단계 D4)에서 생성된 확합물을 선택적으로 염기 조건에서 반응시킨 후， 선택적으로 산화 반웅을 하는 단계; 및 E 4 ) optionally reacting the resultant produced in step D 4 ) under basic conditions, followed by selective reaction reaction; And
F4) 상기 단계 E4)에서 생성된 합물을 ( )2ᄋ, (¾)2ᄋ, R3Z"또는 ¾Z" (여기서， R3 및 ¾은 각각 제 1항에서 정의한 바와 같고， Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; F 4 ) The mixture produced in step E 4 ) is replaced by () 2 O, (¾) 2 O, R 3 Z "or ¾Z", where R 3 and ¾ are as defined in claim 1, respectively, Z " Is a halogen element) to produce a final product;
G4) 상기 단계 F4)에서 생성된 화합물을 S03와 반웅시킨 후， 수소화 환원반웅을 시켜 최종 생성물을 생성하는 단계;를 포함하는 것을 특징으로 하는 제조 방법. G 4 ) reacting the compound produced in step F 4 ) with SO 3, and then performing a hydrogenation reduction reaction to generate a final product.
ί청구항 22】  ί claim 22]
제 1 항에 따른 화학식 (1)의 화합물을 제조하는 방법으로서，  A process for preparing the compound of formula (1) according to claim 1,
Α5) 하기 화학식 (5)의 화합물과 하기 화학식 (6)의 화합물을 염기 조건에서 반응시켜 하기 화학식 (7)의 화합물을 합성하는 단계; A 5 ) synthesizing a compound of formula (7) by reacting a compound of formula (5) with a compound of formula (6) under basic conditions;
Β5) 단계 Α5)에서 생성된 화합물과 HN03을 산 조건에서 반웅시켜 하가화학식 (7)의 화합물에 -Ν02를 도입하는 단계; Β 5 ) reacting the compound produced in step A 5 ) with HN0 3 under acidic conditions to introduce -Ν0 2 to the compound of formula (7);
C5) 단계 B5)에서 생성된 화합물의 환원 반웅을 통하여 -N02를 -NH2로 환원하는 단계; C 5 ) reducing -N0 2 to -NH 2 through reduction reaction of the compound produced in step B 5 );
D5) 단계 C5)에서 생성된 화합물을 산 조건에서 고리화 반웅을 시키는 단계; D 5 ) subjecting the compound produced in step C 5 ) to cyclization reaction under acidic conditions;
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대체용지 (규칙 제 26조) E5) 단계 D5)에서 생성된 합물을 선택적으로 염기 초건에서 반웅시킨 후， 선택적으로 산화 반웅을 하는 단계; 및 Alternative Site (Article 26) E 5 ) optionally reacting the mixture produced in step D 5 ) in base drying, followed by selective oxidation reaction; And
F5) 상기 단계 E5)에서 생성된 확합물을 (R3)20, (¾)20， R3Z"또는 ReZ" (여기서, 및 ¾은 각각 제 1 항에서 정의한 바와 같고， Z"는 할로겐 원소이다)과 반웅시켜 최종 생성물을 생성하는 단계; F 5 ) the resulting product produced in step E 5 ) is (R 3 ) 2 0, (¾) 2 0, R 3 Z "or ReZ" (wherein and ¾ are as defined in claim 1, respectively, Z is Reacting with " a halogen element &quot; to produce the final product;
G5) 상기 단계 F5)에서 생성된 화합물을 R7Z"', R8Z"', (R7)2S04 또는 (R8)2S04(단, 상기 R7및 R8은 각각 독립적으로 제 1항에서 정의한 바와 같고， Z"，는 할로겐 원소이다)와 반웅시킨 후， 수소화 환원반웅을 시켜 최종 생성물을 생성하는 단계;를 포함하는 것을 특징으로 하는 제조 방법. G 5) The compound produced in Step F 5) R 7 Z "' , R 8 Z"', (R 7) 2 S0 4 or (R 8) 2 S0 4 (However, the R 7 and R 8 are And each independently as defined in claim 1, Z ", is a halogen element) and then reacted with hydrogenation to produce a final product.
【청구항 23】  [Claim 23]
(a) 약리학적 유효량의 제 1 항에 따른 화학식 (1)의 화합물， 그것의 약제학적으로 허용되는 염， 수화물, 용매화물， 토토머， 거을상 이성질체' 및 /또는 약학적으로 허용 가능한 부분입체 이성질체; 및 (b) 약제학적으로 허용되는 담체， 회석제， 또는 부형제， 또는 이들의 조합;을 포함하는 것으로 구성된 대사성 질환 치료 및 예방을 위한 약제 조성물. (a) A pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a tautomer, a diastereomer ' and / or a pharmaceutically acceptable diastereomer Isomers; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or combinations thereof.
【청구항 24】  [Claim 24]
제 23 항에 있어서， 상기 대사성 질환은 비만， 지방간， 동맥경화， 뇌졸중， 심근경색， 심혈관 질환, 허혈성 질환， 당뇨병， 고지혈증, 고혈압， 망막증 또는 신부전증, 헌팅턴 병 또는 염증인 것을 특징으로 하는 약제 조성물ᅳ  The pharmaceutical composition of claim 23, wherein the metabolic disease is obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes mellitus, hyperlipidemia, hypertension, retinopathy or kidney failure, Huntington's disease or inflammation.
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대체용지 (규칙 제 26조) 【청구항 25】 Alternative Site (Article 26) [Claim 25]
제 23 항에 있어서， 상기 대사성 질환은 지방간， 당뇨병 또는 헌팅턴 병인 것을 특징 로 하는 약제 조성물.  The pharmaceutical composition of claim 23, wherein the metabolic disease is fatty liver, diabetes or Huntington's disease.
【청구항 26]  [Claim 26]
약리학적 유효량의 제 1 항엠 따른 화학식 (1)의 화합물， 그것의 약제학적으로 허용되는 염， 수화물， 용매화물， 토토머， 거울상 이성질체 또는 약학적으로 허용 가능 부분입체 이 질체를 유효량으로 사용하여, 대사성 질환을 치료하거나 예 하는 방법.  Using an effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer of How to Treat or Prevent Metabolic Diseases.
86 86
대체용지 (규칙 제 26조)  Alternative Site (Article 26)
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