KR20070031774A - ?-Substituted-1?-quinoline-2,4-diones, preparation method thereof and pharmaceutical composition containing the same - Google Patents

Abstract

The present invention relates to an N -substituted-1 H -quinoline-2,4-dione compound acting as a 5-HT6 receptor antagonist, a preparation method thereof, and a pharmaceutical composition for treating central nervous system disease containing the same. N -substituted-1 H -quinoline-2,4-dione compounds have excellent binding to serotonin 5-HT6 receptors, superior selectivity to 5-HT6 receptors compared to other receptors, and intracellular serotonin (5 -HT) not only suppresses the increase in cAMP concentration, but also inhibits hyperactivity of rats induced by methamphetamine (2 mg / kg, ip), which is useful for central nervous system diseases related to 5-HT6 receptors. Can be used.

5-HT6 Receptor Antagonist, CNS Disease

Description

N-substituted-1H-quinoline-2,4-dione compound, preparation method thereof and pharmaceutical composition containing same {N-Substituted-1H-quinoline-2,4-diones, preparation method about and pharmaceutical composition containing the same }

1 is a diagram showing the effect of inhibiting 5-HT6 receptor mediated cAMP accumulation in human HeLa cells of the compound and methiotepine according to an embodiment of the present invention.

2 and 3 is a diagram showing the effect of inhibiting rat hyperactivity symptoms induced by metamphetamine (2 mg / kg, ip) of the compound according to an embodiment of the present invention.

The present invention relates to N -substituted-1 H -quinoline-2,4-dione compounds, methods for their preparation and pharmaceutical compositions comprising the same.

Although the function of serotonin (5-HT) in the central nervous system is not yet fully understood, many studies have linked 5-HT to the pathogenesis of many diseases, particularly depression, anxiety, and schizophrenia. It is known to be an important cause of psychosis such as schizophrenia, eating disorders, obsessive compulsive disorder (OCD), migraine and panic disorder. Recent advances in pharmacology, molecular biology, and genetics related to the serotonin nervous system have enabled the development of more advanced drug therapies for the treatment of certain neurological diseases. In fact, the general treatment for these diseases is currently believed to work by modulating the physiological activity of serotonergic substances.

Over the last decade, several 5-HT receptor subtypes have been characterized. Initially, receptor subtypes were only characterized using pharmacological tools. Based on the receptor binding properties, the functional activity of the ligand, the four major subgroups of the 5-HT receptor, named 5-HT1, 5-HT2, 5-HT3, and 5-HT4, has been identified in common. . More recently, molecular biology techniques have revealed that each subgroup of this classification actually has a relatively dissimilar protein structure, as well as new 5-HT receptors (5-HT1F, 5-HT5, 5-HT6, And 5-HT7), allowing them to replicate and express pharmacologically and functionally in cultured cell lines [Hoyer, D. et al ., Pharmacol . Biochem . Behav . 2002 , 71 , 533-554; Kroeze, WK et al ., Curr. Top. Med . Chem . 2002 , 2 , 507-528.

More recently, 5-HT6 receptors have been cloned from cDNA in rats based on homology with previously cloned G-protein-binding receptors [Monsma, FJ et al. , Mol . Pharmacol. 1993 , 43 , 320-327. The rat receptor consists of 438 amino acids with a transmembrane domain that penetrates the neural cell membrane seven times and increases the activity of adenylyl cyclase via Gs G-protein [Monsma, FJ et al ., Mol . Pharmacol . 1993 , 43 , 320-327. The human 5-HT6 receptor, a 440 amino acid polypeptide, not only shows 89% overall sequence homology with the rat's receptor, but also acts similarly to increase the activity of the secondary signal adenase. [Kohen, R et al. , J. Neurochem . 1996 , 66 , 47-56. Rat and human 5-HT6 m-RNAs are present in the striatum, amygdala, nucleus accumbens, hippocampus, cortex and olfactory tubercle, but are peripheral Nothing has been found in the institution.

In pharmacological studies, tritium 5-HT, [ ³ H] LSD, [ ¹²⁵ I] -2-iodide LSD, and the like are used as isotopically labeled 5-HT6 receptor substrates. 5-HT binds with a relatively high affinity (Ki = 50-150 nM). Tricyclic antipsychotics and some antidepressants bind to the 5-HT6 receptor with significantly higher affinity. More relevant studies have been made and found that representative substances belonging to several groups of antipsychotics bind with high affinity. Representative examples include phenothiazine, chloropromazine, thioxanthene, chloroprothixene, diphenylbutylpiperidine, pimozide, hetero Cyclic antipsychotics loxapine and clozapine [Roth, BL et al. , J. Pharmacol . Exp. Ther . 1994 , 268 , 1403-1410. These results show that the 5-HT6 receptor is associated with certain types of psychosis, and could in particular be a target for atypical antipsychotics.

Until the development of substrates with selectivity, pharmacological studies on 5-HT6 largely relied on the use of non-selective drugs. Functional studies were performed using antisense methods because no selective substrate for the receptor was present. 5-HT6 specific antisense induced specific behaviors such as yawning, stretching and chewing in rats, but did not show other distinct pathological phenomena. Non-selective substrates were useful for pharmacological studies of the 5-HT6 system in the absence of other 5-HT receptors (eg cAMP assays), but their lack of selectivity has limited utility in most pharmacological studies. .

The recent emergence of selective drugs has made great strides in the study of 5-HT6, and the development of more selective ligands can lead to higher efficacy and lower side effects. It is also possible to form completely new therapies. The first 5-HT6 selective antagonist was released in 1998, and the results of this work by other teams were published one after another. Hoffman-La Roche Co. slate and the like are bisaryl sulfonamides Ro 04-6790 ( 1 , Ki = 55 nM), and Ro 63-0563 ( 2 , Ki) as selectivity 5-HT6 antagonists. = 12 nM) (Sleight, AJ et al., Br. J. Pharmacol . 1998 , 124 , 556-562. Soon after, MS-245 ( 3 , Ki = 2.3 nM) was published. Interestingly, these three compounds are independent separate discoveries, and although all of them have been identified by random screening methods, they commonly have sulfonamide bonds as their core structures. One problem with these antagonists was their low penetration into the central nervous system.

At that time, Smith-Kline Beecham Co. announced the following compound 4 through an ultrafast drug screening process. It showed high affinity (Ki = 5 nM) for 5-HT6, showed 50-fold selectivity for 10 different 5-HT receptors, and showed little binding to 50 other receptors and enzymes. . It has also been found to be a pure antagonist (pKb = 7.8) causing intracellular cAMP accumulation [Bromidge, SM et al., J. Med . Chem . 1999 , 42 , 202-205. This compound had some degree of brain permeability (25%) but, as a result, its bioavailability was low due to its rapid blood clearance. On the other hand, it was found that SB-271046 ( 5 , Ki = 1 nM; selectivity for more than 50 other receptors 200 times) retains 5-HT6 receptor antagonism, although brain-permeability was low (10%). It showed very good oral bioavailability (> 80%).

The team's ongoing research has developed SB-357134 ( 6 , Ki = 3 nM) with low blood clearance and good oral bioavailability. In 1999, Glenon et al investigated the structural affinity of tryptamine derivatives to the human 5-HT6 receptor [Glennon, RA et al. , J. Med . Chem . 2000 , 43 , 1011-1018]. MS-245 was found to be an antagonist (pA2 = 8.88) with high affinity (Ki = 2.3 nM). Unlike the sulfonamide or trytamine derivatives mentioned above, Hoffman-La Roche ( 7 ) and Pharmacia-upzone ( 8 , Ki = 1.4 nM) and others recently published several sulfone compounds [Slassi, A. et al ., Expert Opin . Ther . Pat. 2002 , 12 , 513-527. Efforts are being made to develop newer drugs with improved pharmacokinetic or pharmacodynamic flashlights, and interest in the 5-HT6 receptor is growing due to the commercialization of relevant tools.

As mentioned earlier, atypical antipsychotics have particularly shown high affinity for these receptors. In addition, tritium-labeled atypical antipsychotics [ ³ H] clozapine have been shown to be labeled in two receptor groups in the rat brain, one of which was considered to represent 5-HT6 [Glatt, CE] et al. , Mol . Med . 1995 , 1 , 398-406. Bog et al. Conducted systematic mutation scanning of the coding region of the 5-HT6 receptor gene in 137 individuals (including schizophrenia and depressed patients) and concluded that genes may affect bipolar affective disorders [Vogt, IR. et al ., Am. J. Med . Genet . 2000 , 96 , 217-221.

Prior to identifying 5-HT6-receptor selective drugs, Burson et al. Demonstrated that antisense oligonucleotides can be administered to rats by intraventricular (ICV), causing specific behaviors such as yawning, stretching and chewing. Antagonized by atropine [Bourson, A. et al., J. Pharmacol . Exp . Ther . 1995 , 274 , 173-180. Slate et al. Found that Ro 04-6790 ( 1 ) can induce this same effect. Because of the correlation between cholinergic action and cognitive ability, it was possible to predict that 5-HT6 receptors might be associated with memory and cognitive dysfunction [Sleight, AJ et al ., Neuropharmacology 2001 , 41 , 210-219; Rogers, DC et al ., Psychopharmacology (Berlin) 2001 , 158 , 114-119].

In addition, 5-HT6 receptors were expected to be associated with the regulation of feeding due to reduced food intake of rats by pretreatment of antisense oligonucleotides and administration of Ro 04-6790. In addition, Russell and Dias questioned the assumption that 5-HT6 antagonists increase cholinergic delivery [Russell, MGN; Dias, R., Curr . Top. Med . Chem . 2002 , 2 , 643-654.

Despite mechanism inconsistencies, there is evidence that 5-HT6 receptors are involved in learning and memory. In water maze experiments with rats, SB-271046 ( 5 ) and SB-357134 ( 6 ) have been shown to significantly improve the memory time of learned tasks. Furthermore, SB-271046 ( 5 ) increased the concentration of extracellular glutamate several times in the frontal cortex and hippocampus. This suggests that the selective increase in excitatory neurotransmission by SB-271046 supports that 5-HT6 antagonists may play an important role in the treatment of cognitive and memory dysfunction. Dawson, LA et al ., Neuropsychopharmacology 2001 , 25 , 662-668.

In addition, SB-357134 ( 6 ) strongly and proportionally increases the seizure threshold (rat maximum electric seizure threshold) after oral administration, suggesting its use as a therapeutic agent for convulsive disorders [Stean, TO et al ., Pharmacol . Biochem . Behav . 2002 , 71 , 645-654. This finding is consistent with previous findings that SB-271046 ( 5 ) and Ro 04-6790 ( 1 ) have anticonvulsant activity.

As such, there is a great deal of evidence showing that 5-HT6 receptors are associated with psychosis. There is also a growing body of evidence that correlates with the recognition and learning of these receptors, as well as with convulsive disorders and control of appetite. Therefore, much effort is being made in developing a new 5-HT6 antagonist with higher brain-permeability and selectivity than conventional drugs, and the potential of the 5-HT6 receptor ligand as a therapeutic agent for central nervous system diseases is very high.

Accordingly, the present inventors have tried to develop a 5-HT6 antagonist having excellent binding and selectivity, and as a result, a quinoline-2,4-dione derivative other than a known sulfonamide or sulfone structure is a 5-HT6 antagonist having excellent binding and selectivity. Discovered and completed the present invention.

The present invention seeks to provide N -substituted-1 H -quinoline-2,4-dione compounds and pharmaceutically acceptable salts thereof.

In addition, the present invention is to provide a method for preparing the N -substituted -1 H -quinoline-2,4-dione compound.

In addition, the present invention is to treat the central nervous system diseases excellent binding and selectivity to the serotonin receptor comprising the N -substituted-1 H -quinoline-2,4-dione compound, a pharmaceutically acceptable salt thereof or a prodrug thereof To provide a pharmaceutical composition for.

In order to achieve the above technical problem, the present invention provides an N -substituted -1 H -quinoline-2,4-dione compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

Where

R ¹ and R ² are each independently hydrogen, halogen, nitro, amino, amino substituted by 1 to 2 alkyl, cyclic amino, carboxylic acid, thiol, cyano, alkyl, aryl, heteroaryl, alkoxy, aryl Oxy, acyloxy, acylamino, arylsulfonylamino, arylsulfonylureido, alkylthio, arylthio, alkylcarboxylate, arylcarboxylate, aralkylcarboxylate, alkylureido, arylureido, alkylamido Dino or arylamidino.

R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen element, amino, cyclic amino, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, piperidinyl or N-methyl piperidinyl.

R ⁶ is alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl or heteroarylalkyl.

R ⁷ is hydrogen, alkyl or aryl.

"Alkyl" is a linear and branched chain containing from 1 to 7 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, sec -butyl and tert -butyl, pentyl, hexyl, cyclopropylmethyl and cyclohexyl Methyl and the like.

"Cycloalkyl" means a cyclic carbon ring containing 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

"Alkoxy" refers to a linear and branched alkoxy group containing 1 to 7 carbon elements, methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, sec -butoxy, tert -butoxy, pen Oxy, hexyloxy, cyclohexylmethoxy, and the like.

The "haloalkyl" refers to an alkyl group substituted with one or more fluorine, chlorine, ie fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl Means.

"Aryl" means a cyclic carbon aromatic group and includes phenyl, naphthyl, phenanthryl, anthracyl, indenyl, biphenyl, fluorenyl and the like.

"Heteroaryl" means an aryl group including 1 to 3 selected from O, N and S, and pyridyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl , Indolyl, pyranyl, furyl, benzimidazolyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl, thiazolyl and thiadiazolyl.

The aryl and heteroaryl groups mean groups optionally substituted with 1, 2 or 3 independently selected from substituents including alkyl, alkoxy, halogen, nitro, amino, cyano, hydroxy, cyclic amino.

"Heteroarylalkyl" means an alkyl group including the aforementioned heteroaryl group. In the same way, "arylalkyl" means an alkyl group comprising the aforementioned aryl group.

"Amino" refers to NH ₂ , NHR ₅ and NR ₅ R ₆ wherein R ₅ and R ₆ are C ₁ to C ₄ alkyl groups. The "cyclic amino" includes piperidyl, piperazinyl and morpholinyl groups.

Typically halogen elements include fluorine, chlorine, bromine and iodine.

R ¹ and R ² are preferably each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, amino, amino, nitro or benzyloxy substituted with one or two C ₁ -C ₄ alkyl.

R ³ , R ⁴ and R ⁵ are preferably each independently hydrogen, a halogen element or C ₁ -C ₄ alkoxy.

R ⁶ is preferably C ₁ ~ C ₄ alkyl; C ₃ -C ₇ cycloalkyl C ₁ -C ₂ alkyl; Benzyl substituted with a substituent selected from the group consisting of hydrogen, nitro, amino, halogen or C ₁ -C ₄ alkoxyphenyl; Naphthalenylmethyl; Heteroaryl (C ₁ -C ₂ ) alkyl substituted with a substituent selected from the group consisting of pyridine, quinoline, benzoimidazole.

R ⁷ is preferably hydrogen or C ₁ -C ₄ alkyl.

R ¹ is more preferably hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, nitro or benzyloxy.

R ² is more preferably hydrogen, fluorine, chlorine, bromine, iodine, methoxy, nitro, amino or benzyloxy.

R ³ , R ⁴ and R ⁵ are more preferably each independently hydrogen, chlorine, bromine or methoxy.

R ⁶ is more preferably methyl, ethyl, cyclohexylmethyl, benzyl, nitrobenzyl, aminobenzyl, methoxybenzyl, bromobenzyl, biphenylmethyl, naphthalenylmethyl, pyridinylmethyl, quinolinylmethyl Or benzoimidazolylmethyl.

R ⁷ is more preferably hydrogen, methyl or ethyl.

Salts of the compounds represented by Formula 1 of the present invention will be pharmaceutically acceptable non-toxic salts for use in medicine, but other salts may also be used to prepare the compounds of the present invention or pharmaceutically acceptable non-toxic salts thereof. Can be used.

Examples of the pharmaceutically acceptable salt of the compound of Formula 1 include alkali metal salts such as lithium, sodium, potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; And salts consisting of suitable organic ligands such as tetravalent ammonium salts. In the case of acid addition salts, for example, a compound solution according to the invention can be formed by mixing with a pharmaceutically acceptable non-toxic acid solution such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Can be.

Compounds of the present invention include prodrugs of compounds represented by formula (1). In general, such prodrugs are functional derivatives of compounds of formula 1 that are readily converted into the required compounds in vivo. Prodrugs according to the invention can be selected and prepared in conventional manner ["Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985].

Compounds of the present invention include any tautomer of the compound represented by formula (1).

If the compounds of formula 1 of the present invention have at least one asymmetric center, they may exist in the form of enantiomers. If the compounds of the invention have two or more asymmetric centers, they may exist in the form of diastereomers. All isomers of the compounds according to the invention and mixtures thereof are included within the scope of the invention.

Most preferably, the compound of formula 1 of the present invention includes, but is not limited to, the following compounds, pharmaceutically acceptable salts and prodrugs thereof.

(1) 1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones;

(2) 1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones;

(3) 1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -3- (4-nitro-phenyl) -1 H -quinoline-2,4- Diones;

(4) 3- (4-amino-phenyl) -1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4-dione ;

(5) 1-benzyl-7-chloro-3- (4-diethylamino-phenyl) -3-methyl-5- (4-methyl-piperazin- 1 -yl) -1H-quinoline-2,4- Diones;

(6) 1-benzyl-7-chloro-3- (4-ethylamino-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones;

(7) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1- (3-nitro-benzyl) -1 H -Quinoline-2,4-dione;

(8) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1- (3-nitro-benzyl) -1 H -Quinoline-2,4-dione;

(9) 1- (3-Amino-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H- Quinoline-2,4-dione;

(10) 1- (3-Amino-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H- Quinoline-2,4-dione;

(11) 1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -3-phenyl-1 H -quinoline-2,4-dione;

(12) 1-benzyl-3- (4-benzyloxy-3-bromo-phenyl) -7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline -2,4-dione

(13) 1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1 - yl-1 H- quinolin-2,4-dione

(13-1) (S) -1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(13-2) (R) -1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(14) 1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(14-1) (S) -1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(14-2) (R) -1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(15) 1-benzyl-7-chloro-3-methyl-3- (4-nitro-phenyl) -5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(16) 3- (4-amino-phenyl) -1-benzyl-7-chloro-3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(17) 1-benzyl-7-chloro-3- (4-diethylamino-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(18) 1-benzyl-7-chloro-3- (4-ethylamino-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(19) 1-benzyl-7-chloro-3- (4-chloro-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(20) 1-benzyl-3- (4-bromo-phenyl) -7-chloro-3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(21) 1-benzyl-7-chloro-3- (4-iodo-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(22) 1-benzyl-7-chloro-3-methyl-3-phenyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(23) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(24) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(25) 1- (3-amino-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(26) 1- (3-amino-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(27) 7-chloro-1- (3-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(28) 7-chloro-1- (3-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(29) 7-Chloro-1- (2-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(30) 7-chloro-1- (2-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(31) 7-chloro-1- (4-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(32) 7-chloro-1- (4-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(33) 1- (3-Bromo-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(34) 1- (3-Bromo-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(35) 1- (2-Bromo-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(36) 1- (2-Bromo-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione;

(37) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1-pyridin-3-ylmethyl-1 H -quinoline-2,4-dione ;

(38) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1-pyridin-3-ylmethyl-1 H -quinoline-2,4-dione ;

(39) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-1-naphthalen-2-ylmethyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione ;

(40) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-1-naphthalen-2-ylmethyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione ;

(41) 1-biphenyl-4-ylmethyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(42) 1-biphenyl-4-ylmethyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones;

(43) 1- (1H-benzoimidazol-2-ylmethyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline -2,4-dione;

(44) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1-quinolin-2-ylmethyl-1 H -quinoline-2,4-dione ;

(45) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1-quinolin-2-ylmethyl-1 H -quinoline-2,4-dione ;

(46) 7-chloro-1-ethyl-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(47) 5-chloro-1-ethyl-3- (4-hydroxy-phenyl) -3-methyl-7-piperazin-1-yl-1 H -quinoline-2,4-dione;

(48) 7-chloro-1-cyclohexylmethyl-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(49) 7-chloro-1-cyclohexylmethyl-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione;

(50) 1-benzyl-7-chloro-3- (3-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; And

(51) 1-benzyl-7-chloro-3- (3-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione.

In addition, the present invention, in the preparation of N -substituted-1 H -quinoline-2,4-dione compound, represented by the following scheme

(a) obtaining Intermediate I from the condensation reaction of Compound 2 and Compound 3;

(b) cyclizing the intermediate I in the presence of a base to obtain an intermediate II ;

(c) substituting N (1) of the intermediate II in the presence of an electrophilic group and a base to obtain an intermediate III ; And

(d) providing an N -substituted- 1H -quinoline-2,4-dione compound represented by Chemical Formula 1 by reaction of the intermediate III and the amine.

At this time, after step (d) of Scheme 1, according to intermediate III or R ^1- , R ² -and R ⁶ -substituents of formula 1, a step of modifying them into a specific functional group may be added.

Hereinafter, the preparation method of the present invention will be described in detail with reference to Scheme 1 below.

(In the above scheme, R ¹ ~ R ⁷ are as defined in formula 1, R is methyl, ethyl, or propyl group, Z is halogen element fluorine, chlorine, bromine, iodine, X is chlorine, bromine, Iodine, o -methylsulfonyl or o -toluenesulfonyl.)

First, the intermediate I was obtained from the condensation reaction of compound 2 and compound 3 in the presence of a base in step (a). Get

In the present invention, preferably, compound 2 is 2-phenylpropionic acid, compound 3 is anthranilic acid ester, and these are purchased by using commercially available reagents, or obtained commercially. If difficult, it can be prepared and used according to the present invention from compounds known in the art.

In the condensation reaction, 1) Compound 2 is reacted with a chloride such as SOCl ₂ , (COCl) ₂ , PCl ₅ or BOP-Cl (bis (2-oxo-diazolindinyl) phosphinic chloride) in an inert solvent to form an acid chloride. step; 2) mixing the acid chloride of compound 2 with compound 3 in an inert solvent and warming to condense.

As the inert solvent, dichloromethane, 1,2-dichloroethane or methylene chloride is preferable, and step 1) may proceed at room temperature, and step 2) may proceed at about 0 ° C.

Next, in step (b), the intermediate I obtained in step (a) Cyclization reaction in the presence of a base affords intermediate II (quinoline-1 H -dione) in high yield.

The cyclization reaction is easily carried out in the presence of a base and terminates the reaction with weak acidic workup [ Bioorg . Med . Chem . Lett . , 5, 2643 (1995); J. Med. Chem. , 36, 3386 (1993). The base is preferably sodium, potassium, sodium hydride, lithium hexamethyldisilazide and potassium hexamethyldisilazide. The preferred reaction solvent is tetrahydrofuran (THF), and the preferred reaction temperature is from -78 ° C to reflux temperature.

Next, in step (c), N (1) of intermediate II obtained in step (b) is subjected to substitution reaction in the presence of an electrophilic substituent and a base to obtain intermediate III .

The introduction of the substituent R ⁶ into N (1) of intermediate II is carried out using an electrophilic group XR ⁶ , generally in Na ₂ CO ₃ , in an aprotic solvent such as acetonitrile, N, N -dimethylformamide , or the like. At room temperature in the presence of a suitable base such as K ₂ CO ₃ or NaH. X is preferably chlorine, bromine, iodine, o -methylsulfonyl or o -toluenesulfonyl as leaving groups.

Next, in step (d), an N -substituted- 1H -quinoline-2,4-dione compound represented by Chemical Formula 1 is obtained by reaction of intermediate III and amine obtained in step (c).

As the amine, N-methylpiperazine or piperazine is preferable, and the reaction proceeds to a nucleophilic substitution reaction of intermediate III . The nucleophilic substitution reaction is carried out in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ in an aprotic solvent such as acetonitrile, N , N -dimethylformamide, or only in the presence of a basic solvent such as pyridine Under a neat condition or at reflux temperature.

Next, following step (d), according to the R ^1- , R ² -and R ⁶ -substituents of formula (1), they can be transformed into specific functional groups.

Methoxy groups can be modified with hydroxyl groups by treatment with boron tribromide of methylene chloride. Nitro groups can be reduced to amino groups using tin (II) dihydrate under reflux protic solvents such as MeOH, EtOH and acetic acid. In addition, reductive alkylation of amino groups can be carried out using appropriate aldehydes such as formaldehyde, acetaldehyde in the presence of sodium cyanoborohydride as reducing agent.

When a mixture of stereoisomers is produced by the process for preparing a compound of the present invention as described above, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemates, or each enantiomer may be prepared by asymmetric synthesis or resolution. For example, the compound forms a salt with an acid with optical activity such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluyl-l-tartaric acid in part After the stereoisomer pairs have been formed, they can be separated into individual component enantiomers by standard techniques such as separation through fractional crystallization and regeneration of free bases. The compounds may also be separated through formation of esters or amides which are diastereomers, followed by chromatography and removal of chiral auxiliaries. The present invention includes all structural and optical isomers of various compounds as well as racemic mixtures thereof.

In addition, the present invention provides a pharmaceutical composition for 5-HT6 antagonist comprising the compound of Formula 1 and a pharmaceutically acceptable salt thereof.

The compound of the present invention has excellent binding ability to serotonin 5-HT6 receptor (Table 2), excellent selectivity to 5-HT6 receptor for other receptors (Table 4), and cAMP by intracellular serotonin (5-HT). Inhibit the increase in the concentration of (Fig. 1), and the effect of inhibiting the hyperactivity of rats induced by metamphetamine (2 mg / kg, ip) (Fig. 2) as well as rotarod dysfunction at 400 mg / kg or less (Table 6), it can be usefully used as a 5-HT6 antagonist.

Since 5-HT6 receptors are known to bind positively to the adenyl cyclase system, agonists of the receptor can significantly increase the concentration of cAMP in the cell. Thus, the substance that inhibits the increase in the concentration of cAMP by intracellular serotonin (5-HT) can be determined to act as an antagonist of 5-HT6 receptor.

Electrostatic suppression of acoustic startle in animals conducted to investigate the effects of rat hyperactivity is one of the most intensively studied behavioral models with predictive validity to investigate antipsychotics of drugs. As the primary surprise stimulus becomes weaker, the magnitude of the surprise response decreases or stops, a phenomenon known as electromagnetic pole suppression (PPI) (Graham, 1975). PPI deficiency has been reported in patients with schizophrenia and psychotic symptoms [Braff et al ., 1992; Simons and Giardina, 1992].

Therefore, the pharmaceutical composition of the present invention can be used to treat central nervous system diseases involving 5-HT6 receptor, and in particular, cognitive impairment, Alzheimer's disease, anxiety, depression, schizophrenia, stress disorder, panic disorder, phobia , Obsessive-compulsive disorder, post-traumatic-stress syndrome, reduced immune system function, psychosis, paraphrenia, mania, cramps, migraine, drug addiction, alcoholism, obesity, eating disorders Or it can be usefully used for the treatment of sleep disorders.

The compounds of the present invention may be administered in various formulations, such as oral and parenteral, during clinical administration, and may be administered by intravenous injection as one of the preferred embodiments. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants that are commonly used may be added. The pharmaceutical compositions of the present invention are preferably provided in unit dosage form such as tablets, pills, capsules, powders, sterile solutions or suspensions, or suppositories for oral, parenteral, intravenous or rectal administration. To prepare solid preparations, such as tablets, the active ingredient may be formulated with starch, sucrose, lactose, talc, sorbitol, stearic acid, pharmaceutical carriers such as magnesium stearate, dicalcium phosphate or gum, and diluents such as water. It can be mixed, which is to form a solid preformulation composition comprising a homogeneous mixture of a compound of the invention and a pharmaceutically acceptable non-toxic salt thereof, by forming the preform uniformly so that the active ingredient is Equally dispersed throughout, the composition can be easily subdivided into unit dosages having the same effect at any time. Solid preformulation compositions are subdivided into unit dosage forms containing about 0.1 to 500 mg of a compound of the present invention. Tablets or pills of the new composition may be coated or formulated in combination to exhibit a prolonged action. For example, tablets or pills may take the form of the latter enveloping the former, including the medial and female fractions. The two components can be separated by an enteric layer that prevents degradation in the stomach to allow the medial component to pass through the gastrointestinal tract to reach the duodenum or delay release. Various materials can be used as such enteric coatings or coatings, such as polymeric and polymeric acid mixtures such as shellac, cetyl alchol and cellulose acetate. Liquid preparations for oral or injectable administration may include aqueous solutions, syrups, aqueous or oily suspensions and emulsions, which may comprise edible oils, elixirs and similar pharmaceutical solvents such as cottonseed oil, sesame oil, coconut oil, or peanut oil ( vehicle). Suspending agents for suitable dispersants or aqueous suspensions include synthetic or natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gel latin.

The preferred dosage of the pharmaceutical composition of the present invention is 0.01 to 250 mg / kg per day, preferably 0.05 to 100 mg / kg per day, more preferably 0.05 to 5 mg / kg per day, and 1 day It may be administered several times, preferably 1 to 4 times.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited thereto.

Production Example  1-1: Preparation of Intermediate I-1

2,4- Dichloro -6- (2- Phenyl - Propionylamino ) -Benzoic acid methyl  ester

A dichloromethane solution (15 mL) of a mixture of 2-phenylpropionic acid (1.35 g, 9.00 mmol) and thionyl chloride (2.34 mL, 27.0 mmol) was stirred at room temperature for 1 hour and then refluxed under nitrogen stream overnight. . The reaction mixture was cooled to room temperature. The resulting solution was concentrated under reduced pressure to give an intermediate acid chloride. Without further purification, the acid chloride was dissolved in anhydrous methylene chloride (15 mL). To the solution was added dropwise anhydrous methylene chloride solution (20 mL) of methyl 3,5-dichloro anthranilate (1.95 g, 8.88 mmol) in an ice bath. After stirring for 30 min at 0 ° C., the reaction was allowed to warm to room temperature and stirring continued overnight. The resulting mixture was diluted with methylene chloride (50 mL), washed with water (50 mL × 2), brine (50 mL × 2) and saturated NaHCO ₃ solution and dried under MgSO ₄ . After evaporation of the solvent, the residue was purified using flash chromatography ( n -hexane: EtOAc = 10: 1) to give the title compound as a pale yellow oil (2.88 g, 92%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.57 (d, J = 7.0 Hz, 3H, CH ₃ ), 3.75 (s, 3H, CO ₂ CH ₃ ), 3.72-3.88 (m, 1H, CH), 7.10 (d, J = 2.0 Hz, 1H, ArH), 7.24-7.41 (m, 5H, ArH), 8.38 (d, J = 2.0 Hz, 1H, ArH), 8.97 (s, 1H, NH); mp 83-84 ° C .; MS (EI) m / e 353 [M ⁺⁺ 2], 320, 246, 105; HRMS m / e cacld. for C ₁₇ H ₁₅ NO ₃ Cl ₂ 351.0429, found 351.0430.

Production Example  1-2: Preparation of Intermediate I-2

2,4- Dichloro -6- [2- (4- Methoxy - Phenyl )- Propionylamino ] -Benzoic acid methyl  ester

The title compound was purified from 2- (4-methoxy-phenyl) -propionic acid (1.45 g, 8.0 mmol), thionyl chloride (2.09 mL, 24.0 mmol) and methyl 3,5-dichloro anthranilate (1.54 g, 7.0 mmol) was prepared in the same manner as the preparation of Intermediate I-1 . After normal workup, the pure title compound was obtained by pale yellow syrup using flash chromatography ( n-hexane : EtOAc = 10: 1) (2.27 g, 85%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.56 (d, J = 7.0 Hz, 3H, CH ₃ ), 3.77 (s, 3H, CO ₂ CH ₃ ), 3.81 (s, 3H, OCH ₃ ), 3.84- 3.95 (m, 1H, CH), 6.83-6.97 (m, 2H, ArH), 7.12 (d, J = 2.0 Hz, 1H, ArH), 7.21-7.27 (m, 2H, ArH), 8.41 (d, J = 2.0 Hz, 1H, ArH), 8.98 (s, 1H, NH); HRMS (EI) calcd. for C ₁₈ H ₁₇ O ₄ NCl ₂ m / e 381.0536 [M ⁺ ], found 381.0539.

Production Example  1-3: Preparation of Intermediate I-3

2,4- Dichloro -6- [2- (4-nitro- Phenyl )- Propionylamino ] -Benzoic acid methyl  ester

The title compound was purified from 2- (4-nitro-phenyl) -propionic acid (1.40 g, 7.17 mmol), thionyl chloride (5.1 mL, 71.7 mmol) and methyl 3,5-dichloro anthranilate (1.6 g, 5.74 mmol) was prepared in the same manner as the preparation of Intermediate I-1 . After usual work-up, recrystallization from a 1: 5 ratio mixture of ethyl acetate and ethyl ether gave the pure title compound as a pale yellow solid (2.26 g, 99%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.63 (d, J = 7.1 Hz, 3H, CH ₃ ), 3.85-3.86 (m, 4H, CO ₂ CH ₃ & CH), 7.18 (d, J = 2.0 Hz , 1H, ArH), 7.54 (d, J = 8.7 Hz, 2H, ArH), 8.24 (d, J = 8.7 Hz, 2H, ArH), 8.45 (d, J = 2.0 Hz, 1H, ArH), 9.59 ( br s, 1H, ArH); mp 148-149 ° C; MS (EI) m / e 396 [M ⁺ ], 365, 246; HRMS m / e cacld. for C ₁₇ H ₁₄ N ₂ O ₅ Cl ₂ 396.0279, found 396.0276.

Production Example  1-4: Preparation of Intermediate I-4

2- [2- (4- Bromo - Phenyl )- Propionylamino ] -4,6- Dichloro -Benzoic acid methyl  ester

The title compound was purified from 2- (4-bromo-phenyl) -propionic acid (11.7 g, 48.3 mmol), thionyl chloride (35.0 mL, 480 mmol) and methyl 3,5-dichloro anthranilate (10.1 g, 45.9 mmol) in the same manner as for the preparation of Intermediate I-1 . Prepared. After usual workup, flash chromatography ( n-hexane : EtOAc = 10: 1) was used to give the title compound as a white solid (9.31 g, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.58 (d, J = 7.1 Hz, 3H, CH ₃ ), 3.75 (q, J = 7.1 Hz, 1H, CH), 3.81 (s, 3H, CO ₂ CH ₃ ), 7.15 (d, J = 2.0 Hz, 1H, ArH), 7.20-7.53 (m, 4H, ArH), 8.41 (d, J = 1.7 Hz, 1H, ArH), 9.16 (br s, 1H, NH) ; mp 79-80 ° C .; MS (EI) m / e 431 [M ⁺ ], 400, 246; HRMS m / e cacld. for C ₁₇ H ₁₄ N ₁ O ₃ Cl ₂ Br 430.9728, found 430.9728.

Production Example  1-5: Preparation of Intermediate I-5

2,4- Dichloro -6- [2- (3- Methoxy - Phenyl )- Propionylamino ] -Benzoic acid methyl  ester

The title compound was purified from 2- (3-methoxy-phenyl) -propionic acid (3.20 g, 8.40 mmol), thionyl chloride (1.8 mL, 25.0 mmol) and methyl 3,5-dichloro anthranilate (1.50 g). , 6.70 mmol), to prepare Intermediate I-1 . Prepared. After conventional workup, flash chromatography ( n -hexane: EtOAc = 5: 1) gave the pure title compound as a white solid (2.10 g, 84%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.59 (d, J = 6.8 Hz, 3H, CH ₃ ), 3.66 (q, J = 6.8 Hz, 1H, CH), 3.79 (s, 3H, OCH ₃ ), 3.85 (s, 3H, OCH ₃ ), 6.86-6.96 (m, 4H, ArH), 7.15 (d, J = 1.8 Hz, 1H, ArH), 8.42 (d, J = 1.8 Hz, 1H, ArH), 8.99 (br s, 1H, NH); MS (EI) m / e 381 [M ⁺ ], 246, 214; HRMS m / e cacld. for C ₁₈ H ₁₇ NO ₄ Cl ₂ 381.0535, found 381.0541.

Production Example  1-6: Preparation of Intermediate I-6

2- [2- (4-benzyloxy-3-bromo-phenyl) -propionylamino] -4,6-dichloro-benzoic acid methyl ester

The title compound was purified from 2- (4-benzyloxy-3-bromo-phenyl) -propionic acid (1.00 g, 2.98 mmol), thionyl chloride (0.60 mL, 8.33 mmol) and methyl 3,5-dichloro anthranyl In the same manner as the preparation of Intermediate I-1 using the rate (0.53 g, 2.41 mmol) Prepared. After conventional workup, flash chromatography ( n -hexane: EtOAc = 5: 1) gave the pure title compound as a white solid (1.06 g, 82%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.62 (d, J = 6.4 Hz, 3H, CH ₃ ), 3.66 (q, J = 6.4 Hz, 1H, CH), 3.88 (s, 3H, OCH ₃ ), 5.07 (s, 2H, OCH ₂ Ph), 6.73 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 9.0 Hz, 1H, ArH), 6.97 (dd, J = 8.6 Hz, 2.4 Hz , 1H, ArH), 7.12 (d, J = 2.4 Hz, 1H, ArH), 7.23-7.35 (m, 5H, ArH); 8.68 (br s, 1 H, NH); MS (EI) m / e 537 [M ⁺ ], 445, 386.

Production Example  2-1: Preparation of Intermediate II-1

5,7- Dichloro -3- methyl -3- Phenyl -One H -Quinoline-2,4- Dion

Anhydrous THF (25 mL) solution of LiHMDS [hexamethyldisilazide (1.47 mL, 6.90 mmol) was added to anhydrous THF solution (70 mL) of pre - cooled (-78 ° C.) intermediate I-1 (0.82 g, 2.30 mmol). n- BuLi (3.70 mmol, 2.5M hexane solution), treated at −78 ° C. for 1 hour] was added dropwise. The reaction mixture was stirred for 1 hour and then heated to reflux overnight under a nitrogen atmosphere. After the reaction was cooled to room temperature, 1N HCl aqueous solution was added to terminate the reaction. The resultant was extracted with ethyl acetate (150 mL × 3), and the organic layer was washed with brine (150 mL × 2) and water (150 mL × 2) and dried over MgSO ₄ . After evaporation of the solvent, the residue was purified by flash chromatography (n-hexane: EtOAc = 4: 1) to give the title compound (0.57 g, 78%) as a yellow solid.

^{1 H NMR (200 MHz, CD} 3 OD + DMSO- d 6) δ 1.61 (s, 3H, CH 3), 6.96 (m, 1H, ArH), 7.08 - 7.34 (m, 6H, ArH); mp 222-225 ° C; MS (EI) m / e 319 [M ⁺ ], 285, 132, 104.

Production Example  2-2: Preparation of Intermediate II-2

5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared by the same method for preparing Intermediate II-1 using Intermediate I-2 (1.44 g, 3.77 mmol) and LiHMDS (11.0 mmol, 1M THF solution). After normal workup, the pure title compound was obtained using flash chromatography ( n-hexane : EtOAc = 10: 1) (0.55 g, 42%; yellow solid).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.52 (s, 3H, CH ₃ ), 3.67 (s, 3H, CO ₂ CH ₃ ), 6.89 (d, J = 8.9 Hz, 2H, ArH), 6.99-7.08 (m, 3H, ArH), 7.23 (d, J = 1.9 Hz, 1H, ArH), 11.25 (s, 1H, NH); mp 210-212 ° C; MS (EI) m / e 349 [M ^< ⁺ &^gt;], 162, 134; HRMS m / e cacld. for C ₁₇ H ₁₃ NO ₃ Cl ₂ 349.0272, found 349.0278.

Production Example  2-3: Preparation of Intermediate II-3

5,7- Dichloro -3- methyl -3- (4-nitro- Phenyl )-One H -Quinoline-2,4- Dion

Anhydrous tetrahydrofuran (5 mL) solution of intermediate I-3 (0.20 g, 0.50 mmol) was added to anhydrous tetrahydrofuran suspension (20 mL) in sodium hydride (50 mg, 1.25 mmol, 60% dispersion in mineral oil). Add at 0 ° C. The reaction mixture was stirred for 5 hours. The reaction was stopped by addition of 0.5 M HCl solution (30 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3), washed with water (50 mL × 2) and brine (50 mL × 2) and dried under anhydrous MgSO ₄ . After evaporation of the solvent, the residue was purified by recrystallization from a 3: 1 ratio mixture of dichloromethane and ethyl acetate to give the pure title compound as a pale yellow solid (0.18 g, 99%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 6.80 (d, J = 1.8 Hz, 1H, ArH), 7.15 (d, J = 1.8 Hz, 1H, ArH), 7.38 (d, J = 9.0 Hz, 2H, ArH), 8.18 (d, J = 9.0 Hz, 2H), 8.43 (s, 1H, NH); mp 264-265 캜; MS (EI) m / e 364 [M ⁺ ]; HRMS m / e cacld. for C ₁₆ H ₁₀ N ₂ O ₄ Cl ₂ 364.0017, found 364.0010.

Production Example  2-4: Preparation of Intermediate II-4

3- (4-amino- Phenyl ) -5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

To a methanol solution of Intermediate II-3 (1.0 g, 2.74 mmol) (30 mL) was added SnCl ₂ · 2H ₂ O (1.85 g, 8.22 mmol). The resulting solution was stirred overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure to give a yellow residue. The residue was diluted with 1N HCl solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2) and water (200 mL × 2) and dried under MgSO ₄ . After evaporation of the solvent, the resulting residue was purified by flash chromatography ( n -hexane: ethyl acetate = 4: 1) to give the pure title compound as a pale yellow solid (0.61 g, 66%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.68 (s, 3H, CH ₃ ), 3.68 (br s, 2H, NH ₂ ), 6.58 (d, J = 8.8 Hz, 2H, ArH), 6.73 (d, J = 1.8 Hz, 1H, ArH), 6.96 (d, J = 8.8 Hz, 2H, ArH), 7.08 (d, J = 1.8 Hz, 1H, ArH), 8.21 (br s, 1H, NH); mp 226-227 ° C; MS (EI) m / e 335 [M ⁺⁺ 1]; HRMS m / e cacld. for C ₁₆ H ₁₂ N ₂ O ₂ Cl ₂ 334.0276, found 334.0282.

Production Example  2-5: Preparation of Intermediate II-5

5,7- Dichloro -3- (4- Iodo - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

To anhydrous acetonitrile solution (10 mL) of intermediate II-4 (84 mg, 0.25 mmol) t-BuONO (50 μL, 0.38 mmol) was added at 0 ° C. After stirring for 15 minutes, CuI ₂ (119 mg, 0.63 mmol) was added and the cooled solution was allowed to come to room temperature and then further refluxed for 30 minutes. To the resulting suspension was poured ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water (100 mL) and brine (100 mL × 2), dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography ( n- hexane: ethyl acetate = 5: 1) to give the pure title compound as a white solid (42 mg, 38%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.72 (s, 3H, CH ₃ ), 6.77 (d, J = 1.8 Hz, 1H, ArH), 6.91-6.97 (m, 2H, ArH), 7.12 (d, J = 1.8 Hz, 1H, ArH), 7.61-7.68 (m, 2H, ArH), 8.37 (br s, 1H, NH); MS (EI) m / e 445 [M ⁺ ], 258, 230, 103.

Production Example  2-6: Preparation of Intermediate II-6

5,7- Dichloro -3- (4- Chloro - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound is the same as the method for preparing Intermediate II-5 using Intermediate II-4 (168 mg, 0.50 mmol), t- BuONO (100 μl, 0.75 mmol) and CuCl ₂ (168 mg, 1.25 mmol). To make. After usual workup, flash chromatography ( n- hexane: ethyl acetate = 5: 1) gave the pure title compound as a white solid (91 mg, 52%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.73 (s, 3H, CH ₃ ), 6.81 (d, J = 1.8 Hz, 1H, ArH), 7.11-7.30 (m, 5H, ArH), 8.82 (br s , 1H, NH); mp 226-227 ° C; MS (EI) m / e 353 [M ⁺ ], 318, 187, 166, 138; HRMS m / e cacld. for C ₁₆ H ₁₀ NO ₂ Cl ₃ 352.9777, found 352.9764.

Production Example  2-7: Preparation of Intermediate II-7

3- (4- Bromo - Phenyl ) -5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared in the same manner as the preparation of Intermediate II-1 using Intermediate I-4 (400 mg, 0.93 mmol) and LiHMDS (2.20 mmol, 1M THF solution). After conventional workup, the title compound was obtained using flash chromatography ( n- hexane: EtOAc = 5: 1) (240 mg, 72%; white solid).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.69 (s, 3H, CH ₃ ), 6.91-7.48 (m, 6H, ArH); mp 237-238 캜; MS (EI) m / e 397 [M ⁺ ]; HRMS m / e cacld. for C ₁₆ H ₁₀ NO ₂ Cl ₂ Br 396.9272, found 396.9268.

Production Example  2-8: Preparation of Intermediate II-8

5,7- Dichloro -3- (3- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared in the same manner as the preparation of Intermediate II- 1 using Intermediate I-5 (1.0 g, 2.6 mmol) and LiHMDS (7.8 mL, 1M THF solution). After normal workup, the pure title compound was obtained using flash chromatography ( n -hexane: EtOAc = 5: 1) (0.55 g, 66%; white solid).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 3.74 (s, 3H, OCH ₃ ), 6.72-6.82 (m, 4H, ArH), 7.08 (d, J = 1.8 Hz , 1H, ArH), 7.18 (dd, J = 7.8 Hz, 8.8 Hz, 1H, ArH); mp 192-194 ° C; MS (EI) m / e 349 [M ^< ⁺ &^gt;], 335, 315.

Production Example  2-9: Preparation of Intermediate II-9

3- (4- Benzyloxy -3- Bromo - Phenyl ) -5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared in the same manner as the preparation of Intermediate II- 1 using Intermediate I-6 (0.80 g, 1.49 mmol) and LiHMDS (6.0 mL, 1M THF solution). After conventional workup, flash chromatography ( n -hexane: EtOAc = 5: 1) gave the pure title compound as a white solid (0.51 g, 67%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.71 (s, 3H, CH ₃ ), 5.09 (s, 2H, OCH ₂ Ph), 6.78-6.79 (d, J = 2.0 Hz, 1H, ArH), 6.82- 6.87 (d, J = 9.0 Hz, 1H, ArH), 7.02-7.07 (dd, J = 8.6 Hz, 2.4 Hz, 1H, ArH), 7.11-7.12 (d, J = 2.4 Hz, 1H, ArH), 7.33 7.43 (m, 5H, ArH); mp 189-190 ° C; MS (EI) m / e 504 [M ⁺⁺ 1]; HRMS m / e cacld. for C ₂₃ H ₁₆ NO ₃ Cl ₂ Br 502.9691, found 502.9681.

Production Example  3-1: Preparation of Intermediate III-1

1-benzyl-5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

A DMF solution (15 mL) of a mixture of intermediate II-2 (0.53 g, 1.51 mmol), benzyl bromide (0.2 mL, 2.30 mmol) and K ₂ CO ₃ (0.63 g, 4.53 mmol) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was suspended with 0.5N HCl aqueous solution (100 mL). The suspension was extracted with dichloromethane (100 mL × 3). The organic layer was washed with water (100 mL × 2) and brine (100 mL × 2), dried in the presence of anhydrous MgSO ₄ and evaporated in vacuo. The residue was purified by recrystallization from dichloromethane to give the title compound as a white solid (0.56 g, 84%).

¹ H NMR (200 MHz, DMSO-d ₆ ) δ 1.75 (s, 3H, CH ₃ ), 3.68 (s, 3H, OCH ₃ ), 5.30-5.33 (m, 2H, NCH ₂ Ph), 6.86-6.97 ( m, 4H, ArH), 7.14-7.33 (m, 6H, ArH); mp 159-160 ° C .; MS (EI) m / e 439 [M ⁺ +1]; HRMS m / e cacld. for C ₂₄ H ₁₉ NO ₃ Cl ₂ 439.0742, found 439.0738.

Production Example  3-1-1: Preparation of Intermediate III-1-chiral 1

3- (S) -1-benzyl-5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-2-chiral 1 (0.12 g, 0.34 mmol), benzyl bromide (61 μl, 0.51 mmol) and K ₂ CO ₃ (0.14 g, 1.0 mmol) to prepare intermediate III- 1 . Prepared in the same manner as the method. After normal workup, the pure title compound was obtained by flash column chromatography ( n- hexane: EtOAc = 8: 1) (0.11 g, 73%; white solid): Analytical data was melting point (mp 154-156). Same as data of racemic compound of Intermediate III-1 .

Production Example  3--1-2: Preparation of Intermediate III-1-chiral 2

3- (R) -1-benzyl-5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using the intermediate Ⅱ-2- chiral 2 (0.15g, 0.43 mmol), benzyl bromide (50 ㎕, 0.64 mmol) and _{K 2 CO 3 (0.18 g,} 1.30 mmol), Intermediate 1 Ⅲ- It was prepared in the same manner as the method. After normal workup, the pure title compound was obtained using flash column chromatography ( n- hexane: EtOAc = 8: 1) (0.13 g, 72%; white solid): Analytical data was melting point (mp 156-159). Same as data of racemic compound of Intermediate III-1 .

Production Example  3-2: Preparation of Intermediate III-2

1-benzyl-5,7- Dichloro -3- methyl -3- (4-nitro- Phenyl )-One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-3 (0.37 g, 1.0 mmol), benzyl bromide (143 μl, 1.20 mmol) and K ₂ CO ₃ (0.17 g, 1.20 mmol) to prepare intermediate III- 1 . The same was prepared. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 6: 1) to afford the pure title compound as a white solid (0.31 g, 69%).

¹ H NMR (200M Hz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 5.08 (d, J = 16.4 Hz, 1H, NC H HPh), 5.45 (d, J = 16.4 Hz, 1H, NC H HPh), 6.91 (d, J = 1.8 Hz, 1H, ArH), 7.12-7.17 (m, 3H, ArH), 7.26-7.36 (m, 5H, ArH), 8.15 (d, J = 9.2 Hz, 2H, ArH); mp 173-174 ° C; MS (EI) m / e 454 [M ⁺ ]; HRMS m / e cacld. for C ₂₃ H ₁₆ N ₂ O ₄ Cl ₂ 454.0487, found 454.0490.

Production Example  3--3: Preparation of Intermediate III-3

3- (4-amino- Phenyl ) -1-benzyl-5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

To a MeOH solution (25 mL) of intermediate III-2 (1.00 g, 2.19 mmol) was added SnCl ₂ · 2H ₂ O (1.49 g, 6.59 mmol) and the resulting solution was refluxed. After completion of the reaction, the solvent was evaporated under reduced pressure to give a yellow residue. The residue was diluted with 1N HCl solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and water (100 mL × 2) and dried in the presence of MgSO ₄ . After evaporation of the solvent, the resulting residue was purified by column chromatography to give the pure title compound as a white solid (0.50 g, 54%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.68 (s, 3H, CH ₃ ), 3.67 (br s, 2H, NH ₂ ), 4.97 (d, J = 16.4 Hz, 1H, NC H HPh), 5.42 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.54-6.59 (m, 2H, ArH), 6.82-6.90 (m, 3H, ArH), 7.05 (d, J = 1.8 Hz, 1H, ArH), 7.13-7.33 (m, 5H, ArH); mp 209-210 ° C; MS (EI) m / e 424 [M ⁺ ], 333, 307, 291; HRMS m / e cacld. for C ₂₃ H ₁₈ N ₂ O ₂ Cl ₂ 424.0745, found 424.0752.

Production Example  3-4 and Production Example  3-5: Preparation of Intermediate III-4 and III-5

1-benzyl-5,7- Dichloro -3- (4- Diethylamino - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion (Intermediate III-4)

1-benzyl-5,7- Dichloro -3- (4- Ethylamino - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion (Intermediate III-5)

To a MeOH solution (25 mL) of intermediate III-3 (1.00 g, 2.35 mmol) was added NaBH ₃ CN (0.44 g, 7.05 mmol) and CH ₃ CHO (0.49 mL, 7.05 mmol), and the acidity of the mixture was changed to acetic acid. Was adjusted to pH 5-6. The resulting solution was stirred at rt for 10 h. The solvent was evaporated under reduced pressure and the resulting residue was diluted with 1M Na ₂ CO ₃ solution (100 mL). The water layer was extracted with ethyl acetate (100 mL × 3) and the organic layer was washed with brine (100 mL × 2), dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography to give two separable title compounds, Intermediate III-4 (0.46 g, 41%) and III-5 (0.38 g, 36%) as a pale yellow solid.

Intermediate III-4: ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.08 (t, J = 6.9 Hz, 6H, 2 × NCH ₂ CH ₃ ), 1.69 (s, 3H, CH ₃ ), 3.23 (q, J = 7.3 Hz, 4H, 2 × N CH ₂ CH ₃ ), 4.97 (d, J = 16.4 Hz, 1H, NC H HPh), 5.43 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.50-6.54 (m, 2H, ArH), 6.80 (d, J = 1.8 Hz , 1H, ArH), 6.87-6.93 (m, 2H, ArH), 7.05 (d, J = 1.8 Hz, 1H, ArH), 7.12-7.17 (m, 2H, ArH), 7.26-7.32 (m, 3H, ArH); mp 173-174 ° C; MS (EI) m / e 480 [M ⁺ ], 465, 391; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₂ O ₂ Cl ₂ 480.1371, found 480.1386.

Intermediate III-5: ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.06 (t, J = 6.8 Hz, 3H, NCH ₂ CH ₃ ), 1.68 (s, 3H, CH ₃ ), 3.04 (m, 2H, N CH ₂ CH ₃ ), 4.87 (d, J = 16.4 Hz, 1H , NC H HPh), 5.42 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.48-6.52 (m, 2H, ArH), 6.76 (d, J = 1.8 Hz, 1H, ArH), 6.84-6.90 (m, 2H, ArH), 7.02 (d, J = 1.8 Hz, 1H, ArH), 7.15-7.18 (m, 2H, ArH), 7.25-7.34 (m, 3H, ArH); mp 148-149 ° C; MS (EI) m / e 452 [M ⁺ ], 437; HRMS m / e cacld. for C ₂₅ H ₂₂ N ₂ O ₂ Cl ₂ 452.1058, found 452.1062.

Production Example  3--6: Preparation of Intermediate III-6

1-benzyl-5,7- Dichloro -3- (4- Chloro - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-6 (1.00 g, 2.82 mmol), benzyl bromide (0.51 mL, 4.23 mmol) and K ₂ CO ₃ (0.58 g, 4.23 mmol) to prepare intermediate III- 1 . The same was prepared. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 8: 1) to give the pure title compound as a white solid (1.04 g, 83%).

¹ H NMR (200M Hz, CDCl ₃ ) δ 1.72 (s, 3H, CH ₃ ), 4.99 (d, J = 16.5 Hz, 1H, NC H HPh), 5.42 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.87 (d, J = 1.6 Hz, 1H, ArH), 7.02-7.15 (m, 5H, ArH), 7.24-7.34 (m, 5H, ArH); mp 169-170 ° C; MS (EI) m / e 443 [M ⁺ ], 352, 324; HRMS m / e cacld. for C ₂₃ H ₁₆ NO ₂ Cl ₃ 443.0246, found 443.0247.

Production Example  3--7: Preparation of Intermediate III-7

1-benzyl-3- (4- Bromo - Phenyl ) -5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-7 (0.92 g, 2.31 mmol), benzyl bromide (0.41 mL, 3.45 mmol) and K ₂ CO ₃ (0.48 g, 3.45 mmol) to prepare intermediate III- 1 . The same was prepared. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 8: 1) to give the pure title compound as a white solid (0.77 g, 68%).

¹ H NMR (200M Hz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 5.01 (d, J = 16.8 Hz, 1H, NC H HPh), 5.43 (d, J = 16.8 Hz, 1H, NCH H Ph), 6.90 (d, J = 1.4 Hz, 1H, ArH), 7.11-7.18 (m, 3H, ArH), 7.29-7.48 (m, 5H, ArH); mp 192-193 ° C; MS (EI) m / e 489 [M ⁺⁺ 2], 398, 317; HRMS m / e cacld. for C ₂₃ H ₁₆ NO ₂ Cl ₂ Br 486.9741, found 486.9742.

Production Example  3--8: Preparation of Intermediate III-8

1-benzyl-5,7- Dichloro -3- (4- Iodo - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-5 (1.00 g, 2.24 mmol), benzyl bromide (0.40 mL, 3.36 mmol) and K ₂ CO ₃ (0.46 g, 3.36 mmol) to prepare intermediate III- 1 . The same was prepared. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 8: 1) to give the pure title compound as a white solid (1.10 g, 85%).

¹ H NMR (200M Hz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 5.01 (d, J = 16.6 Hz, 1H, NC H HPh), 5.43 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.85-6.90 (m, 3H, ArH), 7.11-7.18 (m, 3H, ArH), 7.29-7.39 (m, 3H, ArH), 7.62-7.68 (m, 2H, ArH); mp 195-196 ° C; MS (EI) m / e 535 [M ⁺ ], 445, 408; HRMS m / e cacld. for C ₂₃ H ₁₆ NO ₂ Cl ₂ I 534.9603, found 534.9608.

Production Example  3--9: Preparation of Intermediate III-9

1-benzyl-5,7- Dichloro -3- methyl -3- Phenyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-1 (1.00 g, 3.12 mmol), benzyl bromide (0.45 mL, 3.75 mmol) and K ₂ CO ₃ (0.52 g, 3.75 mmol) to prepare intermediate III-1 . The same was prepared. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 8: 1) to give the pure title compound as a white solid (0.96 g, 75%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 4.99 (d, J = 16.3 Hz, 1H, NC H HPh), 5.43 (d, J = 16.3 Hz, 1H, NCH H Ph ), 6.83 (d, J = 1.6 Hz, 1H, ArH), 7.06-7.33 (m, 11H, ArH); mp 150-151 ° C; MS (EI) m / e 409 [M ⁺ ], 396, 375; HRMS m / e cacld. for C ₂₃ H ₁₇ NO ₂ Cl ₂ 409.0636, found 409.0637.

Production Example  3-10: Preparation of the Intermediate III-10

5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -1- (3-nitro-benzyl) -1 H -Quinoline-2,4- Dion

Using the title compound intermediate Ⅱ-2 (2.20 g, 6.30 mmol), 3-nitro-benzyl bromide polyimide (1.62 g, 9.40 mmol) and _{K 2 CO 3 (2.60 g,} 19.0 mmol) as base, intermediate Ⅲ It was prepared in the same manner as the method for preparing -1 . After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 3: 1) to give the pure title compound as a pale yellow solid (2.20 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.71 (s, 3H, CH ₃ ), 3.764 (s, 3H, OCH ₃ ), 4.87 (d, J = 16.6 Hz, 1H, CH H Ph ), 5.72 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.67 (d, J = 1.6 Hz, 1H, ArH), 6.81-6.87 (m, 2H, ArH), 7.01-7.06 ( m, 2H, ArH), 7.12 (d, J = 1.6 Hz, 1H, ArH), 7.48-7.58 (m, 2H, ArH), 8.01 (s, 1H, ArH), 8.14-8.19 (m, 1H, ArH ); mp 161-163 ° C; MS (EI) m / e 484 [M ⁺ ], 450, 348; HRMS m / e cacld. for C ₂₄ H ₁₈ N ₂ O ₅ Cl ₂ 484.0593, found 484.0595.

Production Example  3-11: Intermediate III-11

1- (3-amino-benzyl) -5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

To a methanol solution (20 mL) of intermediate III-10 (0.50 g, 1.03 mmol) was added SnCl ₂ · 2H ₂ O (0.70 g, 3.10 mmol). The resulting solution was heated to reflux for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a yellow residue. The residue was diluted with 1N HCl solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and water (100 mL × 2) and dried in the presence of MgSO ₄ . After evaporation of the solvent, the resulting residue was purified by flash column chromatography ( n -hexane: ethyl acetate = 2: 1) to give the pure title compound as a pale yellow solid (0.23 g, 50%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.57 (s, 3H, CH ₃ ), 3.68 (s, 3H, OCH ₃ ), 5.03-5.26 (m, 2H, NCH ₂ Ph), 6.31-6.45 (m, 3H, ArH), 6.86-6.98 (m, 5H, ArH), 7.12-7.14 (d, J = 2.2 Hz, 1H, ArH), 7.34-7.34 (d, J = 1.6 Hz, 1H, ArH); mp 205-206 캜; MS (EI) m / e 454 [M ⁺ ], 420, 348; HRMS m / e cacld. for C ₂₄ H ₂ 0N ₂ 0 ₃ Cl ₂ 454.0851, found 454.0861.

Production Example  3-12: Preparation of the Intermediate III-12

5,7- Dichloro -1- (3- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

To anhydrous DMF suspension (7 mL) of NaH (60% dispersion in mineral oil; 44 mg, 1.14 mmol) was added anhydrous DMF solution (7 mL) of intermediate II-2 (0.20 g, 0.57 mmol) at 0 ° C. After stirring for 30 minutes, anhydrous DMF solution (2 mL) of 3-methoxybenzyl chloride (0.13 g, 0.86 mmol) was added to the mixture at 0 ° C. using a syringe. The resulting mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was cooled using cold water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with water (100 mL × 2) and brine (100 mL × 2), dried in the presence of anhydrous MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to give the title compound as a white solid (0.18 g, 67%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.71 (s, 3H, CH ₃ ), 3.43 (s, 6H, 2 × OCH ₃ ), 4.92 (d, J = 16.6 Hz, 1H, NC H HPh), 5.48 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.67-6.84 (m, 6H, ArH), 7.02-7.08 (m, 2H, ArH), 7.19-7.27 (m, 1H, ArH).

Production Example  3-13: Preparation of Intermediate III-13

5,7- Dichloro -1- (2- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

Using the title compound intermediate Ⅱ-2 (0.2 g, 0.57 mmol), 2- methoxy-benzyl chloride (0.11 ㎖, 0.74 mmol) and _{K 2 CO 3 (0.24 g,} 1.70 mmol) as base, intermediate Ⅲ- 1 was prepared in the same manner as the preparation method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 4: 1) to give the pure title compound as a white solid (0.25 g, 93%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.71 (s, 3H, CH ₃ ), 3.78 (s, 3H, OCH ₃ ), 3.94 (s, 3H, OCH ₃ ), 5.08 (d, J = 16.8 Hz, 1H, NC H HPh), 5.38 (d, J = 16.8 Hz, 1H, NCH H Ph), 6.79-6.86 (m, 2H, ArH), 6.88-6.98 (m, 4H, ArH), 7.03-7.11 (m , 3H, ArH), 7.24-7.32 (m, 1H, ArH); mp 170-171 ° C; MS (EI) m / e 469 [M ⁺ ], 435, 348; HRMS m / e cacld. for C ₂₅ H ₂₁ NO ₄ Cl ₂ 469.0848, found 469.0852.

Production Example  3-14: Preparation of Intermediate III-14

5,7- Dichloro -1- (4- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

Using the title compound intermediate Ⅱ-2 (1.00 g, 2.85 mmol), 4- methoxybenzyl bromide (0.69 g, 3.43 mmol) and _{K 2 CO 3 (0.47 g,} 3.43 mmol) as base, intermediate Ⅲ- 1 was prepared in the same manner as the preparation method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 4: 1) to give the pure title compound as a white solid (1.11 g, 83%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.69 (s, 3H, CH ₃ ), 3.74 (s, 3H, OCH ₃ ) 3.78 (s, 3H, OCH ₃ ), 4.94 (d, J = 16.5 Hz, 1H, NC H HPh), 5.40 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.76-6.88 (m, 3H, ArH), 6.99-7.10 (m, 3H, ArH); mp 134-135 ° C; MS (EI) m / e 469 [M ⁺ ], 348, 214; HRMS m / e cacld. for C ₂₅ H ₂₁ NO ₄ Cl ₂ 469.0848, found 469.0847.

Production Example  3-15: Preparation of Intermediate III-15

1- (3- Bromo -Benzyl) -5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-2 (0.2 g, 0.57 mmol), 3-bromobenzyl bromide (0.21 g, 0.85 mmol) and K ₂ CO ₃ (0.24 g, 1.70 mmol) as the base. It manufactured similarly to the method of manufacturing III-1 . After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to give the pure title compound as a light yellow solid (0.29 g, 96%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.70 (s, 3H, CH ₃ ), 3.75 (s, 3H, OCH ₃ ), 4.77 (d, J = 16.6 Hz, 1H, NC H HPh), 5.54 (d , J = 16.6 Hz, 1H, NCH H Ph), 6.73 (d, J = 1.6 Hz, 1H, ArH), 6.81-6.88 (m, 2H, ArH), 7.01-7.06 (m, 2H, ArH), 7.10 (d, J = 1.6 Hz, 1H, ArH), 7.17-7.26 (m, 3H, ArH), 7.41 (d, J = 7.8 Hz, 1H, ArH); mp 165-166 캜; MS (EI) m / e 519 [M ⁺ ], 348, 320.

Production Example  3-16: Preparation of Intermediate III-16

1- (2- Bromo -Benzyl) -5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

Using the title compound intermediate Ⅱ-2 (1.00 g, 2.85 mmol), 2- bromo-benzyl bromide (0.86 g, 3.43 mmol) and _{K 2 CO 3 (0.47 g,} 3.43 mmol) as base, intermediate Ⅲ- 1 was prepared in the same manner as the preparation method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to afford the title compound as a yellow solid (1.19 g, 81%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 3.78 (s, 3H, OCH ₃ ), 4.98 (d, J = 16.5 Hz, 1H, NC H HPh), 5.45 (d, J = 16.5 Hz, 1H, NCH H Ph ), 6.65 (d, J = 1.8 Hz, 1H, ArH), 6.71-6.79 (m, 1H, ArH), 6.83-6.89 (m, 2H, ArH), 7.05-7.19 (m, 5H, ArH), 7.60 7.66 (m, 1 H, ArH); mp 200-201 ° C; MS (EI) m / e 519 [M ⁺ ], 438, 348; HRMS m / e cacld. for C ₂₄ H ₁₈ NO ₃ Cl ₂ Br 518.9692, found 518.9692.

Production Example  3-17: Preparation of Intermediate III-17

5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -1-pyridine-3- Methyl -One H -Quinoline-2,4- Dion

The title compound by using an intermediate Ⅱ-2 (0.20 g, 0.57 mmol), 3- picolyl chloride hydrochloride (0.14 g, 0.86 mmol) and _{K 2 CO 3 (0.24 g,} 1.70 mmol) as base, intermediate Ⅲ It was prepared in the same manner as the method for preparing -1 . After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 4: 1) to give the pure title compound as a pale yellow solid (2.20 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.70 (s, 3H, CH ₃ ), 3.75 (s, 3H, OCH ₃ ), 5.04 (d, J = 16.6 Hz, 1H, NC H HPh), 5.43-5.51 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.72 (d, J = 1.6 Hz, 1H, ArH), 6.75-6.84 (m, 2H, ArH), 6.93-7.02 (m, 2H, ArH) , 7.11 (d, J = 1.6 Hz, 1H, ArH), 7.23-7.26 (m, 1H, ArH), 7.43-7.47 (m, 1H, ArH), 8.53 (m, 2H, ArH); mp 133-134 ° C; MS (EI) m / e 440 [M ⁺ ], 348, 134; HRMS m / e cacld. for C ₂₃ H ₁₈ N ₂ O ₃ Cl ₂ 440.0694, found 440.0682.

Production Example  3-18: Preparation of Intermediate III-18

5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -1-naphthalene-2- Methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-2 (0.20 g, 0.57 mmol), 2-bromomethyl naphthalene (0.19 g, 0.86 mmol) and NaH (60% dispersion in mineral oil; 44 mg, 1.14 mmol) as base. In the same manner as in the preparation of Intermediate II-12 . After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 10: 1) to afford the pure title compound as a white solid (0.16 g, 57%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.67 (s, 3H, CH ₃ ), 3.73 (s, 3H, OCH ₃ ), 4.99 (d, J = 16.6 Hz, 1H, NC H HPh), 5.64-5.72 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.75-6.82 (m, 3H, ArH), 6.98-7.04 (m, 3H, ArH), 7.25-7.30 (m, 1H, ArH), 7.35- 7.45 (m, 3H, ArH), 7.53-7.60 (m, 1H, ArH), 7.75-7.81 (m, 2H, ArH); mp 232-234 ° C; MS (EI) m / e 491 [M ⁺⁺ 2], 381, 348; HRMS m / e cacld. for C ₂₈ H ₂₁ N ₁ O ₃ Cl ₂ 489.0898, found 489.0904.

Production Example  3-19: Preparation of Intermediate III-19

One- Biphenyl -4- Methyl -5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound contained intermediate II-2 (0.10 g, 0.29 mmol), 4- (chloromethyl) biphenyl (0.09 g, 0.43 mmol) and NaH (60% dispersion in mineral oil; 22 mg, 0.057 mmol) as a base. It was manufactured similarly to the method of manufacturing intermediate II-12 using the same. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to give the pure title compound as a pale yellow solid (83 mg, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.72 (s, 3H, CH ₃ ), 3.75 (s, 3H, OCH ₃ ), 5.04 (d, J = 16.4 Hz, 1H, NC H HPh), 5.52 (d , J = 16.4 Hz, 1H, NCH H Ph), 6.79-6.83 (m, 2H, ArH), 6.88-6.89 (d, J = 2.0 Hz, 1H, ArH), 7.02-7.09 (m, 3H, ArH) , 7.22 (d, J = 8.0 Hz, 2H, ArH), 7.35-7.48 (m, 3H, ArH), 7.52-7.59 (m, 4H, ArH); mp 170-171 ° C; MS (EI) m / e 517 [M ⁺⁺ 2], 515 [M < + >], 348, 167; HRMS m / e cacld. for C ₃₀ H ₂₃ N ₁ O ₃ Cl ₂ 515.1055, found 515.1062.

Production Example  3-20: Preparation of Intermediate III-20

1- (1H- Benzoimidazole -2- Methyl ) -5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using Intermediate II-2 (1.00 g, 2.85 mmol), 2-chloromethyl-1H-benzimidazole (0.57 mL, 3.43 mmol) and K ₂ CO ₃ (0.47 g, 3.43 mmol) as the base. In the same manner as in the preparation of intermediate III- 1 , the preparation was carried out. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 2: 1) to give the pure title compound as a pale yellow solid (0.93 g, 68%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 3.67 (s, 3H, OCH ₃ ), 5.04 (d, J = 16.5 Hz, 1H, NC H HPh), 5.60 (d, J = 16.5 Hz, 1H, NCH H Ph ), 6.65-6.75 (m, 2H, ArH), 6.85-6.93 (m, 2H, ArH), 7.10 (d, J = 1.83 Hz, 1H, ArH), 7.25-7.34 (m, 2H, ArH), 7.44 7.48 (m, 1H, ArH), 7.74-7.80 (m, 2H, ArH), 9.85 (br s, 1H, ArH).

Production Example  3-21: Preparation of the intermediate III-21

5,7- Dichloro -3- (4- Methoxy - Phenyl ) -3- methyl -1-quinoline-2- Methyl -One H -Quinoline-2,4- Dion

The title compound by using an intermediate Ⅱ-2 (1.00 g, 2.85 mmol), 2- chloromethyl-quinoline (0.61 g, 3.42 mmol) and _{K 2 CO 3 (0.47 g,} 3.43 mmol) as base, intermediate Ⅲ-1 It was prepared in the same manner as the preparation method. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 2: 1) to give the pure title compound as a pale yellow solid (1.19 g, 85%).

¹ H NMR (200MHz, DMSO- d6 ) δ 1.61 (s, 3H, CH ₃ ), 3.72 (s, 3H, OCH ₃ ), 5.32 (d, J = 17.2 Hz, 1H, NC H HPh), 5.73 (d, J = 17.2 Hz, 1H, NCH H Ph ), 6.88-6.95 (m, 2H, ArH), 7.19-7.36 (m, 4H, ArH), 7.58-7.64 (m, 2H, ArH), 7.78-7.83 (m, 2H, ArH), 7.98-8.02 ( m, 1H, ArH), 8.38-8.47 (m, 1H, ArH); mp 201-202 ° C; MS (EI) m / e 490 [M ⁺ ], 456, 348; HRMS m / e cacld. for C ₂₇ H ₂ 0N ₂ 0 ₃ Cl ₂ 490.0850, found 490.0840.

Production Example  3-22: Preparation of the intermediate III-22

5,7- Dichloro -1-ethyl-3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

Using the title compound intermediate Ⅱ-2 (0.20 g, 0.57 mmol), dibromoethane (64 ㎕, 0.86 mol) and _{K 2 CO 3 (0.22 g,} 1.60 mmol) as a base, producing the intermediate Ⅲ- 1 It was prepared in the same manner as the method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 8: 1) to give the pure title compound as a white solid (0.14 g, 65%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.27 (t, J = 6.4 Hz, 3H, CH ₂ CH ₃ ), 1.64 (s, 3H, CH ₃ ), 3.70 (s, 3H, OCH ₃ ), 3.79- 4.33 (m, 2H, NCH ₂ Ph), 6.74-6.80 (m, 2H, ArH), 6.89 (d, J = 1.6 Hz, 1H, ArH), 6.93-6.99 (m, 2H, ArH), 7.03 (d , J = 1.6 Hz, 1H, ArH); mp 152-153 ° C; MS (EI) m / e 377 [M < + >], 364, 348; HRMS m / e cacld. for C ₁₉ H ₁₇ NO ₃ Cl ₂ 377.0584, found 377.0582.

Production Example  3-23: Preparation of Intermediate III-23

5,7- Dichloro -One- Cyclohexylmethyl -3- (4- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound by using an intermediate Ⅱ-2 (0.20 g, 0.57 mmol), bromomethyl cyclohexane (0.54 ㎖, 0.85 mmol) and _{K 2 CO 3 (0.24 g,} 1.7 mmol) as base, intermediate Ⅲ- 1 It was prepared in the same manner as the preparation method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to give the pure title compound as a white solid (0.14 g, 65%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.01-1.28 (m, 5H, cyclohexyl), 1.49-1.55 (m, 1H, cyclohexyl), 1.65 (s, 3H, CH ₃ ), 1.66-1.75 (m , 4H, cyclohexyl), 3.66-3.76 (m, 1H, NC H H), 3.73 (s, 3H, OCH ₃ ), 4.01-4.12 (m, 1H, NCH H ), 6.75-6.79 (m, 2H, ArH), 6.89 (d, J = 2.4 Hz, 1H, ArH), 6.96-7.00 (m, 2H, ArH), 7.07 (d, J = 2.4 Hz, 1H, ArH); mp 166-167 캜; MS (EI) m / e 445 [M ⁺ ], 411, 349; HRMS m / e cacld. for C ₂₄ H ₂₅ NO ₃ Cl ₂ 445.1211, found 445.1200.

Production Example  3-24: Preparation of Intermediate III-24

1-benzyl-5,7- Dichloro -3- (3- Methoxy - Phenyl ) -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-8 (0.55 g, 1.60 mmol), benzylbromide (0.28 mL, 2.40 mmol) and K ₂ CO ₃ (0.66 g, 4.80 mmol) as the base to prepare intermediate III-1 . Prepared in the same manner as the method. After usual workup, the crude product was purified by flash column chromatography ( n- hexane: ethyl acetate = 5: 1) to give the pure title compound as a white solid (0.48 g, 67%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH ₃ ), 3.71 (s, 3H, OCH ₃ ), 4.95 (d, J = 16.8 Hz, 1H, NC H HPh), 5.45 (d , J = 16.8 Hz, 1H, NCH H Ph), 6.64 (dd, J = 2.2, 2.2 Hz, 1H, ArH), 6.68-6.73 (m, 1H, ArH), 6.77-6.82 (m, 1H, ArH) , 6.83 (d, J = 1.4 Hz, 1H, ArH), 7.07 (d, J = 1.4 Hz, 1H, ArH), 7.14-7.20 (m, 3H, ArH), 7.24-7.33 (m, 3H, ArH) ; mp 124-125 ° C. MS (EI) m / e 439 [M ⁺ ], 411, 348; HRMS m / e cacld. for C ₂₄ H ₁₉ NO ₃ Cl ₂ 439.0742, found 439.0746.

Production Example  3-25: Preparation of Intermediate III-25

1-benzyl-3- (4- Benzyloxy -3- Bromo - Phenyl ) -5,7- Dichloro -3- methyl -One H -Quinoline-2,4- Dion

The title compound was prepared using intermediate II-9 (0.15 g, 0.30 mmol), benzylbromide (53 μl, 0.45 mmol) and K ₂ CO ₃ (124 mg, 0.90 mmol) as the base to prepare intermediate III- 1 . Prepared in the same manner as the method. After usual workup, the crude product was purified by flash column chromatography ( n -hexane: ethyl acetate = 10: 1) to give the pure title compound as a white solid (130 mg, 72%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.70 (s, 3H, CH ₃ ), 4.88-4.99 (d, J = 16.6 Hz, 1H, NC H HPh), 5.09 (s, 2H, OCH ₂ Ph), 5.51-5.55 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.81-6.86 (m, 2H, ArH), 6.95 (dd, J = 8.6, 2.4 Hz, 1H, ArH), 7.13-7.17 (m , 3H, ArH), 7.25-7.45 (m, 9H, ArH); mp 184-185 ° C; MS (EI) m / e 594 [M ⁺⁺ 1].

Example  1: 1-benzyl-7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

A mixture of intermediate III-1 (0.10 g, 0.23 mmol) and 1-methyl piperazine (5.0 mL) was heated at reflux overnight. Excess 1-methyl piperazine was removed in vacuo. The resulting residue was suspended with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with water (100 mL × 2) and brine (100 mL × 2) and dried over anhydrous MgSO ₄ Under dryness and evaporated in vacuo. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 30: 1) to afford the title compound as a yellow solid (0.07 g, 60%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 2.36 (s, 3H, NCH ₃ ), 2.25-2.60 (m, 4H, 2 x NCH 2), 2.80-2.91 (m, 2H , 2 × NC H H), 3.06-3.17 (m, 2H, 2 × NC H H), 3.74 (s, 3H, OCH ₃ ), 5.10 (d, J = 16.2 Hz, 1H, NC H HPh), 5.42 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.61 (d, J = 1.6 Hz, 1H, ArH), 6.65 (d, J = 1.6 Hz, 1H, ArH), 6.75 (d, J = 8.4 Hz, 2H, ArH), 7.04 (d, J = 8.4 Hz, 2H, ArH), 7.17-7.36 (m, 5H, ArH); mp 66-67 ° C .; MS (EI) m / e 503 [M ⁺ ]; HRMS m / e cacld. for C ₂₉ H _{3 0} N ₃ O ₃ Cl ₁ 503.1976, found 503.1971.

Example  2: 1-benzyl-7- Chloro -3- (4- Hydroxy - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

Example 1 (0.14 g, 0.28 mmol) in a dichloromethane solution (5 mL) was added BBr ₃ (0.83 mmol, in 1M dichloromethane) at −78 ° C. under a nitrogen atmosphere. The resulting mixture was raised to room temperature. After 4 hours, the reaction mixture was quenched with cold water and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with 2N sodium thiosulfate solution (100 mL), water (100 mL × 2) and brine (100 mL), dried over anhydrous MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) to afford the title compound as a yellow solid (75 mg, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 2.40 (s, 3H, NCH ₃ ), 2.62-2.74 (m, 4H, 2 × NCH ₂ ), 2.84-3.00 (m , 4H, 2 x NCH ₂ ), 5.21 (d, J = 16.6 Hz, 1H, NC H HPh), 5.36 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.56-6.63 (m, 4H, ArH ), 6.95-6.99 (d, J = 8.6 Hz, 2H, ArH), 7.19-7.36 (m, 5H, ArH); mp 258-259 ° C; MS (EI) m / e 489 [M ⁺ ], 446, 432; HRMS m / e cacld. for C ₂₈ H ₂₈ N ₃ O ₃ Cl ₁ 489.1819, found 489.1819.

Example  3: 1-benzyl-7- Chloro -3- methyl -5- (4- methyl Piperazin-1-yl) -3- (4-nitro- Phenyl )-One H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 1 , using Intermediate III-2 (57 mg, 0.11 mmol) and 1-methyl piperazine (33 μl, 0.33 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 50: 1) to give the pure title compound as a yellow solid (32 mg, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.83 (s, 3H, CH ₃ ), 2.38 (s, 3H, NCH ₃ ), 2.56-2.74 (m, 4H, NCH ₂ ), 2.86-2.96 (m, 2H , NCH ₂ ), 3.19-3.27 (m, 2H, NCH ₂ ), 5.10 (d, J = 16.4 Hz, 1H, NC H HPh), 5.38 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.65 (d, J = 1.6 Hz, 1H, ArH), 6.72 (d, J = 1.6 Hz, 1H, ArH), 7.16 -7.20 (m, 2H, ArH), 7.25-7.37 (m, 5H, ArH), 8.11 (d, J = 9.0 Hz, 2H, ArH); mp 179-180 ° C; MS (EI) m / e 518 [M ⁺ ]; HRMS m / e cacld. for C ₂₈ H ₂₇ N ₄ O ₄ Cl 518.1721, found 518.1716.

Example  4: 3- (4-amino- Phenyl ) -1-benzyl-7- Chloro -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 1 , using Intermediate III-3 (85 mg, 0.20 mmol) and 1-methyl piperazine (60 μl, 0.60 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) to give the pure title compound as a yellow solid (38 mg, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.76 (s, 3H, CH ₃ ), 2.37 (s, 3H, NCH ₃ ), 2.60-2.67 (m, 4H, NCH ₂ ), 2.81-2.92 (m, 2H , NCH ₂ ), 3.06-3.16 (m, 2H, NCH ₂ ), 3.65 (br s, 2H, NH ₂ ), 5.12 (d, J = 16.4 Hz, 1H, NC H HPh), 5.42 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.50-6.65 (m, 4H, ArH), 6.89 (d, J = 8.6 Hz, 2H, ArH), 7.19-7.37 (m, 5H, ArH); MS (EI) m / e 488 [M ⁺ ].

Example  5: 1-benzyl-7- Chloro -3- (4- Diethylamino - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

To MeCN solution (20 mL) of intermediate III-4 (1.00 g, 2.07 mmol) was added 1-methyl piperazine (0.62 g, 6.23 mmol) and K ₂ CO ₃ (0.34 g, 2.48 mmol). The resulting solution was heated to reflux overnight. Water (200 mL) was poured into the reaction mixture and extracted with ethyl acetate (200 mL × 3). The organic layer was washed with water (200 mL × 2) and brine (200 mL), dried over anhydrous MgSO ₄ and dried in vacuo. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : CH ₃ OH = 10: 1) to give the pure title compound as a light yellow solid (0.85 g, 75%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.08 (t, J = 6.96 Hz, 6H, 2 x NCH ₂ CH ₃ ), 1.69 (s, 3H, CH ₃ ), 2.37 (s, 3H, NCH ₃ ), 2.59-2.64 (m, 4H, piperazine CH ₂ ), 2.84-2.90 (m, 2H, CH ₂ of piperazine), 3.04-3.10 (m, 2H, CH ₂ of piperazine), 3.22 (q, J = 7.3 Hz, 4H, 2 x N CH ₂ CH ₃ ), 5.07 (d, J = 16.5 Hz, 1H, NC H HPh), 5.38 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.46-6.50 (m, 2H, ArH), 6.59-6.62 (m, 2H, ArH), 6.90-6.95 (m, 2H, ArH), 7.23-7.32 (m, 5H, ArH). mp 204-206 ° C; MS (EI) m / e 544 [M ⁺ ], 501, 487; HRMS m / e cacld. for C ₃₂ H ₃₇ N ₄ O ₂ Cl 544.2605, found 544.2611.

Example  6: 1-benzyl-7- Chloro -3- (4- Ethylamino - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

The title compound intermediate Ⅲ-5 (1.00 g, 2.20 mmol), 1- methylpiperazine (60 ㎕, 0.60 mmol) and K ₂ CO ₃ using a (0.36 g, 2.64 mmol), performed as in Example 5 It was prepared according to the method. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the pure title compound as a pale yellow solid (0.85 g, 75%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.19 (t, J = 6.9 Hz, 3H, NCH ₂ CH ₃ ), 1.78 (s, 3H, CH ₃ ), 2.39 (s, 3H, NCH ₃ ), 2.61-2.66 (m, 4H, CH ₂ of piperazine ), 2.83-2.93 (m, 2H, CH ₂ of piperazine), 3.05-3.15 (m, 4H, CH ₂ & ArNH CH ₂ CH ₃ of piperazine), 5.09 (d, J = 16.5 Hz, 1H, NC H HPh), 5.39 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.41-6.49 (m, 2H, ArH), 6.61-6.65 (m, 2H, ArH), 6.89-6.96 (m, 2H, ArH), 7.21-7.39 (m, 5H, ArH). mp 153-155 ° C; MS (EI) m / e 516 [M ⁺ ], 473, 459, 446, 368; HRMS m / e cacld. for C ₃₀ H ₃₃ N ₄ O ₂ Cl 516.2292, found 516.2287.

Example  7: 7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1- (3-nitro-benzyl) -1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 1 , using Intermediate III-10 (0.10 g, 0.21 mmol) and 1-methyl piperazine (5 mL). After usual work up, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) to give the pure title compound as a yellow solid (2.20 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.77 (s, 3H, CH ₃ ), 2.37 (s, 3H, NCH ₃ ), 2.58-2.65 (m, 4H, 2 × NCH ₂ ), 2.90-2.93 (m , 2H, 2 × NC H H), 3.12-3.16 (m, 2H, 2 × NCH H ), 3.75 (s, 3H, OCH ₃ ), 4.97 -5.06 (d, J = 17.0 Hz, 1H, NC H HPh ), 5.57-5.65 (d, J = 17.0 Hz, 1H, NCH H Ph), 6.41 (d, J = 1.6 Hz, 1H, ArH), 6.70 (d, J = 1.6 Hz, 1H, ArH), 6.76- 6.81 (m, 2H, ArH), 7.01-7.06 (m, 2H, ArH), 7.50-7.53 (m, 2H, ArH), 8.05 (s, 1H, ArH), 8.14-8.15 (m, 1H, ArH) ; mp 171-174 ° C; MS (EI) m / e 548 [M ⁺ ], 505, 491; HRMS m / e cacld. for C ₂₉ H ₂₉ N ₄ O ₅ Cl ₁ 548.1826, found 548.1826.

Example  8: 7- Chloro -3- (4- Hydroxy - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1- (3-nitro-benzyl) -1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2, using Example 7 (50 mg, 9.10 mmol) and BBr ₃ (0.03 mmol, in 1M dichloromethane). After usual workup, the crude product was recrystallized from dichloromethane to give the pure title compound as a yellow solid (25 mg, 51%).

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 1.63 (s, 3H, CH ₃ ), 2.18 (s, 3H, NCH ₃ ), 2.36-2.38 (m, 4H, 2 × NCH ₂ ), 2.83-2.87 (m, 4H, 2 x NCH ₂ ), 5.43 (m, 2H, NCH ₂ Ph), 6.64 (d, J = 9.0 Hz, 2H, ArH), 6.74 (dd, J = 8.4, 1.6 Hz, 1H, ArH ), 6.86-6.90 (m, 3H, ArH), 7.59-7.73 (m, 2H, ArH), 8.11-8.15 (m, 2H, ArH), 9.55 (s, 1H, ArH); mp 262-264 캜; HRMS m / e cacld. for C ₂₈ H ₂₇ N ₄ O ₅ Cl ₁ 534.1669, found 534.1669.

Example  9: 1- (3-amino-benzyl) -7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

To a pyridine solution (7 mL) of intermediate III-11 (0.10 g, 0.22 mmol) was added 1-methyl piperazine (61 μl, 0.60 mmol). The reaction mixture was heated at reflux for 2 days. Water (80 mL) was poured into the reaction mixture and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with water (200 mL × 2) and brine (200 mL), dried over anhydrous MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.076 g, 70%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 2.38 (s, 3H, NCH ₃ ), 2.58-2.74 (m, 4H, 2 × NCH ₂ ), 2.83-2.93 (m , 2H, NC H H × 2), 3.10-3.21 (m, 2H, NCH H × 2), 3.74 (s, 3H, OCH ₃ ), 4.89 (d, J = 16.6 Hz, 1H, NC H HPh), 5.33 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.37 (m, 1H, ArH), 6.54-6.62 (m, 3H, ArH), 6.66 (d, J = 1.6 Hz, 1H, ArH), 6.72-6.80 (m, 2H, ArH), 7.01-7.16 (m, 3H, ArH); mp 90-93 ° C; MS (EI) m / e 518 [M ⁺ ], 476, 461; HRMS m / e cacld. for C ₂₉ H ₃₁ N ₄ O ₃ Cl 518.2085, found 518.2098.

Example  10: 1- (3-amino-benzyl) -5- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 9 (0.020 g, 0.039 mmol) and BBr ₃ (0.12 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.015 g, 75%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.69 (s, 3H, CH ₃ ), 2.31 (s, 3H, NCH ₃ ), 2.54-2.59 (m, 4H, 2 × NCH ₂ ), 2.74 -2.83 (m, 2H, 2 x NC H H), 3.00-3.11 (m, 2H, 2 x NCH H ), 3.17 (br, 2H, NH ₂ ), 4.79 (d, J = 16.2 Hz, 1H, NC H HPh), 5.30 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.26-6.31 (m, 1H, ArH), 6.50-6.64 (m, 6H, ArH), 6.85-6.91 (m, 2H, ArH), 7.01-7.08 (m, 1H, ArH); decomp. 277 ° C .; MS (EI) m / e 505 [M ⁺ +1], 461, 447; HRMS m / e cacld. for C ₂₈ H ₂₉ N ₄ O ₃ Cl 504.1928, found 504.1937.

Example  11: 1-benzyl-7- Chloro -3- methyl -5- (4- methyl Piperazin-1-yl) -3- Phenyl -One H Preparation of -quinoline-2,4-dione

The title compound was prepared as in Example 5 , using Intermediate III-9 (0.5 g, 1.2 mmol), 1-methyl piperazine (0.44 mL, 3.7 mmol) and K ₂ CO ₃ (0.84 g, 6.10 mmol). It was prepared according to the method. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.41 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.82 (s, 3H, CH ₃ ), 2.36 (s, 3H, NCH ₃ ), 2.52-2.62 (m, 4H, 2 x NCH ₂ ), 2.81-2.91 (m , 2H, NCH ₂ ), 3.06-3.17 (m, 2H, NCH ₂ ), 5.07 (d, J = 16.4 Hz, 1H, NC H HPh), 5.38 (d, J = 16.4 Hz, 1H, NCH H Ph) , 6.59 (d, J = 2.2 Hz, 1H, ArH), 6.65 (d, J = 2.2 Hz, 1H, ArH), 7.10-7.32 (m, 10H, ArH); mp 138-140 ° C; MS (EI) m / e 473 [M ⁺ ]; HRMS m / e cacld. for C ₂₈ H ₂₈ N ₃ O ₂ Cl 473.1870, found 473.1846.

Example  12: 1-benzyl-3- (4- Benzyloxy -3- Bromo - Phenyl ) -7- Chloro -3- methyl -5- (4- methyl Piperazin-1-yl) -1 H Preparation of -quinoline-2,4-dione

The title compound was prepared as in Example 5 , using Intermediate III-25 (0.11 g, 0.19 mmol), 1-methyl piperazine (0.05 mL, 0.46 mmol) and Cs ₂ CO ₃ (0.176 g, 0.54 mmol). It was prepared according to the method. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) to give the pure title compound as a pale yellow solid (79 mg, 68%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.74 (s, 3H, CH 3), 2.32 (s, 3H, NCH ₃ ), 2.60-2.65 (m, 4H, 2 × NCH ₂ ), 2.83-2.90 (m, 2H, NCH ₂ ), 3.15-3.19 (m, 2H, NCH ₂ ), 4.96-5.05 (d, J = 16.4 Hz, 1H, NC H HPh), 5.19 (s, 2H, OCH ₂ Ph), 5.41-5.49 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.59 (d, J = 2.4 Hz, 1H, ArH), 6.69-6.70 (d, J = 1.6 Hz, 1H, ArH), 6.75-6.79 (d , J = 8.6 Hz, 1H, ArH), 6.94-6.99 (dd, J = 8.6, 2.4 Hz, 1H, ArH), 7.15-7.41 (m, 1H, ArH); mp 95-97 ° C .; MS (EI) m / e 659 [M ⁺ +2].

Example  13: 1-benzyl-7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 9 , using Intermediate III-1 (0.10 g, 0.23 mmol) and Piperazine (0.05 g, 0.57 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.06 g, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.77 (s, 3H, CH ₃ ), 2.21 (br s, 1H, NH), 2.83-2.91 (m, 2H, NCH ₂ ), 3.07-3.16 (m, 4H, 2 x NCH ₂ ), 3.48 -3.49 (m, 2H, NCH ₂ ), 3.75 (s, 3H, OCH ₃ ), 5.09 (d, J = 16.6 Hz, 1H, NC H HPh), 5.42 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.62-6.66 (m, 2H, ArH), 6.73-6.77 (m, 2H, ArH), 7.00-7.05 (m, 2H, ArH), 7.17 -7.33 (m, 2H , ArH); mp 120-123 ° C; MS (EI) m / e 489 [M ⁺ ], 447, 433; HRMS m / e cacld. for C ₂₈ H ₂₈ N ₃ O ₃ Cl 489.1819, found 489.1806.

Example  13-1: Example  13 chiral-1

(S) -1-benzyl-7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Quinoline-2,4- D Manufacture of

The title compound was prepared as Intermediate III-1-chiral 1 (0.11 g, 0.26 mmol), piperazine (0.11 g, 1.3 mmol) and K ₂ CO ₃ (0.16 g, 1.3 mmol) was prepared according to the same method as in Example 5. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.07 g, 61%): Analytical data is shown in the Examples. It was the same as the data of the racemic compound of 13 .

Example -13-2: Example  13 chiral-2

(R) -1-benzyl-7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Quinoline-2,4- D Manufacture of

The title compound was prepared with intermediates III-1-chiral 2 (0.20 g, 0.39 mmol), piperazine (80 mg, 0.96 mmol) and K ₂ CO ₃ (0.16 g, 1.20 mmol) was prepared according to the same method as in Example 5. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (0.17 g, 73%). It was the same as the data of the racemic compound of 13 .

Example  14: 1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 13 (50 mg, 0.01 mmol), BBr ₃ (0.03 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (27 mg, 56%).

¹ H NMR (200 MHz, CD ₃ OD) δ 1.70 (s, 3H, CH ₃ ), 2.88-2.98 (m, 2H, NCH ₂ ), 3.15-3.32 (m, 6H, 3 x NCH ₂ ), 5.16- 5.24 (d, J = 16.6 Hz, 1H, NC H HPh), 5.35-5.44 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.63-6.69 (m, 2H, ArH), 6.78-6.82 (m , 2H, ArH), 6.89-6.95 (m, 2H, ArH), 7.14-7.31 (m, 5H, ArH); mp 197-200 ° C; MS (EI) m / e 476 [M ⁺ +1]; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₃ O ₃ Cl 475.1663, found 475.1656.

Example  14-1: Example  14 chiral-1

(S) -1-benzyl-7- Chloro -3- (4- Hydroxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 13-chiral 1 (0.090 g, 0.19 mmol) and BBr ₃ (0.56 mmol, in 1M dichloromethane). After conventional workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (56 mg, 62%): Analytical data is shown in the Examples. It was the same as the data of the racemic compound of 14 .

Example  14-2: Example  14 chiral-2

(R) -1-benzyl-7- Chloro -3- (4- Hydroxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 13-chiral 2 (0.10 g, 0.21 mmol) and BBr ₃ (0.63 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (68 mg, 68%): Analytical data is shown in the Examples. It was the same as the data of the racemic compound of 14 .

Example  15: 1-benzyl-7- Chloro -3- methyl -3- (4-nitro- Phenyl ) -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-2 (1.00 g, 2.20 mmol), Piperazine (0.95 g, 10.9 mmol) and K ₂ CO ₃ (0.91 g, 6.59 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.83 g, 75%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.81 (s, 3H, CH ₃ ), 2.87 2.96 (m, 2H, NCH ₂ ), 3.01-3.27 (m, 6H, 3 × NCH ₂ ), 5.05 (d, J = 16.1 Hz, 1H, NC H HPh), 5.36 (d, J = 16.1 Hz, 1H, NCH H Ph), ArH), 6.67 (dd, J = 1.8 Hz, 10.9 Hz, 2H, ArH), 7.15- 7.37 (m, 5H, ArH), 8.09 (d, J = 8.79 Hz, 2H, ArH); mp 145-146 ° C; MS (EI) m / e 504 [M ⁺ ]; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₄ O ₄ Cl 504.1564, found 504.1566.

Example  16: 3- (4-amino-phenyl) -1-benzyl-7-chloro-3-methyl-5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 using Intermediate III-3 (200 mg, 0.47 mmol), Piperazine (141 μl, 1.41 mmol) and K ₂ CO ₃ (0.19 g, 1.41 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (174 mg, 78%).

^{1 H NMR (200 MHz, CDCl} 3) δ 1.74 (s, 3H, CH 3), 2.54 - 2.62 (m, 4H, NCH 2), 2.78 - 2.82 (m, 2H, NCH 2), 3.12-3.18 (m , 2H, NCH ₂ ), 3.62 (br s, 2H, NH ₂ ), 5.14 (d, J = 16.4 Hz, 1H, NC H HPh), 5.39 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.48-6.62 (m, 4H, ArH), 6.79 (d, J = 8.6 Hz, 2H, ArH), 7.20-7.34 (m, 5H, ArH); MS (EI) m / e 474 [M ⁺ ].

Example  17: 1-benzyl-7- Chloro -3- (4- Diethylamino - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-4 (1.00 g, 2.07 mmol), Piperazine (0.53 g, 6.23 mmol) and K ₂ CO ₃ (0.34 g, 2.48 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.82 g, 75%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.07 (t, J = 6.9 Hz, 6H, 2 x NCH ₂ CH ₃ ), 1.76 (s, 3H, CH ₃ ), 2.85-2.93 (m, 2H, NCH ₂ ), 3.07-3.18 (m, 6H, 3 × NCH ₂ ), 3.22 (q, J = 7.3 Hz, 4H, 2 × N CH ₂ CH ₃ ), 5.06 (d, J = 16.5 Hz, 1H, NC H HPh), 5.39 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.46-6.52 (m, 2H, ArH), 6.60-6.64 (m, 2H, ArH), 6.87-6.95 (m, 2H, ArH), 7.19-7.36 (m, 5H, ArH) ; decomp. 195 ° C .; MS (EI) m / e 530 [M ⁺ ], 501, 487; HRMS m / e cacld. for C ₃₁ H ₃₅ N ₄ O ₂ Cl 530.2448, found 530.2445.

Example  18: 1-benzyl-7- Chloro -3- (4- Ethylamino - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-5 (1.00 g, 2.20 mmol), Piperazine (0.57 g, 6.62 mmol) and K ₂ CO ₃ (0.36 g, 2.64 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.83 g, 76%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.17 (t, J = 6.9 Hz, 3H, NCH ₂ CH ₃ ), 1.76 (s, 3H, CH ₃ ), 2.87-2.91 (m, 4H, 2 x NCH ₂ ), 3.02-3.15 (m, 7H, 3 × NCH2 & NH), 5.06 (d, J = 16.5 Hz, 1H, NC H HPh), 5.37 (d, J = 16.5 Hz, 1H, NCH H Ph), 6.40-6.46 (m, 2H, ArH), 6.62 6.65 (m, 2H, ArH), 6.85-6.90 (m, 2H, ArH), 7.18-7.37 (m, 5H, ArH); mp 236-238 ° C; MS (EI) m / e 502 [M ⁺ ], 472, 459, 368; HRMS m / e cacld. for C ₂₉ H ₃₁ N ₄ O ₂ Cl 502.2135, found 502.2149.

Example  19: 1-benzyl-7- Chloro -3- (4- Chloro - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-6 (1.00 g, 2.25 mmol), Piperazine (0.97 g, 11.24 mmol) and K ₂ CO ₃ (0.93 g, 6.74 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.83 g, 75%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.77 (s, 3H, CH ₃ ), 2.85-2.93 (m, 2H, NCH ₂ ), 3.03-3.18 (m, 6H, 3 x NCH ₂ ), 5.03 (d, J = 16.2 Hz, 1H, NC H HPh ), 5.39 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.63-6.69 (m, 2H, ArH), 7.01-7.05 (m, 2H, ArH), 7.16-7.38 (m, 5H, ArH) ; mp 135-136 ° C; MS (EI) m / e 493 [M ⁺ ]; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₃ O ₂ Cl ₂ 493.1324, found 493.1325.

Example  20: 1-benzyl-3- (4- Bromo - Phenyl ) -7- Chloro -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-7 (1.00 g, 2.04 mmol), Piperazine (0.88 g, 10.22 mmol) and K ₂ CO ₃ (0.85 g, 6.13 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (0.79 g, 72%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.77 (s, 3H, CH ₃ ), 2.80 2.92 (m, 2H, NCH ₂ ), 3.02-3.20 (m, 6H, 3 x NCH ₂ ), 5.02 (d, J = 16.2 Hz, 1H, NC H HPh) , 5.37 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.63 (m, 2H, ArH), 6.95 (m, 2H, ArH), 7.15-7.38 (m, 7H, ArH); mp 116-117 캜; MS (EI) m / e 538 [M ⁺ +1], 537 [M +]; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₃ O ₂ ClBr 537.0818, found 537.0818.

Example  21: 1-benzyl-7- Chloro -3- (4- Iodo - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-8 (1.00 g, 1.87 mmol), Piperazine (0.80 g, 9.35 mmol) and K ₂ CO ₃ (0.77 g, 5.61 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.85 g, 78%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.76 (s, 3H, CH ₃ ), 2.29 (s, 1H, NH), 2.78-2.89 (m, 2H, NCH ₂ ), 2.96-3.17 (m, 6H, 3 × NCH ₂ ), 5.02 (d, J = 16.2 Hz, 1H, NC H HPh), 5.36 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.62 (d, J = 1.6 Hz, 1H, ArH) , 6.68 (d, J = 1.6 Hz, 1H, ArH), 6.83 (m, 2H, ArH), 7.15-7.19 (m, 2H, ArH), 7.21-7.37 (m, 3H, ArH), 7.54 (m, 2H, ArH); mp 176-177 ° C; MS (EI) m / e 585 [M ^< ⁺ &^gt;], 555, 543; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₃ O ₂ ClI 585.0680, found 585.0675.

Example  22: 1-benzyl-7- Chloro -3- methyl -3- Phenyl -5-piperazin-1-yl-1 H- Quinoline-2,4- Dion's  Produce

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-9 (0.5 g, 1.20 mmol), Piperazine (0.31 g, 3.70 mmol) and K ₂ CO ₃ (0.84 g, 6.10 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (0.41 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.84 (s, 3H, CH ₃ ), 2.78-2.88 (m, 2H, NCH ₂ ), 3.06-3.12 (m, 6H, 3 × NCH ₂ ), 5.10 (d , J = 16.2 Hz, 1H, NC H HPh), 5.41 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.62 (d, J = 1.6 Hz, 1H, ArH), 6.67 (d, J = 1.6 Hz, 1H, ArH), 7.13-7.35 (m, 10H, ArH); MS (EI) m / e 459 [M ⁺ ]; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₃ O ₂ Cl 459.1714, found 459.1704.

Example  23: 7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-10 (1.00 g, 2.06 mmol), Piperazine (0.89 g, 10.3 mmol) and K ₂ CO ₃ (0.85 g, 6.18 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.83 g, 75%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.77 (s, 3H, CH ₃ ), 2.85-2.93 (m, 2H, NCH ₂ ), 3.03-3.23 (m, 6H, 3 × NCH ₂ ), 4.96 (d , J = 16.8 Hz, 1H, NC H HPh), 5.59 (d, J = 16.8 Hz, 1H, NCH H Ph), 6.71 (d, J = 1.8 Hz, 1H, ArH), 6.76-6.82 (m, 3H , ArH), 7.01 (m, 2H, ArH), 7.51 (m, 2H, ArH), 8.05 (s, 1H, ArH), 8.13-8.19 (m, 1H, ArH); mp 153-154 캜; MS (EI) m / e 534 [M ⁺ ], 517, 504, 492; HRMS m / e cacld. for C ₂₈ H ₂₇ N ₄ O ₅ Cl 534.1670, found 534.1675.

Example  24: 7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 23 (0.20 g, 0.04 mmol) and BBr ₃ (0.12 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.16 g, 81%).

¹ H NMR (200 MHz, CD ₃ OD) δ 1.73 (s, 3H, CH ₃ ), 2.85-2.93 (m, 2H, NCH ₂ ), 3.07-3.21 (m, 6H, 3 × CH ₂ ), 5.25 ( d, J = 16.6 Hz, 1H, NC H HPh), 5.53 (d, J = 16.6 Hz, 1H, NCH H Ph), 6.65-6.75 (m, 3H, ArH), 6.85 (d, J = 1.6 Hz, 1H, ArH), 6.91-6.99 (m, 2H, ArH), 7.56-7.68 (m, 2H, ArH), 8.15-8.20 (m, 2H, ArH); mp 252-253 ° C; MS (EI) m / e 520 [M ⁺ ], 496, 478; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₄ O ₅ Cl 520.1513, found 520.1510.

Example  25: 1- (3-amino-benzyl) -7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-11 (1.00 g, 2.20 mmol), Piperazine (0.95 g, 10.98 mmol) and K ₂ CO ₃ (0.91 g, 6.59 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (0.81 g, 73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.76 (s, 3H, CH ₃ ), 2.87-2.96 (m, 2H, NCH ₂ ), 3.16-3.27 (m, 6H, 3 × NCH ₂ ), 3.59 (br s, 2H, NH ₂ ), 3.74 (s, 3H, OCH ₃ ), 4.89 (d, J = 16.1 Hz, 1H, NC H HPh), 5.30 (d, J = 16.1 Hz, 1H, NCH H Ph), 6.37 (d, J = 1.8 Hz, 1H, ArH), 6.53-6.61 (m, 2H, ArH), 6.65 (m, 2H, ArH), 6.74 (m, 2H, ArH), 7.01-7.14 (m, 3H , ArH); mp 183-184 ° C; MS (EI) m / e 504 [M ⁺ ]; HRMS m / e cacld. for C ₂₈ H ₂₉ N ₄ O ₃ Cl 504.1928, found 504.1925.

Example  26: 1- (3-amino-benzyl) -7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 25 (0.20 g, 0.39 mmol) and BBr ₃ (1.19 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 8: 1) to afford the title compound as a yellow solid (0.17 g, 87%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.68 (s, 3H, CH ₃ ), 2.80-2.94 (m, 2H, NCH ₂ ), 3.10-3.21 (m, 6H, 3 × NCH ₂ ), 3.54 (br s, 2H, NH ₂ ), 4.79 (d, J = 16.2 Hz, 1H, NC H HPh), 5.30 (d, J = 16.2 Hz, NCH H Ph), 6.31 (d, J = 1.8 Hz, 1H, ArH ), 6.50-6.62 (m, 2H, ArH), 6.65-6.85 (m, 2H, ArH), 6.94 (m, 2H, ArH), 7.01-7.14 (m, 3H, ArH); MS (EI) m / e 490 [M ⁺ ].

Example  27: 7- Chloro -1- (3- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 9 using intermediate III-12 (0.39 g, 0.83 mmol) and piperazine (0.11 g, 1.1 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.24 g, 56%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.76 (s, 3H, CH ₃ ), 2.70 (br s, 1H, NH), 2.85-2.93 (m, 1H, NCH H ), 3.05-3.20 (m, 7H, 3 x NCH ₂ , NC H H), 3.73 (s, 3H, OCH ₃ ), 3.74 (s, 3H, OCH 3), 4.96 (d, J = 16.2 Hz, 1H, NC H HPh), 5.39 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.63-6.68 (m, 2H, ArH), 6.70-6.83 (m, 5H, ArH), 6.99-7.07 (m, 2H, ArH), 7.19-7.27 (m, 1H, ArH); mp 110-112 ° C; MS (EI) m / e 519 [M ⁺ ], 490, 477; HRMS m / e cacld. for C ₂₉ H ₃₀ N ₃ O ₄ Cl 519.1925, found 519.1947.

Example  28: 7- Chloro -1- (3-hydroxy-benzyl) -3- (4-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 27 (0.030 g, 0.058 mmol) and BBr ₃ (0.15 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (15 mg, 52%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.59 (s, 3H, CH ₃ ), 2.75-2.86 (m, 2H, NCH ₂ ), 3.02-3.18 (m, 5H, 2 × NCH ₂ & NC H H), 3.21-3.23 (m, 1H, NCH H ), 4.98 (d, J = 16.0 Hz, 1H, NC H HPh), 5.13 (d, J = 16.0 Hz, 1H, NCH H Ph), 6.52- 6.61 (m, 7H, ArH), 6.75-6.80 (m, 2H, ArH), 6.97-7.30 (m, 2H, ArH); mp 229-230 ° C; MS (EI) m / e 491 [M ⁺ ], 461, 449; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₃ O ₄ Cl 491.1611, found 491.1615.

Example  29: 7- Chloro -1- (2- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-13 (0.22 g, 0.47 mmol), Piperazine (0.10 g, 1.28 mmol) and K ₂ CO ₃ (0.33 g, 2.40 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.18 g, 74%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.81 (s, 3H, CH ₃ ), 2.82-2.90 (m, 2H, NCH ₂ ), 3.06-3.09 (m, 6H, NCH ₂ × 3), 3.77 (s , 3H, OCH ₃ ), 3.95 (s, 3H, OCH ₃ ), 5.12 (d, J = 16.4 Hz, 1H, NC H HPh), 5.38 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.65 (d, J = 2.4 Hz, 1H, ArH), 6.73 (d, J = 2.4 Hz, 1H, ArH), 6.75-6.80 (m, 2H, ArH), 6.85-6.98 (m, 3H, ArH), 7.04 7.10 (m, 2H, ArH), 7.22-7.31 (m, 1H, ArH); mp 153-155 ° C; MS (EI) m / e 519 [M ⁺ ], 502, 489, 477; HRMS m / e cacld. for C ₂₉ H ₃₀ N ₃ O ₄ Cl 519.1925, found 519.1930.

Example  30: 7-chloro-1- (2-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 29 (0.074 g, 0.14 mmol) and BBr ₃ (0.43 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (37 mg, 52%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.77 (s, 3H, CH ₃ ), 2.78-2.84 (m, 2H, NCH ₂ ), 2.99-3.02 (m, 6H, 3 × NCH ₂ ) , 5.14 (d, J = 16.4 Hz, 1H, NC H HPh), 5.30 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.65-6.69 (m, 2H, ArH), 6.75-6.84 (m, 2H, ArH), 6.88-6.97 (m, 3H, ArH), 7.02-7.18 (m, 2H, ArH); mp 165-167 ° C.

Example  31: 7- Chloro -1- (4- Methoxy -Benzyl) -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-14 (1.00 g, 2.12 mmol), Piperazine (0.55 g, 6.37 mmol) and K ₂ CO ₃ (0.88 g, 6.37 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the pure title compound as a pale yellow solid (0.86 g, 78%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 2.74-2.90 (m, 4H, 2 x NCH ₂ ), 3.02-3.13 (m, 4H, 2 x NCH ₂ ), 3.75 (s, 3H, OCH ₃ ) 3.80 (s , 3H, OCH ₃ ), 5.01 (d, J = 16.4 Hz, 1H, NC H HPh), 5.31 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.66-6.67 (m, 2H, ArH), 6.72-6.79 (m, 2H, ArH), 6.82-6.89 (m, 2H, ArH), 6.99-7.07 (m, 2H, ArH), 7.13-7.28 (m, 2H, ArH); mp 182-183 ° C; MS (EI) m / e 519 [M ⁺ ], 489, 477, 357; HRMS m / e cacld. for C ₂₉ H ₃₀ N ₃ O ₄ Cl 519.1924, found 519.1926.

Example  32: 7- Chloro -1- (4- Hydroxy -Benzyl) -3- (4- Hydroxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 31 (1.00 g, 1.92 mmol) and BBr ₃ (5.77 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (0.75 g, 79%).

¹ H NMR (200MHz, CD ₃ OD) δ 1.72 (s, 3H, CH ₃ ), 2.77-2.92 (m, 2H, NCH ₂ ), 2.97-3.10 (m, 6H, 3 x NCH ₂ ), 5.08 (d, J = 16.1 Hz, 1H, NC H HPh ), 5.25 (d, J = 16.1 Hz, 1H, NCH H Ph), 6.63-6.82 (m, 6H, ArH), 6.90-6.98 (m, 2H, ArH), 7.05-7.10 (m, 2H, ArH) ; mp 241-242 ° C; MS (EI) m / e 491 [M ⁺ ]; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₃ O ₄ Cl 491.1612, found 491.1612.

Example  33: 1- (3- Bromo -Benzyl) -7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-15 (0.2 g, 0.39 mmol), Piperazine (80 mg, 0.96 mmol) and K ₂ CO ₃ (0.16 g, 1.20 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.15 g, 65%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 2.83-2.92 (m, 2H, NCH ₂ ), 3.09-3.22 (m, 6H, 3 × NCH ₂ ), 3.77 (s , 3H, OCH ₃ ), 4.89 (d, J = 16.4 Hz, 1H, NC H HPh), 5.48 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.52 (d, J = 1.6 Hz, 1H, ArH), 6.71 (d, J = 1.6 Hz, 1H, ArH), 6.76-6.84 (m, 2H, ArH), 7.00-7.06 (m, 2H, ArH), 7.12-7.31 (m, 3H, ArH), 7.41-7.45 (m, 1H, ArH); mp 113-114 ° C .; HRMS m / e cacld. for C ₂₈ H ₂₇ N ₃ O ₃ BrCl 567.0924, found 567.0933.

Example  34: 1- (3-Bromo-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 33 (106 mg, 0.19 mmol) and BBr ₃ (0.56 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (84 mg, 76%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.73 (s, 3H, CH ₃ ), 2.82-2.87 (m, 2H, NCH ₂ ), 3.00-3.18 (m, 6H, 3 × NCH ₂ ) , 4.82 (d, J = 16.2 Hz, 1H, NC H HPh), 5.46 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.49 (d, J = 1.6 Hz, 1H, ArH), 6.70 (d , J = 1.6 Hz, 1H, ArH), 6.76-6.86 (m, 2H, ArH), 7.04-7.12 (m, 2H, ArH), 7.14-7.28 (m, 3H, ArH), 7.36-7.40 (m, 1H, ArH); decomp. 270 ° C .; MS (EI) m / e 553 [M ⁺ ]; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₃ O ₃ ClBr 553.0768, found 553.0789.

Example  35: 1- (2- Bromo -Benzyl) -7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III-16 (1.00 g, 1.92 mmol), Piperazine (0.49 g, 5.77 mmol) and K ₂ CO ₃ (0.87 g, 80%). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.15 g, 65%).

¹ H NMR (200MHz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 2.88-2.93 (m, 2H, NCH ₂ ), 3.11-3.20 (m, 6H, 3 x NCH ₂ ), 3.76 (s, 3H, OCH ₃ ), 5.03 (d, J = 16.4 Hz, 1H, NC H HPh), 5.45 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.41 (d, J = 1.8 Hz, 1H, ArH), 6.71-6.81 (m, 4H, ArH), 7.03-7.17 (m, 4H, ArH), 7.60-7.64 (m, 1H, ArH); mp 150-151 ° C; MS (EI) m / e 569 [M ⁺ ], 539, 527; HRMS m / e cacld. for C ₂₈ H ₂₇ N ₃ O ₃ ClBr 567.0924, found 567.0934.

Example  36: 1- (2- Bromo -Benzyl) -7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 35 (1.00 g, 1.76 mmol) and BBr ₃ (5.27 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to afford the pure title compound as a pale yellow solid (0.75 g, 77%).

¹ H NMR (200MHz, CD ₃ OD) δ 1.72 (s, 3H, CH ₃ ), 2.94-3.03 (m, 2H, NCH ₂ ), 3.22-3.37 (m, 6H, 3 × NCH ₂ ), 5.08 (d, J = 16.4 Hz, 1H, NC H HPh ), 5.45 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.52 (d, J = 1.8 Hz, 1H, ArH), 6.68-6.73 (m, 2H, ArH), 6.80-7.00 (m, 4H , ArH), 7.18-7.27 (m, 2H, ArH), 7.65-7.69 (m, 1H, ArH); mp 264-265 캜; MS (EI) m / e 553 [M ⁺ ], 525, 513; HRMS m / e cacld. for C ₂₇ H ₂₅ N ₃ O ₃ ClBr 553.0768, found 553.0746.

Example  37: 7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1-pyridine-3- Ilme Teal-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 1 , using Intermediate III- 17 (0.12 g, 0.27 mmol) and piperazine (0.06 g, 0.68 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to afford the title compound as a yellow solid (0.03 g, 23%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.76 (s, 3H, CH ₃ ), 2.581 (br s, 1H, NH), 2.83-2.94 (m, 2H, NCH ₂ ), 3.09-3.24 (m, 6H , 3 × NCH ₂ ), 3.74 (s, 3H, OCH ₃ ), 5.12 (d, J = 16.4 Hz, 1H, NC H HPh), 5.37-5.45 (d, J = 16.4 Hz, 1H, NCH H Ph) , 6.56 (d, J = 1.6 Hz, 1H, ArH), 6.68-6.69 (d, J = 1.6 Hz, 1H, ArH), 6.73-6.77 (m, 2H, ArH), 6.94-7.00 (m, 2H, ArH), 7.21-7.28 (m, 1H, ArH), 7.47-7.51 (m, 1H, ArH), 8.53-8.56 (m, 2H, ArH); mp 160-162 ° C; MS (EI) m / e 490 [M ⁺ ], 460, 448; HRMS m / e cacld. for C ₂₇ H ₂₇ N ₄ O ₃ Cl 490.1772, found 490.1779.

Example  38: 7- Chloro -3- (4- Hydroxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1-pyridin-3-ylmethyl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 37 (30 mg, 0.061 mmol) and BBr ₃ (0.18 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (12 mg, 41%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.74 (s, 3H, CH ₃ ), 2.90-2.97 (m, 3H, NCH ₂ , NC H H), 3.16-3.24 (m, 5H, 2 × NCH ₂ , NC H H), 4.97 (d, J = 16.2 Hz, 1H, NC H HPh), 5.48 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.56 (d, J = 2.4 Hz, 1H , ArH), 6.66-6.71 (m, 2H, ArH), 6.74 (d, J = 2.4 Hz, 1H, ArH), 7.31-7.37 (m, 1H, ArH), 7.58-7.62 (m, 1H, ArH) , 8.42 (m, 1H, ArH), 8.49-8.52 (m, 1H, ArH); decomp. 270 ° C .; MS (EI) m / e 476 [M ⁺ ], 446, 434; HRMS m / e cacld. for C ₂₆ H ₂₅ N ₄ O ₃ Cl 476.1615, found 476.1615.

Example  39: 7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -1-naphthalene-2- Methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared in the same manner as in Example 5 using intermediate III- 18 (0.1 g, 0.20 mmol), piperazine (44 mg, 0.51 mmol) and triethylamine (0.15 mL, 1.00 mmol) as the base. Prepared accordingly. After normal workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (67 mg, 61%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 2.86-2.90 (m, 2H, NCH ₂ ), 3.08-3.17 (m, 6H, NCH ₂ × 3), 3.76 (s , 3H, OCH ₃ ), 5.08 (d, J = 16.8 Hz, 1H, NC H HPh), 5.63 (d, J = 16.8 Hz, 1H, NCH H Ph), 6.64 (d, J = 1.8 Hz, 1H, ArH), 6.67 (d, J = 1.8 Hz, 1H, ArH), 6.75-6.80 (m, 2H, ArH), 7.03-7.09 (m, 2H, ArH), 7.33 (dd, J = 8.6, 1.6 Hz, ArH), 7.43-7.50 (m, 3H, ArH), 7.63-7.68 (m, 1H, ArH), 7.81-7.85 (m, 2H, ArH); mp 169-170 ° C; MS (EI) m / e 539 [M ^< ⁺ &^gt;], 509, 497; HRMS m / e cacld. for C ₃₂ H ₃₀ N ₃ O ₃ Cl 539.1976, found 539.1957.

Example  40: 7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -1-naphthalene-2- Methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 39 (50 mg, 0.094 mmol) and BBr ₃ (0.28 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (30 mg, 61%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.78 (s, 3H, CH ₃ ), 2.86-2.98 (m, 2H, NCH ₂ ), 3.10-3.27 (m, 6H, 3 × NCH ₂ ) , 5.11 (d, J = 16.8 Hz, 1H, NC H HPh), 5.63 (d, J = 16.8 Hz, 1H, NCH H Ph), 6.70-6.76 (m, 4H, ArH), 6.94-6.99 (m, 2H, ArH), 7.34-7.39 (m, 1H, ArH), 7.43-7.51 (m, 3H, ArH), 7.66-7.71 (m, 1H, ArH), 7.81-7.86 (m, 2H, ArH); decomp. 265 ° C .; HRMS m / e cacld. for C ₃₁ H ₂₈ N ₃ O ₃ Cl 525.1819, found 525.1794.

Example  41: 1-biphenyl-4-ylmethyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 9 , using a pyridine solution (5 mL) of intermediate III- 19 (0.23 g, 0.45 mmol) and piperazine (0.1 g, 1.1 mmol). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a yellow solid (0.15 g, 60%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.78 (s, 3H, CH ₃ ), 2.90-2.93 (m, 3H, NCH ₂ , NC H H), 3.13-3.22 (m, 5H, 2 × NCH ₂ , NC H H, NH), 3.74 (s, 3H), 5.06 (d, J = 16.0 Hz, 1H, NC H HPh), 5.44 (d, J = 16.0 Hz, 1H, NCH H Ph), 6.68 (m, 2H, ArH), 6.73-6.78 (m, 2H, ArH), 7.01-7.06 (m, 2H, ArH), 7.25-7.29 (m, 2H, ArH), 7.34-7.59 (m, 7H, ArH); mp 142-144 ° C; MS (EI) m / e 565 [M ⁺ ], 548, 523; HRMS m / e cacld. for C ₃₄ H ₃₂ N ₃ O ₃ Cl 565.2132, found 565.2136.

Example  42: 1- Biphenyl -4- Methyl -7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 41 (70 mg, 0.12 mmol) and BBr ₃ (0.37 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (35 mg, 53%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.78 (s, 3H, CH ₃ ), 2.86-2.95 (m, 2H, NCH ₂ ), 3.12-3.21 (m, 5H, 2 × NCH ₂ , NC H H), 3.35-3.38 (m, 1H, NC H H), 5.12 (d, J = 16.2 Hz, 1H, NC H HPh), 5.43 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.69-6.73 (m, 2H, ArH) 6.92-6.98 (m, 2H, ArH), 7.26-7.30 (m, 2H, ArH), 7.34-7.48 (m, 4H, ArH), 7.55-7.61 (m, 5H , ArH); mp 240-241 ° C .; MS (EI) m / e 551 [M ⁺ ], 521, 509; HRMS m / e cacld. for C ₃₃ H ₃₀ N ₃ O ₃ Cl 551.1976, found 551.1963.

Example  43: 1- (1 H- Benzoimidazole -2- Methyl ) -7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III- 20 (1.00 g, 2.08 mmol), Piperazine (0.54 g, 6.24 mmol) and K ₂ CO ₃ (0.86 g, 6.24 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.80 g, 73%).

¹ H NMR (200MHz, CD ₃ OD) δ 1.78 (s, 3H, CH ₃ ), 2.83-2.89 (m, 2H, NCH ₂ ), 3.03-3.15 (m, 6H, 3 x NCH ₂ ), 3.72 (s, 3H, OCH ₃ ), 5.27 (d, J = 16.4 Hz, 1H, NC H HPh), 5.87 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.77-6.83 (m, 3H, ArH), 6.98-7.09 (m, 3H, ArH), 7.22-7.27 (m, 2H, ArH), 7.50-7.58 (m, 2H, ArH); mp 178-179 캜; MS (EI) m / e 529 [M ⁺ ], 495, 465, 439; HRMS m / e cacld. for C ₂₉ H ₂₈ N ₅ O ₃ Cl 529.1881, found 529.1875.

Example  44: 7- Chloro -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1-quinoline-2- Ilme Teal-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III- 21 (1.00 g, 2.03 mmol), Piperazine (0.52 g, 6.10 mmol) and K ₂ CO ₃ (0.84 g, 6.10 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.87 g, 79%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.85 (s, 3H, CH 3), 2.78-2.86 (m, 2H, NCH ₂ ), 2.99-3.07 (m, 6H, 3 × NCH ₂ ), 3.77 (s, 3H, OCH ₃ ), 5.21 (d, J = 16.4 Hz, 1H, NC H HPh), 5.82 (d, J = 16.4 Hz, 1H, NCH H Ph), 6.63 (d, J = 1.8 Hz, 1H, ArH ), 6.77-6.83 (m, 2H, ArH), 6.94 (d, J = 1.8 Hz, 1H, ArH), 7.23-7.29 (m, 2H, ArH), 7.38 (d, J = 8.4 Hz, 1H, ArH) ), 7.52-7.60 (m, 1H, ArH), 7.70-7.85 (m, 2H, ArH), 8.06-8.18 (m, 2H, ArH); mp 200-201 ° C; MS (EI) m / e 540 [M ⁺ ], 523, 510, 498, 484, 464; HRMS m / e cacld. for C ₃₁ H ₂₉ N ₄ O ₃ Cl 540.1928, found 540.1930.

Example  45: 7- Chloro -3- (4-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1-quinolin-2-ylmethyl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 44 (1.00 g, 1.85 mmol) and BBr ₃ (5.54 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (0.83 g, 85%).

¹ H NMR (200 MHz, CD ₃ OD) δ 1.78 (s, 3H, CH ₃ ), 2.83-2.92 (m, 2H, NCH ₂ ), 3.11-3.19 (m, 6H, 3 × NCH ₂ ), 5.37 ( d, J = 17.2 Hz, 1H, NC H HPh), 5.74 (d, J = 17.2 Hz, 1H, NCH H Ph), 6.69-6.78 (m, 2H, ArH), 6.87 (dd, J = 9.5, 1.8 Hz, 1H, ArH), 7.04 (d, J = 1.8 Hz, 1H, ArH), 7.20-7.26 (m, 2H, ArH), 7.47-7.63 (m, 2H, ArH), 7.72 (td, J = 7.3 , 1.8 Hz, 1H, ArH), 7.95 (t, J = 8.4 Hz, 2H, ArH), 7.38 (d, J = 8.4 Hz, 1H, ArH); mp 278-279 ° C; MS (EI) m / e 526 [M ⁺ ], 510, 497.

Example  46: 7- Chloro -1-ethyl-3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared in the same manner as in Example 5 using Intermediate III- 22 (0.14 g, 0.37 mmol), Piperazine (80 mg, 0.93 mmol) and Triethylamine (0.3 mL, 1.9 mmol) as the base. Prepared accordingly. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (90 mg, 56%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.32 (t, J = 6.8 Hz, 3H, CH ₂ C H ₃ ), 1.73 (s, 3H, CH ₃ ), 2.22 (br s, 1H, NH), 2.80 2.88 (m, 2H, NCH ₂ ), 3.04-3.11 (m, 6H, 3 x NCH ₂ ), 3.73 (s, 3H, OCH ₃ ), 3.90-4.00 (m, 1H, NC H HMe), 4.21- 4.31 (m, 1H, NCH H Me), 6.65-6.68 (m, 2H, ArH), 6.72-6.77 (m, 2H, ArH), 6.98-7.02 (m, 2H, ArH); mp 127-129 캜; MS (EI) m / e 427 [M ^< ⁺ &^gt;], 397, 385; HRMS m / e cacld. for C ₂₃ H ₂₆ N ₃ O ₃ Cl 427.1663, found 427.1667.

Example  47: 5-Chloro-1-ethyl-3- (4-hydroxy-phenyl) -3-methyl-7-piperazin-1-yl-1 H Preparation of -quinoline-2,4-dione

The title compound was prepared according to the same method as in Example 2 , using Example 46 (0.09 g, 0.25 mmol) and BBr ₃ (0.74 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to give the pure title compound as a pale yellow solid (0.06 g, 68%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.14 (t, 3H, J = 6.8 Hz, CH ₂ C H ₃ ), 1.50 (s, 3H, CH ₃ ), 2.68-2.79 (m, 2H , NCH ₂ ), 2.99-3.10 (m, 6H, 3 x NCH ₂ ), 3.71-3.82 (m, 1H, NC H HCH ₃ ), 6.47-6.60 (m, 4H, ArH), 6.67-6.71 (m, 2H, ArH); mp 290-292 ° C MS (EI) m / e 413 [M ⁺ ], 383, 371 HRMS m / e cacld. for C ₂₂ H ₂₄ N ₃ O ₃ Cl 413.1506, found 413.1507.

Example  48: 7- Chloro -One- Cyclohexylmethyl -3- (4- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared in the same manner as in Example 5 , using Intermediate III- 23 (0.18 g, 0.40 mmol), piperazine (90 mg, 1.00 mmol) and triethylamine (0.30 mL, 2.00 mmol) as the base. Prepared accordingly. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.13 g, 65%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.01-1.25 (m, 5H, cyclohexyl), 1.53-1.71 (m, 5H, CH ₃ , cyclohexyl), 2.03-2.09 (m, 4H, cyclohexyl), 2.83-2.89 (m, 2H, NCH ₂ ), 3.08-3.10 (m, 6H, 3 x NCH ₂ ), 3.67-3.77 (m, 4H, OCH ₃ & NC H H -cyclohexyl), 4.06-4.18 (m , 1H, NCH H -cyclohexyl), 6.66 (br s, 2H, ArH), 6.70-6.75 (m, 2H, ArH), 6.96-7.00 (m, 2H, ArH); mp 127-128 ° C; MS (EI) m / e 495 [M ⁺ ], 465, 453; HRMS m / e cacld. for C ₂₈ H ₃₄ N ₃ O ₃ Cl 495.2289, found 495.2284.

Example  49: 7- Chloro -One- Cyclohexylmethyl -3- (4- Hydroxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 48 (128 mg, 0.26 mmol) and BBr ₃ (0.77 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (98 mg, 75%).

¹ H NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ 1.07-1.26 (m, 6H, cyclohexyl), 1.58-1.70 (m, 8H, cyclohexyl, CH ₃ ), 2.85-2.93 (m, 2H, NCH ₂ ), 3.13-3.20 (m, 6H, 3 x NCH ₂ ), 3.67-3.77 (m, 1H, NC H H -cyclohexyl), 4.08-4.19 (m, 1H, NCH H -cyclohexyl), 6.63 6.71 (m, 4H, ArH), 6.85-6.90 (m, 2H, ArH); mp 175-176 ° C; MS (EI) m / e 481 [M ⁺ ], 451, 439; HRMS m / e cacld. for C ₂₇ H ₃₂ N ₃ O ₃ Cl 481.2232, found 481.2137.

Example  50: 1-benzyl-7- Chloro -3- (3- Methoxy - Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 5 , using Intermediate III- 24 (0.47 g, 1.10 mmol), Piperazine (0.28 g, 3.22 mmol) and K ₂ CO ₃ (0.76 g, 5.50 mmol). Prepared. After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give the pure title compound as a pale yellow solid (0.39 g, 72%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 2.80-2.90 (m, 2H, NCH ₂ ), 2.99-3.17 (m, 6H, 3 × NCH ₂ ), 3.68 (s , 3H, OCH ₃ ), 5.02 (d, J = 17.4 Hz, 1H, NC H HPh), 5.41 (d, J = 17.4 Hz, 1H, NCH H Ph), 6.61 (d, J = 1.4 Hz, 1H, ArH), 6.66-6.68 (m, 3H, ArH), 6.72-6.78 (m, 2H, ArH), 7.11-7.33 (m, 6H, ArH); mp 110-112 ° C; MS (EI) m / e 489 [M ⁺ ], 459, 447; HRMS m / e cacld. for C ₂₈ H ₂₈ N ₃ O ₃ Cl 489.1819, found 489.1831.

Example  51: 1-benzyl-7- Chloro -3- (3-hydroxy- Phenyl ) -3- methyl -5-piperazin-1-yl-1 H- Preparation of Quinoline-2,4-Dione

The title compound was prepared according to the same method as in Example 2 , using Example 50 (0.27 g, 0.55 mmol) and BBr ₃ (1.60 mmol, in 1M dichloromethane). After usual workup, the crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 5: 1) to afford the pure title compound as a pale yellow solid (0.20 g, 77%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79 (s, 3H, CH ₃ ), 2.80-2.84 (m, 2H, NCH ₂ ), 3.02 (m, 6H, 3 × NCH ₂ ), 5.08 (d, J = 16.2 Hz, 1H, NC H HPh), 5.39 (d, J = 16.2 Hz, 1H, NCH H Ph), 6.60-6.69 (m, 4H, ArH), 7.04-7.12 (dd, J = 8.2 Hz, 8.1 Hz, 1H, ArH), 7.21-7.35 (m, 6H, ArH); mp 238-240 ° C MS (EI) m / e 475 [M ⁺ ], 91, 56; HRMS m / e cacld. for C ₂₇ H ₂₆ N ₃ O ₃ Cl 475.1663, found 475.1665.

The structural formulas of the compounds prepared in the above examples are shown in Table 1 below.

Experimental Example  1: 5- of the compound of the present invention HT6  Binding force to receptor

1-1: Human Serotonin 5- HT6  Expression of receptors

In order to measure the binding capacity of the compound of the present invention to the 5-HT6 receptor, human serotonin 5-HT6 receptor protein was expressed in insect-derived cells as follows.

Human 5-HT6 cDNA was cloned from the human brain cDNA library by PCR amplification using 5'-TCATCTGCTTTCCCGCCACCCTAT-3 'and 5'-TCAGGGTCTGGGTTCTGCTCAATC-3' as forward and reverse primers, respectively (Clontech, Palo Alto, USA ). Amplified cDNA fragments were introduced into the pGEMT easy vector (Promega, Madison, USA). DNA sequencing was performed to confirm receptor DNA sequences. After subcloning the serotonin 5-HT6 clone into the insect cell expression vector BacPAK8 (Clontech), the pBacPAK8 / 5-HT6 was eukaryotically transformed into insect Sf 21 cells (Clontech) and subjected to 5-HT6 through SDS PAGE and receptor binding assays. Receptor protein expression was confirmed. Cell disintegration was performed at 4 ° C. for 2 minutes by ultrasound, followed by centrifugation at 3000 × g for 10 minutes to remove cell debris. Membrane fractions were partially purified from the supernatant by centrifugation for 1 hour at 100,000 × g.

1-2: Replicated 5- of the compound of the present invention HT6  Binding force to receptor

Using the cloned 5-HT6 receptor prepared in Experimental Example 1-1, 5-HT6 receptor binding affinity of the compounds of the present invention was measured as follows.

[ ³ H] LSD (lysergic acid diethylamide) binding assays were performed in 96-well plates. For drug screening, compounds of the invention, replicated receptor membranes (9 μg / well), 50 mM Tris-HCl buffer (pH 7.4) including [ ³ H] LSD 1.87 nM, 10 mM MgCl ₂ and 0.5 mM EDTA, and the like. To this was added 0.25 ml of the final volume of the reaction mixture, which was incubated at 37 ° C. for 60 minutes. For drug screening, the compounds of the present invention were incubated as above in a reaction mixture comprising 1.87 nM of [ ³ H] LSD. After incubation, the reaction was terminated by rapid filtration through a Welllac GF / C glass fiber filter (Wallac, Finland) pre-soaked in 0.5% PEI using an Inotech harvester (Inotech). Washed with HCl buffer. The filter was covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). Compounds of the present invention at 7 to 8 levels were prepared to perform competitive binding studies in two test tubes, and the isotherms of three replicates were calculated by nonlinear regression analysis by computer (GraphPad Prism Program, San Diego). , USA), IC ₅₀ (inhibitory concentration) values were calculated. Nonspecific binding was measured in the presence of 10 μM Methiothepin. All compounds used in the test for binding analysis were dissolved in DMSO and diluted to various concentrations.

The results are shown in Table 2.

Binding Affinity to 5-HT6 Receptors of Compounds of the Invention Example IC ₅₀  (nM) Example IC ₅₀  (nM) One 1.9 25 6.2 2 2.5 26 8.7 3 4.7 27 2.3 4 7.4 28 3.0 5 37.8 29 34.2 6 3.4 30 15.9 7 16.6 31 26.5 8 23.8 32 1.7 9 5.2 33 1.8 10 6.2 34 3.6 11 1.4 35 9.2 12 9.2 36 29.0 13 0.9 37 21.4 13-1 1.4 38 30.6 13-2 9.0 39 4.7 14 1.0 40 55.7 14-1 1.9 41 351.2 14-2 13.3 42 163.7 15 12.1 43 136.7 16 3.2 44 6.9 17 41.5 45 11.4 18 14.6 46 49.1 19 2.3 47 151.4 20 1.9 48 250.9 21 6.9 49 11.7 22 2.7 50 1.8 23 2.7 51 6.2 24 14.5

As shown in Table 2, most of the compounds prepared in Examples 1 to 51 of the present invention showed a good binding affinity for the 5-HT6 receptor of [ ³ H] LSD. In particular, Examples 1, 11, 13, 13-1, 14, 14-1, 20, 32, 33 and 50 showed very good effects.

Experimental Example  2: radioactive marker Ligand  5- of the compound of the present invention used HT6  Investigation of selectivity for receptor

In Experimental Example 1, the following experiment was performed to determine whether the compound exhibiting excellent affinity for the 5-HT6 receptor exhibits selectivity for the 5-HT6 receptor compared to other 5-HT and dopamine receptors.

2-1: 5-HT Receptor To family  For binding analysis

Binding assays for the 5-HT receptor family were carried out with a radioligand binding probe according to the test method provided by the supplier of the receptor membrane (Euroscreen / BioSignal Packard Inc.).

Detailed analysis conditions are shown in Table 3 below, and the results are shown in Table 4 below.

Analysis condition 5- HT _1a 5- HT _2a 5- HT _2c 5- HT ₇ origin Stable CHO-K1 Cell Line Expressing Human Recombinant Receptor (Euroscreen / BioSignal) Binding buffer 50 mM Tris-HCl pH 7.4 10 mM MgSO ₄ 0.5 mM EDTA 0.1% Ascorbic Acid 50 mM Tris-HCl, pH 7.4 50 mM Tris-HCl (pH 7.7) 0.1% Ascorbic Acid 10 μM Pargiline (Pargyline) 50 mM Tris-HCl (pH 7.4) 10 mM MgSO ₄ 0.5 mM EDTA Final volume 250 μl 250 μl 250 μl 250 μl Film contents 40 ㎍ 15 μg 4 μg 10 μg Radioligand [ ³ H] 8-OH-DPAT 0.5 nM ^[3 H] Ketanserin 1 nM [ ³ H] Mesulergine 1 nM [ ³ H] LSD 3 nM Nonspecific binding Methiotepine 0.5 μM Mianserin 1 μM Methiotepine 10 μM  Methiotepine 10 μM culture 27 ℃, 60 min 37 ℃, 15 min 37 ℃, 30 min 27 ℃, 120 min percolation GF / C, 0.3% PEI GF / C, 0.05% Brij GF / C, 1% BSA GF / C, 0.3% PEI

2-2: dopamine receptor To family  For binding analysis

Binding assays for the dopamine receptor family were performed by radioligand binding assays according to the test methods provided by the supplier of receptor proteins (BioSignal Packard Inc., Montreal, Canada). As the radioligand ^[3 H] RY Peron (hD _2L and hD ₃ receptors, 1 nM) and ^{[3 H] YM-09151-2 (} hD 4 .2 receptor, 0.06 nM) was used. In short, D ₂ and D ₃ The buffers used for receptor binding assays were 50 mM Tris-HCl (pH 7.4), 10 mM MgCl ₂ , 1 mM EDTA, or 50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ , 5 mM EDTA, 5 mM KCl, 1.5 mM CaCl ₂ , 120 mM NaCl. In the [ ³ H] YM-09151-2 receptor binding assay, 50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ , 5 mM EDTA, 5 mM KCl and 1.5 mM CaCl ₂ were used as buffers. For nonspecific binding assays, haloperidol (10 μM) was used for D ₂ and D ₃ and clozapine (clozapine, 10 μM) was used for D ₄ receptor, respectively.

The compound of the present invention was prepared at a concentration of 7 to 8 steps to perform competitive binding irradiation in a double test tube, and isotherms obtained from three replicates were calculated by nonlinear regression analysis by a computer (GraphPad Prism Program, San Diego). , Canada), IC ₅₀ (inhibitory concentration) values were obtained.

Selectivity results for other serotonin receptor subtypes and dopamine receptors of the compounds of the present invention are shown in Table 4 .

Binding Affinity to Other Serotonin Receptor Subtypes and Dopamine Receptors of Compounds of the Invention Example Binding affinity, IC ₅₀   (nM) 5- HT6 5- HT7 5- HT1a 5- HT2a 5- HT2c D _One D ₂ D ₃ D ₄ One 1.9 7486 4411 1120 > 10000 174 > 10000 2277 8017 2 2.5 920 > 10000 2621 487 4971 > 10000 589 > 10000 3 4.7 4568 5728 1544 > 10000 814 > 10000 360 > 10000 4 15.0 5046 5801 7011 5780 7089 6546 8115 8190 5 16.8 7615 6451 7540 4657 7701 7054 7084 8745 6 3.4 > 1000 > 10000 > 1000 > 1000 > 1000 > 1000 981 > 10000 7 20.0 8456 6554 6538 9405 8456 7148 8967 9087 8 16.8 9445 7513 6947 8812 7040 7289 9015 9154 9 5.2 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 821 > 10000 10 6.2 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 5374 > 10000 11 1.4 2205 2594 1232 514 4668 844 678 > 10000 12 9.2 136 2516 95 1287 1239 6446 153 > 10000 13 0.9 9003 1363 543 437 3586 > 10000 345 > 10000 13-1 1.4 5845 5433 2505 7742 6153 > 10000 8933 > 10000 13-2 9.0 9525 3280 2841 9741 5214 > 10000 2575 > 10000 14 1.0 3575 > 10000 2144 > 10000 6821 > 10000 1504 > 10000 14-1 1.9 9864 7953 2003 > 10000 7065 > 10000 7648 > 10000 14-2 13.3 9236 5894 6377 > 10000 1545 > 10000 1757 > 10000 15 15.2 9512 6345 8125 9954 5805 6659 9744 9456 16 17.6 9351 6023 8083 9876 9012 6740 9065 8906 17 21.5 > 10000 8546 7549 9812 8415 9047 8197 9115 18 15.5 6008 8045 7013 8450 > 10000 > 1000 8900 8990 19 15.3 7573 6548 9105 6914 7045 8451 9143 8091 20 18.2 6841 6357 5705 > 10000 8544 8253 9378 8987 21 6.9 3338 468 553 1808 1617 1641 1048 5871 22 2.3 5066 3910 2895 1832 5139 2454 1811 > 10000 23 16.7 8455 9012 6480 8405 7640 6931 9651 9091 24 14.5 > 10000 > 10000 5041 6085 4933 3001 2330 > 10000 25 15.9 8051 5894 6612 7603 6520 7650 9660 9753 26 19.0 5634 5900 5746 7334 6951 8415 9120 9412 27 2.3 > 1000 > 10000 > 1000 > 1000 > 1000 > 1000 2636 > 10000 28 3.0 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 1000 > 10000 29 15.0 7500 7581 9154 8045 7812 9170 9413 9003 30 18.1 7345 7236 8405 9450 8004 7653 9784 8760 31 21.3 8439 6952 8336 7946 7545 6431 8945 8707 32 15.2 8312 6584 7450 7891 9013 6956 9107 9451 33 1.8 > 10000 > 1000 > 1000 > 1000 > 1000 > 1000 > 1000 > 10000 34 16.8 9066 7546 6960 7031 9158 8045 8999 9354 35 16.4 7819 9512 7640 7716 9754 7149 9450 8884 36 15.1 > 10000 9324 6213 7164 6031 7987 9611 9000 37 19.8 5994 9056 6015 8045 7680 8045 > 10000 9378 38 20.4 6412 8453 8405 9144 9410 7689 9310 9238 39 4.7 > 1000 > 10000 > 1000 > 1000 > 1000 > 1000 > 1000 > 10000 40 18.2 7814 7514 9475 8512 7508 8540 9308 8980 41 15.5 7010 7806 8467 8095 6004 7680 8997 9111 42 16.1 6732 6640 8195 7601 6120 6849 9207 9413 43 19.3 9522 8022 5801 7885 6355 9007 9438 9465 44 19.0 7654 7532 6105 7688 7651 > 1000 9840 9271 45 16.4 9451 > 10000 > 10000 > 1000 8407 7680 9165 8506 46 15.8 7950 6705 6356 9110 7894 8574 9408 9569 47 17.4 > 1000 9546 > 1000> 6405 > 10000 > 10000 8634 9144 > 10000 48 16.0 8520 7544 5906 8665 7650 7506 8987 9008 49 17.5 9513 6301 5812 7532 8142 > 10000 8679 8779 50 18.4 7643 > 1000 9154 7472 7743 7185 9756 9044 51 20.7 7580 8455 7550 8744 6389 8647 9884 9458 52 15.6 6139 5740 6185 8500 6770 7331 9901 9881 SB-271046 0.8 3498 313 4651 3963 9138 > 10000 4119 > 10000

As shown in Table 4 , the compounds of the present invention exhibited significantly lower IC ₅₀ values at the 5-HT6 receptor than at the other 5-HT receptors, resulting in a very high binding affinity for the 5-HT6 receptor as compared to the 5-HT receptors. Found to be high. In addition, the IC ₅₀ value was much lower at the 5-HT6 receptor than at the dopamine receptor family as other receptors, indicating a higher binding affinity for the 5-HT6 receptor than the dopamine receptor family.

Therefore, the compounds of the present invention was confirmed to have a high selectivity for 5-HT6 receptor.

Experimental Example  3: in vitro ( In vitro A) function research

Adenylyl cyclase in HeLa cells with eukaryotic transformation of human 5-HT6 receptors by known methods (Routledge C et al., 2000) modified using MDSPS (MDS Pharma Service PT # 318000). Activity was measured.

Detailed analysis conditions are shown in Table 5. The assay mixture consisted of Hanks' balanced salt solution (HBSS), pH 7.4, 1 mM MgCl ₂ , 1 mM CaCl ₂ , 100 mM 1-methyl-3-isobutylxanthine (IBMX). Incubation was started by addition of the enzyme protein suspension and the compound of the present invention. After culturing at 37 ° C. for 20 minutes, the intracellular cAMP concentration was measured by EIA (enzyme-immunoassay) to classify a compound that inhibits serotonin (5-HT) -induced cAMP increase by 50% or more as an antagonist. At this time, methiothepin, known as an antagonist of 5-HT6, was used as a comparison group.

Analysis condition Target Human HeLa cells Carrier 0.4% DMSO Incubation time and temperature 20 minutes, 37 ℃ Culture buffer HBSS (pH. 7.4), 1 mM MgCl ₂ , 1 mM CaCl ₂ , 100 mM IBMX Quantitative Method EIA quantification of cAMP storage Standard as an antagonist CAMP increase by ≥ 50% serotonin (0.3 μM) inhibition Standard as agonist ≥ 50% increase in cAMP against serotonin

The results are shown in FIG.

As shown in FIG. 1, 5-HT concentration-dependent cAMP levels increased to EC ₅₀ = 8.7 nM and the increase in cAMP was inhibited by Example 13, Example 14 or 5-HT6 antagonist methiotepine. In particular, Example 14 at concentrations of 0.001, 0.01, 0.1, 1 and 10 μM inhibited 0.3 μM serotonin (5-HT) -induced increase in cAMP levels to 10, 22, 81, 100 and 100% at each concentration, IC ₅₀ was 28.7 nM and IC ₅₀ was 60.9 nM. Thus, it showed significant antagonist activity, and Examples 13 and 14 also showed no cytotoxicity at experimental concentrations for HeLa cells transformed with human 5-HT6 receptor.

Experimental Example  4: the compound of the present invention In the rat Metamphetamine -Judo Electrode  Effect on the destruction of prepulse inhibition (in vivo ) Measure

 In order to confirm whether the compound of the present invention has antipsychotic properties, an electrode suppression experiment using a rat was performed as follows.

Surprise response was measured using an SR-LAB surprise chamber (San Diego Instruments, San Diego, USA).

The experimental animals consist of a Plexiglas cylinder with a flat bottom diameter of 40 mm and is ventilated, connected to a piezoelectric accelerometer (vibration sensor) that detects and converts behavior within the cylinder. A low noise surprise of ambient noise levels was put into the chamber. Acoustic noise burst was generated through a loudspeaker placed 24 cm above the animal.

Behavioral testing was performed by modified Mansbach et al. [Mansbach RS, Brooks EW, Sanner MA, Zorn SH, Selective dopamine D ₄ receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition., Psychopharmacology ( Berl ) , 135: 194-200, 1998 ] Between 10 am and 5 pm during bright conditions. Each surprise period started with a 5 minute environmental acclimation period to adapt to the 68 dB fundamental noise of the chamber. A test period consisting of the following four different test types was performed for all experiments: 40 ms wideband 120 dB burst (P; vibration alone test), 20 ms noise burst (pP) 100 ms ahead of P. ; Full-vibration + vibration test), 40 ms wideband 78 dB burst (full-vibration alone test), and non-irritating test (basic). Eight trials of each type were conducted in pseudorandom order, for a total of 32 trials, with an average of 15 seconds between each trial. Five vibrational independent tests were further performed at the beginning and end of each test, but were not used to calculate PPI values. PPI was defined as the percentage reduction in the startle amplitude when the full vibration was performed as compared to when the full vibration was not performed using Equation 1 below.

PPI (%) = [100- (surprise size of 100 × pP test / surprise size of P test)]

Example 30 minutes before injecting metamphetamine (3 mg / kg, ip) to rats 13, 14, SB-271046 or the carrier was administered (ip) and placed in a surprise chamber 30 minutes after injecting metamphetamine for testing. Compounds of the invention (25 or 50 mg / kg, ip) or SB-271046 were used suspended in Tween 80 solution.

The statistical significance of the results was calculated by one-way ANOVA with Dunnett's post-hoc test for comparison of the control group. Deviations were considered at significance P <0.05. Statistical analysis was performed using SigmaState software (SigmaStat, Jandel Co., San Rafael, Calif.). Data are expressed as mean ± SEM.

The results are shown in FIGS. 2 and 3.

As shown in Figures 2 and 3, the administration of the compounds of the present invention alone did not show a significant effect on PPI compared to the case of administration of only the carrier to the rat as a negative control group. However, when pretreated with the compound of the present invention (P <0.05) and SB-271046 (P <0.05), destruction of PPI by methamphetamine (3 mg / kg, ip) was inhibited and showed antipsychotic activity. . In addition, compared with the administration of methamphetamine as a positive control group, significant difference in mean alarm size when the compounds of the present invention including S13-2 and SB-271046 were administered 30 minutes before methamphetamine administration There was no.

Experimental Example  5: the compound of the present invention Rotarod  defect( rotarod  deficit)

In order to evaluate the effects of the compounds of the present invention on the central nervous system and behavior, a rotarod test was conducted using mice as follows.

Place the mouse on a plastic rod with a 1-inch diameter node and rotate it at 6 rpm (Ugo-Basile, Milano, Italy), and drop it from the rod rotating within 1 minute at 60, 90 and 120 minutes after the test compound was injected. The number of individuals was counted (Dunham et al., 1957) to calculate the rotarod defect (%). The median neurotoxic dose (TD ₅₀ ) was determined to be 50% of the animals that exhibited a rotarod defect. The compounds prepared in the examples were used suspended in Tween 80 solution and administered 60 minutes before the test (po).

The results are shown in Table 6.

Effect of Compounds of the Invention on Rotarod Deletion in Mice Example number Rotarod deficiency (%) (mg / kg, p.o.) TD ₅₀ (mg / kg, po) 200 300 400 One 0 0 0 >> 400 2 0 0 0 >> 400 3 0 0 0 >> 400 6 0 0 0 >> 400 9 0 0 0 >> 400 10 0 0 0 >> 400 11 0 0 0 >> 400 12 0 0 0 >> 400 13 0 0 0 >> 400 13-1 0 0 0 >> 400 13-2 0 0 0 >> 400 14 0 0 0 >> 400 14-1 0 0 0 >> 400 14-2 0 0 0 >> 400 21 0 0 0 >> 400 22 0 0 0 >> 400 24 0 0 0 >> 400 27 0 0 0 >> 400 28 0 0 0 >> 400 33 0 0 0 >> 400 39 0 0 0 >> 400

As shown in Table 6, a single dose (po) of Example 13 or 14 did not show rotarod dysfunction at the dose of 400 mg / kg or less for 120 minutes after treatment. Thus, the TD ₅₀ of these compounds was calculated to be greater than 400 mg / kg (po) in each mouse, so that Example 13 or 14 showed a very low tendency to induce extraramidal side effects.

Examples of preparations for the compositions of the present invention are illustrated below.

Formulation example  1: Preparation of Pharmaceutical Formulations

1-1: Powder  Produce

2 g of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a prodrug thereof

1g lactose

The above ingredients were mixed and filled in airtight cloth to prepare a powder.

1-2: Preparation of Tablets

Compounds of the invention, pharmaceutically acceptable salts thereof or prodrugs thereof

                                                                100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

1-3: Preparation of Capsule

Compounds of the invention, pharmaceutically acceptable salts thereof or prodrugs thereof

                                                                100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

The N -substituted-1 H -quinoline-2,4-dione compound represented by the general formula (1) of the present invention has excellent binding ability to the serotonin 5-HT6 receptor, and excellent selectivity to the 5-HT6 receptor for other receptors. , Inhibits the increase of cAMP level by intracellular serotonin (5-HT) and inhibits hyperactivity of rats induced by methamphetamine (2 mg / kg, ip) as well as 400 mg / kg or less. It does not show rotarod dysfunction and can be usefully used in diseases of the central nervous system related to the 5-HT6 receptor.

Claims (13)

N -substituted-1 H -quinoline-2,4-dione compound of Formula 1 or a pharmaceutically acceptable salt thereof. <Formula 1>

(Wherein R ¹ and R ² are each independently hydrogen, halogen, nitro, amino, amino substituted by 1 to 2 alkyl, cyclic amino, carboxylic acid, thiol, cyano, alkyl, aryl, heteroaryl, alkoxy, aryl Oxy, acyloxy, acylamino, arylsulfonylamino, arylsulfonylureido, alkylthio, arylthio, alkylcarboxylate, arylcarboxylate, aralkylcarboxylate, alkylureido, arylureido, alkylamido Dino or arylamidino; R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen, amino, cyclic amino, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, piperidinyl or N-methyl piperidinyl; R ⁶ is alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl or heteroarylalkyl; R ⁷ is hydrogen, alkyl or aryl.) The method of claim 1, R ¹ and R ² are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, amino, amino, nitro or benzyloxy substituted with one or two C ₁ -C ₄ alkyl, R ³ , R ⁴ and R ⁵ are each independently hydrogen, a halogen element or C ₁ to C ₄ alkoxy, R ⁶ is C ₁ -C ₄ alkyl; C ₃ -C ₇ cycloalkyl C ₁ -C ₂ alkyl; Benzyl substituted with a substituent selected from the group consisting of hydrogen, nitro, amino, halogen or C ₁ -C ₄ alkoxyphenyl; Naphthalenylmethyl; Heteroaryl (C ₁ -C ₂ ) alkyl substituted with a substituent selected from the group consisting of pyridine, quinoline, benzimidazole, and R ⁷ is preferably hydrogen or C ₁ to C ₄ alkyl, wherein the N -substituted-1 H -quinoline-2,4-dione compound or a pharmaceutically acceptable salt thereof. The method of claim 2, R ¹ is hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, nitro or benzyloxy; R ² is hydrogen, fluorine, chlorine, bromine, iodine, methoxy, nitro, amino or benzyloxy; R ³ , R ⁴ and R ⁵ are each independently hydrogen, chlorine, bromine or methoxy; R ⁶ is methyl, ethyl, cyclohexylmethyl, benzyl, nitrobenzyl, aminobenzyl, methoxybenzyl, bromobenzyl, biphenylmethyl, naphthalenylmethyl, pyridinylmethyl, quinolinylmethyl or benzoimida Zolylmethyl; R ⁷ is hydrogen, methyl, ethyl N -substituted-1 H -quinoline-2,4-dione compound or a pharmaceutically acceptable salt thereof. 4. The compound of claim 3, wherein the N -substituted-1 H -quinoline-2,4-dione compound is (1) 1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones; (2) 1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones; (3) 1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -3- (4-nitro-phenyl) -1 H -quinoline-2,4- Diones; (4) 3- (4-amino-phenyl) -1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4-dione ; (5) 1-benzyl-7-chloro-3- (4-diethylamino-phenyl) -3-methyl-5- (4-methyl-piperazin- 1 -yl) -1H-quinoline-2,4- Diones; (6) 1-benzyl-7-chloro-3- (4-ethylamino-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline-2,4- Diones; (7) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1- (3-nitro-benzyl) -1 H -Quinoline-2,4-dione; (8) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1- (3-nitro-benzyl) -1 H -Quinoline-2,4-dione; (9) 1- (3-Amino-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H- Quinoline-2,4-dione; (10) 1- (3-Amino-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5- (4-methyl-piperazin-1-yl) -1 H- Quinoline-2,4-dione; (11) 1-benzyl-7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -3-phenyl-1 H -quinoline-2,4-dione; (12) 1-benzyl-3- (4-benzyloxy-3-bromo-phenyl) -7-chloro-3-methyl-5- (4-methyl-piperazin-1-yl) -1 H -quinoline -2,4-dione (13) 1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1 - yl-1 H- quinolin-2,4-dione (13-1) (S) -1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (13-2) (R) -1-benzyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (14) 1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (14-1) (S) -1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (14-2) (R) -1-benzyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (15) 1-benzyl-7-chloro-3-methyl-3- (4-nitro-phenyl) -5-piperazin-1-yl-1 H -quinoline-2,4-dione; (16) 3- (4-amino-phenyl) -1-benzyl-7-chloro-3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (17) 1-benzyl-7-chloro-3- (4-diethylamino-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (18) 1-benzyl-7-chloro-3- (4-ethylamino-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (19) 1-benzyl-7-chloro-3- (4-chloro-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (20) 1-benzyl-3- (4-bromo-phenyl) -7-chloro-3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (21) 1-benzyl-7-chloro-3- (4-iodo-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (22) 1-benzyl-7-chloro-3-methyl-3-phenyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (23) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (24) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-1- (3-nitro-benzyl) -5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (25) 1- (3-amino-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (26) 1- (3-amino-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (27) 7-chloro-1- (3-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (28) 7-chloro-1- (3-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (29) 7-Chloro-1- (2-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (30) 7-chloro-1- (2-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (31) 7-chloro-1- (4-methoxy-benzyl) -3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (32) 7-chloro-1- (4-hydroxy-benzyl) -3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (33) 1- (3-Bromo-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (34) 1- (3-Bromo-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (35) 1- (2-Bromo-benzyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (36) 1- (2-Bromo-benzyl) -7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4 -Dione; (37) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1-pyridin-3-ylmethyl-1 H -quinoline-2,4-dione ; (38) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1-pyridin-3-ylmethyl-1 H -quinoline-2,4-dione ; (39) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-1-naphthalen-2-ylmethyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione ; (40) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-1-naphthalen-2-ylmethyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione ; (41) 1-biphenyl-4-ylmethyl-7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (42) 1-biphenyl-4-ylmethyl-7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4- Diones; (43) 1- (1H-benzoimidazol-2-ylmethyl) -7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline -2,4-dione; (44) 7-chloro-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1-quinolin-2-ylmethyl-1 H -quinoline-2,4-dione ; (45) 7-chloro-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1-quinolin-2-ylmethyl-1 H -quinoline-2,4-dione ; (46) 7-chloro-1-ethyl-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (47) 5-chloro-1-ethyl-3- (4-hydroxy-phenyl) -3-methyl-7-piperazin-1-yl-1 H -quinoline-2,4-dione; (48) 7-chloro-1-cyclohexylmethyl-3- (4-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (49) 7-chloro-1-cyclohexylmethyl-3- (4-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; (50) 1-benzyl-7-chloro-3- (3-methoxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione; And (51) 1-benzyl-7-chloro-3- (3-hydroxy-phenyl) -3-methyl-5-piperazin-1-yl-1 H -quinoline-2,4-dione N -substituted-1 H -quinoline-2,4-dione compound or a pharmaceutically acceptable salt thereof. As shown in Scheme 1, (a) obtaining Intermediate I from the condensation reaction of Compound 2 and Compound 3 below; (b) cyclizing the intermediate I in the presence of a base to obtain an intermediate II ; (c) substituting N (1) of the intermediate II in the presence of an electrophilic group and a base to obtain an intermediate III ; And (d) obtaining an N-substituted-1H-quinoline-2,4-dione compound represented by Chemical Formula 1 by reaction of the intermediate III and the amine; Method for producing an N -substituted -1 H -quinoline-2,4-dione compound comprising a. <Scheme 1>

(In the above reaction formula, R ¹ ~ R ⁷ are as defined in formula 1, R is methyl, ethyl, or propyl group, Z is a halogen element, fluorine, chlorine, bromine, iodine element, X is chlorine, bromine , Iodine, o -methylsulfonyl or o -toluenesulfonyl.) 6. The compound of claim 5, further, wherein when the R ^1- , R ² -or R ⁶ -substituent of the compound of formula 1 is methoxy (OMe), the methoxy is hydroxy in the presence of boron tribromide. A process for preparing an N -substituted-1 H -quinoline-2,4-dione compound, characterized in that it is modified with (OH). 6. The method of claim 5, further, wherein when the R ^1- , R ² -or R ⁶ -substituent of the compound of formula 1 is nitro (NO ₂ ), the nitro is an amino group in the presence of tin (II) dihydrate A process for producing an N -substituted-1 H -quinoline-2,4-dione compound, characterized in that it is modified. 8. The N -substituted-I H according to claim 7, wherein the amino group is reductively modified to mono- or di-alkylamino in the presence of sodium cyanoborohydride and formaldehyde or acetaldehyde. Method for preparing quinoline-2,4-dione compound. The method of claim 5, wherein the condensation reaction is Reacting compound 2 with a chloride such as SOCl ₂ , (COCl) ₂ , PCl ₅ or BOP-Cl (bis (2-oxo-diazolindinyl) phosphinic chloride) in an inert solvent to form an acid chloride; And A method for preparing an N -substituted- 1H -quinoline-2,4-dione compound, comprising the step of mixing the acid chloride and compound 3 of Compound 2 in an inert solvent and warming to condense. Process for producing a quinoline-compound-substituted -1 H-according to claim 5, N, characterized in that the amine is N- methyl-piperazine or piperazine. A pharmaceutical composition for 5-HT6 serotonin receptor antagonist comprising the compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient. A pharmaceutical composition for treating central nervous system disease, comprising the compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient. The method of claim 12, wherein the central nervous system disorders are cognitive impairment, Alzheimer's disease, anxiety, depression, schizophrenia, stress disorder, panic disorder, phobia, obsessive compulsive disorder, post-traumatic stress disorder, reduced immune system function, psychosis, schizophrenia, Pharmaceutical composition, characterized by mania, cramps, personality disorders, migraines, drug addiction, alcoholism, obesity, eating disorders or sleep disorders.

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