KR100878443B1 - OPG secretagogues for preventing and treating of metabolic bone diseases - Google Patents

Abstract

The present invention relates to a novel quinoline ester derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof, or a solvate thereof, a preparation method thereof, and a prophylactic and therapeutic agent for metabolic bone disease containing the same as an active ingredient. The novel quinoline ester derivative according to the present invention promotes the amount of OPG secreted from osteoblasts and inhibits the differentiation of osteoclasts, and thus can be usefully used as a preventive and therapeutic agent for diseases such as osteoporosis and osteoarthritis, which are metabolic bone diseases. Since the expression level of OPG can be controlled, it has the advantage of controlling the OPG concentration in the blood by stopping the administration of the overexpression of OPG, and furthermore, because the quinoline ester derivative of the present invention starts from a low-molecular substance that is easy to synthesize Low cost, easy quality control, high stability, and oral administration It has the advantage of no problem even in long-term administration due to its low toxicity.

<Formula 1>

Wherein X, Z and R are as defined in the specification.

Quinoline esters, metabolic bone disease, OPG, osteoblasts, osteoclasts

Description

OPG secretagogues for preventing and treating of metabolic bone diseases

The present invention relates to a novel quinoline ester derivative or a pharmaceutically acceptable salt thereof or a solvate thereof, a preparation method thereof, and a prophylactic and therapeutic agent for metabolic bone disease containing the same as an active ingredient.

Osteoporosis, the most common metabolic bone disease, is a disease in which bones are formed in the bones as proteins, calcium and phosphorus in the bones escape, and bones become like windy radish and can be easily fractured even in light impact. This is because calcium, which determines the physical strength of bone tissue, is reduced due to genetic factors, nutrition, hormone changes, exercise, lifestyle, etc. for a wide range of bone marrow cavity, resulting in fractures even under a mild impact. This is a symptom that significantly reduces the quality of life. In particular, in women, bone density continues to decrease after the age of 30 years, and at the end of menopause, the hormone estrogen decreases rapidly, resulting in the production of large amounts of B-lymphocytes, as in the case of interleukin-7, and the accumulation of B cell precursors in the bone marrow. The amount of interleukin-6 is increased to increase the activity of osteoclasts, thereby reducing bone mineral density.

Osteoporosis does not affect both young and old, but especially in postmenopausal women. Recently, as osteoporosis patients are increasing exponentially due to the aging of the world, there is a need for the development of drugs effective for the prevention and treatment of osteoporosis. The growing population of older people in the world and the growing interest in improving quality of life are increasing the market for osteoporosis drugs. According to a World Health Organization (WHO) survey, in the United States, 30% of women postmenopausal have osteoporosis and 54% report osteopenia. In the United States, about 26 million people are at risk of fractures from osteoporosis. These osteoporosis patients are expected to grow about 2% annually, with 27% of women aged 65 and older and 21% of Danish women aged 70 and older likely to have vertebral fractures. According to a recent report by WHO and NIH, research and development on senile diseases are urgently needed since the medical development in the 21st century will account for about 25% of the total population. In the case of osteoporosis, treatment was not performed until a fatal etiology such as buttocks and vertebral fractures was discovered. However, the development of bone mineral density (BMD) measuring devices has increased the number of medical treatments, and thus the need for prevention and treatment of osteoporosis with new functions. Is increasing.

The widely used therapeutic agents for osteoporosis are classified as inhibitors of bone absorption and accelerators of bone production. The bone resorption inhibitor is a therapeutic agent for regulating the formation and activity of osteoclasts, estrogen, selective Estrogen Receptor Modulators (SERMs) therapy, bisphosphonates, calcitonin therapy and the like, fluoride as a bone formation promoter First, there is parathyroid hormone (PTH).

Other classifications include hormones such as estrogen, calcitonin, and parathyroid hormones, and non-hormonal agents such as fluorides and bisphosphonates.

Bisphosphonate formulations that account for the largest portion of the osteoporosis therapeutic market include etidronate, pamidronate, alendronate (Merck), risedronate (Hoffman Laroxa), zoleronate (Novatis, EP Patent No. 275821) Ibandronate (Hoffman Laroxa, U.S. Patent No. 4942157), Minodronate (YM-529, European Patent No. 354806), etc. are commercially available or in clinical trials. Side effects such as esophagitis, esophageal perforation, etc., should be taken when taken, and have the disadvantage of low body absorption.

Hormone preparations include Raloxifene (Eli Lilly), Droloxifene (Pfizer, EP Patent No. 54168), Lasopoxifen (Pfizer, WO / 97/16434), FC-1271 (No. Morse Medical Orion, WO / 96/07402), TSE-424 (Ligand American Home products, U.S. Patent No. 5948775) are commercially available or in clinical trials. This hormonal preparation has side effects that increase the risk of developing vaginal secretion, breast and uterine cancer.

In addition, vitamin D formulations are expensive and ineffective, calcitonin formulations are expensive and difficult to administer, and calcium formulations have fewer side effects but are limited to prevention rather than treatment of osteoporosis.

In addition, integrin receptor antagonists for preventing osteoclasts from attaching to bone are disclosed in WO / 98/18401 (Merck) and WO / 99/06049 (SmithKline Beecham); Cathepsin inhibitors for inhibiting bone absorption include WO / 98/05336, WO / 2001/34158 (Smithcline non-additive), WO / 2001/47930 (Aventis) and WO / 99/24460 (Novatis).

Recently, the direction of the development of osteoporosis treatment is a non-hormonal drug, which overcomes the low body absorption and side effects of the bisphosphonate system or develops a low-molecular compound with a new mechanism of action that promotes bone formation. In order to maintain the remodeling balance between osteoclasts and osteoblasts, researches have been conducted to explore new osteoporosis therapeutics by identifying mutual signaling and coupling from a molecular biological perspective. .

Osteoprotegerin (OPG) is found in osteoblasts, and OPG mRNA is a 44 kDa protein identified in dendritic cells and lymphocytes. This is when the osteoclasts differentiate, when the receptor Activation of Nuclear factor κB (RANK) portion of the osteoclasts binds to the receptor Activation of Nuclear factor κB Ligand (RANKL) portion of the osteoblasts, competitively intercepting the binding. As a kind of deed, it is involved in regulating osteoclast differentiation and has been identified as a substance that inhibits induction of bone resorption.

Thus, the present inventors proceed with a study focusing on a new action point capable of deriving a new osteoporosis therapeutic agent according to the mechanism found while understanding the mechanism of action on bone absorption and bone formation, by adjusting the OPG found in osteoblasts As a result of researches to develop low molecular weight substances that inhibit the growth of osteoclasts and improve bone density, the present invention has been completed by synthesizing novel compounds capable of treating bone metabolic diseases and developing therapeutic agents using the same.

It is an object of the present invention to provide novel quinoline ester derivatives.

Another object of the present invention is to provide a method for preparing the quinoline ester derivative.

It is another object of the present invention to provide an agent for the prevention and treatment of bone metabolic diseases containing the quinoline ester derivatives, pharmaceutically acceptable salts thereof and solvates thereof as an active ingredient.

In order to achieve the above object,

The present invention provides a novel quinoline ester derivative, a pharmaceutically acceptable salt thereof, and a solvate thereof, a preparation method thereof, and a prophylactic and therapeutic agent for bone metabolic disease containing the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides novel quinoline ester derivatives represented by the following formula (1), pharmaceutically acceptable salts thereof and solvates thereof.

In Chemical Formula 1,

X is hydrogen or halogen;

Z is hydrogen, halogen, unsubstituted or substituted straight or branched C ₁ to C ₁₀ alkyl, C ₅ to C ₁₀ aryl, C ₂ to C ₈ heterocyclyl, C ₁ to C ₁₀ alkylamine, C ₁ to C ₁₀ Alkenylamine, C ₅ -C ₁₀ aryl C ₁ -C ₁₀ alkylamine, C ₅ -C ₁₀ cycloalkylamine, and C ₁ -C ₁₀ hydroxyalkylamine;

R is a phenylcarboxyl group substituted with U and Y represented by the following formula (2);

In Chemical Formula 2,

U is —O— (CH ₂ ) _m —V or —CH ₂ —O— (CH ₂ ) _m —V, wherein m is an integer from 0 to 10;

V is any one selected from the group consisting of hydrogen, halogen, C ₅ -C ₁₀ aryl substituted with R ₁ , C ₂ -C ₈ heterocyclyl, C ₅ -C ₁₀ aryloxy and C ₅ -C ₁₀ arylamine ego;

R ₁ is any one selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₂ -C ₈ heteroaryl and C ₂ -C ₈ heterocyclo C ₁ -C ₁₀ alkyloxy;

Y is hydrogen, halogen, hydroxy, amino, nitro, unsubstituted or substituted straight or branched C ₁ to C ₁₀ alkyl, C ₂ to C ₈ heterocyclyl, C ₁ to C ₁₀ alkyl C ₅ to C ₁₀ Aryl and any one selected from the group consisting of C ₂ to C ₈ heteroaryl;

The heterocyclyl, heteroaryl or heterocycloalkyloxy may include one or more hetero atoms selected from the group consisting of N, O and S.

Preferably, in the quinoline derivative of Formula 1 according to the present invention,

X is hydrogen, fluorine, chlorine or bromine;

Z is hydrogen, fluorine, chlorine, bromine, unsubstituted or substituted straight or branched C ₁ -C ₄ alkyl, C ₅ -C ₇ aryl, C ₂ -C ₅ heterocyclyl, C ₁ -C ₄ alkylamine, C Any one selected from the group consisting of ₁ to C ₄ alkenylamine, C ₅ to C ₆ aryl C ₁ to C ₄ alkylamine, C ₅ to C ₁₀ cycloalkylamine, and C ₁ to C ₄ hydroxyalkylamine;

U is —O— (CH ₂ ) _m —V or —CH ₂ —O— (CH ₂ ) _m —V, wherein m is an integer from 0 to 5;

V is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C ₅ -C ₆ aryl substituted with R ₁ , C ₂ -C ₅ heterocyclyl, C ₅ -C ₆ aryloxy and C ₅ -C ₆ arylamine Is any one selected;

R ₁ is any _{one selected} from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, cyano, C ₂ -C ₅ heteroaryl and C ₂ -C ₅ heterocyclo C ₁ -C ₄ alkyloxy;

Y is hydrogen, fluorine, chlorine, bromine, hydroxy, amino, nitro, unsubstituted or substituted straight or branched C ₁ to C ₄ alkyl, C ₂ to C ₅ heterocyclyl, C ₁ to C ₄ alkyl C ₅ to C ₆ Aryl and any one selected from the group consisting of C ₂ to C ₅ heteroaryl;

The heterocyclyl, heteroaryl or heterocycloalkyloxy may include one or more hetero atoms selected from the group consisting of N, O and S.

More preferably, in the quinoline derivative of Formula 1 according to the present invention,

X is hydrogen, chlorine or bromine;

Z is hydrogen, chlorine, bromine, methyl, ethyl, propyl, butyl, o-tolyl, ethylphenyl, pyrrolidinyl, piperidinyl, ethylamine, propylamine, isopropylamine, diisopropylamine, diisobutylamine , Propenylamine, butenylamine, 2-butenylamine, phenylethylamine, phenylpropylamine, phenylbutylamine, cyclopentylamine, cyclohexylamine and hydroxyethylamine, hydroxypropylamine and hydroxybutylamine Any one selected from the group consisting of;

V is any one selected from the group consisting of hydrogen, chlorine, bromine, phenyl substituted with R ₁ , pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyloxy, or phenylamine;

R ₁ is any one selected from the group consisting of hydrogen, chlorine, bromine, nitro, cyano, pyridinyl and morpholinomethyloxy, morpholinoethyloxy, and morpholinopropyloxy.

In Formula 1 according to the present invention, R is preferably 2 or 3, 4 or 8, and Z is independently or selectively substituted at any one of positions 2 or 3 of the quinoline ring. .

In addition, U and Y of the formula (2) according to the present invention is preferably independently or selectively substituted at any one of positions 2, 3, 4, 5 or 6 of the benzene ring.

The novel quinoline derivative represented by the formula (1) according to the present invention,

(1) 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate;

(2) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-bromo-ethoxy) -phenylester;

(3) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-phenylamino-ethoxy) -phenylester;

(4) 3,7-dichloro-quinoline-8-carboxylic acid-2- [2- (2-nitro-phenylamino) -ethoxy] -phenyl ester;

(5) 3,7-dichloro-quinoline-8-carboxylic acid-2- [2- (2-fluoro-phenylamino) -ethoxy] -phenylester;

(6) 3,7-dichloro-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(7) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-pyrrolidin-1-yl-ethoxy) -phenylester;

(8) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-piperidin-1-yl-ethoxy) -phenyl ester;

(9) 3,7-dichloro-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester;

(10) 3,7-dichloro-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxymethyl) -phenylester;

(11) 3,7-dichloro-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxymethyl) -phenylester;

(12) 3,7-dichloro-quinolin-8-carboxylic acid 4- (2-morpholin-4-yl-ethoxymethyl) -phenylester;

(13) 3,7-dichloro-quinoline-8-carboxylic acid-2- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -ethoxy-phenylester;

(14) 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate;

(15) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2- (2-bromo-ethoxy) -phenylester;

(16) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(17) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (2-piperidin-1-yl-ethoxy) -phenylester;

(18) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester;

(19) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2-benzyloxy-phenylester;

(20) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-cyano-benzyloxy) -phenylester;

(21) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-chloro-benzyloxy) -phenylester;

(22) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2- (4-bromo-benzyloxy) -phenylester;

(23) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (pyridin-2-ylmethoxy) -phenylester;

(24) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (pyridin-4-ylmethoxy) -phenyl ester;

(25) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-morpholin-4-yl-butoxy) -phenylester;

(26) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {2- [2- (2-morpholin-4-yl-ethoxy) -phenoxy] -Ethoxy} -phenyl ester;

(27) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {4- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -Butoxy} -phenyl ester;

(28) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {4- [2- (2-morpholin-4-yl-ethoxy) -phenoxy] -Butoxy} -phenyl ester;

(29) 7-chloro-3-piperidin-1-yl-quinolin-8-carboxylic acid-2-hydroxy-phenylester;

(30) 3-butylamino-7-chloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(31) 7-chloro-3- (2-hydroxy-ethylamino) -quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(32) 7-chloro-3-phenethylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(33) 7-chloro-3-diisopropylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(34) 7-chloro-3-cyclopentylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(35) 7-chloro-3-cyclohexylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(36) 7-chloro-3-allylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(37) 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2-hydroxy-phenylester;

(38) 7-chloro-3-o-tolyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(39) 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2- {2- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -ethoxy} -Phenyl ester;

(40) 2-methyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(41) 2-butyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(42) quinoline-2-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(43) quinoline-2-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester;

(44) quinoline-2-carboxylic acid-4- (2-morpholin-4-yl-ethoxy) -phenylester;

(45) quinoline-3-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester;

(46) quinoline-3-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester;

(47) quinoline-4-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; And

(48) quinolin-4-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester

It is any one selected from the group consisting of.

The quinoline derivative represented by Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by pharmaceutically acceptable free acid are useful. The quinoline derivative represented by Formula 1 may be formed of a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Inorganic and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. can be used as the inorganic acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfuric acid. Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galluxuronic acid, embonic acid, glutamic acid or aspartic acid, and the like can be used. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid. In addition, the quinoline derivative represented by Formula 1 according to the present invention may include all salts, hydrates, and solvates that may be prepared by conventional methods, as well as pharmaceutically acceptable salts.

The present invention also provides a method for preparing a quinoline derivative represented by the formula (1).

Specifically, the method for producing the quinoline derivative according to the present invention,

Dissolving the compound of Formula 3 in a suitable solvent to prepare a starting material (step 1); And

It comprises the step of preparing a compound of formula 1 by reacting the starting material and the compound of formula 2 in the presence of a base (step 2).

Wherein U, X, Y and Z are as defined in Formula 1 of claim 1

In step 1, it is preferable to use a solvent such as chloroform, toluene, acetone, acetonitrile, N, N-dimethylformamide, methylene chloride, water or a mixture thereof.

In step 2, it is preferable to use triethylamine, sodium hydroxide, potassium carbonate and the like as the base.

The present invention also provides a prophylactic and therapeutic agent for metabolic bone disease containing the quinoline derivative of Formula 1 as an active ingredient.

The therapeutic agent using the quinoline derivative of the present invention as an active ingredient can promote the secretion of OPG secreted from osteoblasts and treat the metabolic bone disease by inhibiting the differentiation of osteoclasts.

The metabolic bone disease according to the present invention includes osteoporosis, osteoarthritis and the like.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< Example  1> 2- Hydroxyphenyl -3,7- Dichloroquinoline -8- Carboxylate  Produce

To a solution of 3,7-dichloro-8-quinolinecarboxylic acid (100 g) dissolved in chloroform (500 ml) was added triethyl amine (5.7 ml) and thionyl chloride (45 ml) and refluxed for 4 hours. After cooling to room temperature, catechol (90.9 g) was added and refluxed for 10 hours. After cooling down to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (300 ml) and water (300 ml), separated from the organic layer, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then recrystallized with ethanol (115). g, 83%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.00 (s, 1H), 8.88 (d, 1H), 8.25 (d, 1H), 7.88 (d, 1H), 7.65 (d, 1H), 7.27-6.90 ( m, 4H);

MS m / z 334, 336 (M ⁺ )

< Example  2> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- (2- Bromo - Ethoxy )- Phenyl ester Manufacture

Tetrabutylammonium bromide (2.3 g), sodium hydroxide (2.8 g), 1, in a solution of 2-hydroxyphenyl 3,7-dichloroquinoline-8-carboxylate (8.0 g) dissolved in toluene (100 ml). 2-dibromoethane (10.3 ml) was added followed by reflux for 5 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed. Then, the mixture was recrystallized from a mixture of ethyl acetate and hexane to obtain the target compound (8.9 g, 84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.48 (s, 1H), 8.04 (d, 1H), 7.67 (d, 1H), 7.06-7.03 (m, 2H), 6.90- 6.83 (m, 2 H), 4.44 (t, 2 H), 3.72 (t, 2 H);

MS m / z 441, 443 (M ⁺ )

<Example 3> 3,7-dichloro-phenyl ester Preparation of the quinolin-8-carboxylic acid 2- (2-phenyl-ethoxy)

Tetrabutylammonium bromide (0.65 g), sodium hydroxide (30 g) dissolved in toluene 0.68 g), aniline (0.7 ml) was added and refluxed for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and recrystallized with ethyl acetate to obtain the target compound (2.5 g, 75%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.77 (d, 1H), 8.11 (d, 1H), 7.76 (d, 1H), 7.58 (d, 1H), 7.37-6.98 (m, 6H), 6.72- 6.61 (m, 3H), 5.10 (s, 1H), 4.27 (t, 2H), 3.65 (t, 2H);

MS m / z 453, 455 (M ⁺ )

< Example  4> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- [2- (2-nitro- Phenylamino )- Ethoxy ] -Phenyl Ester Preparation

Tetrabutylammonium bromide (0.65 g) and sodium hydroxide (0.68) in a solution of 2- (2-bromoethoxy) phenyl 3,7-dichloroquinoline-8-carboxylate (3.0 g) dissolved in toluene (30 ml). g), 2-nitroaniline (0.93 g) was added and then refluxed for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and recrystallized with ethyl acetate to obtain the target compound (2.4 g, 72%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35-6.69 (m, 12H), 4.17 (t, 2H), 4.08 (s, 1H), 3.48 (t, 2H);

MS m / z 498 (M ⁺ )

< Example  5> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- [2- (2- Fluoro - Phenylamino )- Etok Of phenyl] -phenyl ester

Tetrabutylammonium bromide (0.65 g) and sodium hydroxide (0.68) in a solution of 2- (2-bromoethoxy) phenyl 3,7-dichloroquinoline-8-carboxylate (3.0 g) dissolved in toluene (30 ml). g), 2-fluoroaniline (0.65 ml) was added and then refluxed for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and recrystallized with ethyl acetate to obtain the target compound (2.2 g, 68%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35-6.41 (m, 12H), 4.17 (t, 2H), 4.04 (s, 1H), 3.48 (t, 2H);

MS m / z 471 (M ⁺ )

< Example  6> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy )- Phenyl ester

Sodium hydroxide (7.1 g), 4- in a solution obtained by dissolving 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate (20 g) in acetonitrile and a water mixture (7: 3, 160 ml) (2-chloroethyl) morpholine hydrochloride (11.1 g) was added thereto, followed by stirring at room temperature for 7 hours. After extraction with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and recrystallized with a mixture of ethyl acetate, hexane to give the target compound (19.7 g, 73%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.91 (d, 1H), 8.14 (d, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.42 (d, 1H), 7.29-7.23 ( m, 1H), 7.07-7.02 (m, 2H), 4.24 (t, 2H), 3.68 (t, 4H), 2.90 (t, 2H), 2.57 (t, 4H);

MS m / z 447, 449 (M ⁺ )

< Example  7> Preparation of 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-pyrrolidin-1-yl-ethoxy) -phenylester

Sodium hydroxide (5.1 g), 4- () in a solution of 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate (17 g) dissolved in acetonitrile and a water mixture (7: 3, 150 ml) 2-Chloroethyl) pyrrolidine hydrochloride (8.6 g) was added, followed by stirring at room temperature for 12 hours. After extraction with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and recrystallized with a mixture of ethyl acetate, hexane to give the target compound (15.6 g, 71%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.90 (d, 1H), 8.13 (d, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.41 (d, 1H), 7.28-7.22 ( m, 1H), 7.08-7.01 (m, 2H), 4.24 (t, 2H), 3.00 (t, 2H), 2.64-2.59 (m, 4H), 1.81-1.72 (m, 4H);

MS m / z 431, 433 (M ⁺ )

< Example  8> Preparation of 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-piperidin-1-yl-ethoxy) -phenylester

Sodium hydroxide (4.3 g), 4- in a solution of 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate (12 g) dissolved in acetonitrile and a water mixture (7: 3,120 ml) (2-chloroethyl) piperidine hydrochloride (6.6 g) was added thereto, followed by stirring at room temperature for 10 hours. Extraction with ethyl acetate, drying with anhydrous magnesium sulfate, concentration under reduced pressure, removal of the solvent, and recrystallization with a mixture of ethyl acetate and hexane to obtain the target compound (11.3 g, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.92 (d, 1H), 8.15 (d, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.41 (d, 1H), 7.28-7.23 ( m, 1H), 7.09-7.01 (m, 2H), 4.24 (t, 2H), 2.88 (t, 2H), 2.51 (t, 4H), 1.61-1.54 (m, 4H), 1.46-1.40 (m, 2H);

MS m / z 445, 447 (M ⁺ )

< Example  9> 3,7- Dichloro -Quinoline-8- Carboxylic acid -3- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

Triethyl amine (0.3 ml) and thionyl chloride (2.3 ml) were added to the solution of 3,7-dichloro-8-quinolinecarboxylic acid (5.0 g) in chloroform (100 ml), followed by reflux for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dissolved in chloroform (100 ml). Triethyl amine (5.7 ml) and morpholinoethyl resorcinol (4.6 g) were added and the mixture was refluxed for 10 hours. After cooling to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (50 ml), separated from the organic layer, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (7.1 g, 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.91 (d, 1H), 8.17 (d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.36 (t, 1H), 7.03-6.97 ( m, 2H), 6.87-6.84 (m, 1H), 4.16 (t, 2H), 3.77-3.71 (m, 4H), 2.83 (t, 2H), 2.62-2.55 (m, 4H);

MS m / z 447, 449 (M ⁺ )

< Example  10> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxyme Preparation of Tyl) -Phenyl Ester

Triethyl amine (0.05 ml) and thionyl chloride (0.45 ml) were added to the solution of 3,7-dichloro-8-quinolinecarboxylic acid (1.0 g) in chloroform (20 ml), followed by reflux for 4 hours. After cooling to room temperature, concentrated under reduced pressure, dried in vacuo, dissolved in chloroform (20 ml), and triethyl amine (0.5 ml) and 2- (2-morpholin-4-yl-ethoxymethyl) -phenol (1.1 g) were added thereto. It was refluxed for 8 hours. After cooling to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (20 ml), and then the organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain the target compound (1.2 g). , 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35-7.08 (m, 8H), 4.63 (s, 2H), 3.67 (t, 4H), 3.47 (t, 2H), 2.53 (t, 2H), 2.37 ( t, 4H);

MS m / z 461 (M ⁺ )

< Example  11> 3,7- Dichloro -Quinoline-8- Carboxylic acid -3- (2- Morpholine -4- days- Ethoxymethyl Preparation of) -phenylester

To a solution of 3,7-dichloro-8-quinolinecarboxylic acid (1.0 g) in chloroform (20 ml0) was added triethyl amine (0.05 ml) and thionyl chloride (0.45 ml) and refluxed for 4 hours. It was then concentrated under reduced pressure, dried under vacuum, dissolved in chloroform (20 ml), triethyl amine (0.5 ml) and 3- (2-morpholin-4-yl-ethoxymethyl) -phenol (1.1 g) were added thereto. After cooling down to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (20 ml), and then the organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography. Compound (1.3 g, 68%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35-7.08 (m, 8H), 4.63 (s, 2H), 3.67 (t, 4H), 3.47 (t, 2H), 2.53 (t, 2H), 2.37 ( t, 4H);

MS m / z 461 (M ⁺ )

< Example  12> 3,7- Dichloro -Quinoline-8- Carboxylic acid 4 -(2- Morpholine -4- days- Ethoxyme Preparation of Tyl) -Phenyl Ester

Triethyl amine (0.05 ml) and thionyl chloride (0.45 ml) were added to the solution of 3,7-dichloro-8-quinolinecarboxylic acid (1.0 g) in chloroform (20 ml), followed by reflux for 4 hours. After cooling down to room temperature, it was concentrated under reduced pressure, dried in vacuo, dissolved in chloroform (20 ml), and triethyl amine (0.5 ml) and 4- (2-morpholin-4-yl-ethoxymethyl) -phenol (1.1 g) were added thereto. It was refluxed for 8 hours. After cooling down to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (20 ml), separated from the organic layer, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain the target compound (1.0 g, 52%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.35-7.08 (m, 8H), 4.63 (s, 2H), 3.67 (t, 4H), 3.47 (t, 2H), 2.53 (t, 2H), 2.37 ( t, 4H); MS m / z 461 (M +)

< Example  13> 3,7- Dichloro -Quinoline-8- Carboxylic acid -2- [3- (2- Morpholine -4- days- Ethoxy Preparation of) -phenoxy] -ethoxy-phenylester

Potassium carbonate (10.1 g) in a solution of 2- (2-bromoethoxy) phenyl 3,7-dichloroquinoline-8-carboxylate (6.5 g) dissolved in acetonitrile and a water mixture (7: 3, 50 ml) After addition of morpholinoethyl resorcinol (3.28 g), the mixture was refluxed for 16 hours. After cooling down to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (6.5 g, 76%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (d, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.55 (d, 1H), 7.39 (d, 1H), 7.27-7.22 ( m, 1H), 7.10-7.02 (m, 2H), 6.57-6.51 (m, 4H), 4.47-4.38 (m, 4H), 4.07 (t, 2H), 3.63-3.59 (m, 4H), 2.76 ( t, 2H), 2.59-2.52 (m, 4H);

MS m / z 583, 585 (M ⁺ )

< Example  14> Preparation of 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate

Copper oxide (I) (8.3 g), potassium carbonate (43.4 g), in a solution of 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate (35 g) dissolved in toluene (300 ml), Pyrrolidine (12.4 ml) was added at reflux for 3 hours after addition. After the mixture was cooled to room temperature, the reaction solution was filtered using a mixture of ethyl acetate and hexane in a ratio of 1: 2, filtered through celite and silica gel, concentrated under reduced pressure to remove the solvent, and the resulting solid compound was filtered and washed with ethanol (32 g , 84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.08 (s, 1H), 8.65 (d, 1H), 7.98 (d, 1H), 7.59 (d, 1H), 7.25-6.86 (m, 5H), 3.61- 3.55 (m, 4 H), 2.16-2.04 (m, 4 H);

MS m / z 259, 369, 371 (M ⁺ )

< Example  15> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (2- Bromo - on Preparation of oxy) -phenyl ester

Tetrabutylammonium bromide (4.3 g) in a solution of 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (10 g) dissolved in toluene (100 ml). ), Sodium hydroxide (5.4 g), 1,2-dibromoethane (11.6 ml) were added and refluxed for 3 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the resulting solid compound was filtered and washed with ethanol to obtain the target compound (10.7 g, 3%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 7.88 (d, 1H), 7.59 (d, 1H), 7.34 (s, 1H), 7.06-7.02 (m, 2H), 6.91- 6.82 (m, 2H), 4.44 (t, 2H), 3.72 (t, 2H), 2.83-2.76 (m, 4H), 1.62-1.56 (m, 4H);

MS m / z 475, 479 (M ⁺ )

< Example  16> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (2- Morpholine Preparation of 4-yl-ethoxy) -phenylester

Tetrabutylammonium bromide (3.2 g) in a solution of 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (7.5 g) dissolved in toluene (100 ml). ), Sodium hydroxide (4.6 g) and 4- (2-chloroethyl) morpholine hydrochloride (5.67 g) were added and refluxed for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed, and then recrystallized with ethyl acetate to obtain the target compound (7.8 g, 80%). 1 H NMR (300 MHz, CDCl 3) δ 8.73 (d, 1H), 7.90 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.22-7.05 (m, 4H), 4.18 (t, 2H), 3.70-3.64 (m, 8H), 2.77 (t, 2H), 2.54-2.49 (m, 4H), 2.09-2.03 (m, 4H); MS m / z 223, 259, 482, 484 (M +)

< Example  17> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid Preparation of 2- (2-piperidin-1-yl-ethoxy) -phenylester

Tetrabutylammonium bromide (3.2 g) in a solution of 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (7.5 g) dissolved in toluene (100 ml). ), Sodium hydroxide (4.6 g) and 4- (2-chloroethyl) piperidine hydrochloride (4.5 g) were added and refluxed for 8 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed. Then, the resultant was recrystallized with a mixture of ethyl acetate and hexane to obtain the target compound (6.9 g, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (d, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.25-7.02 (m, 4H), 4.18 ( t, 2H), 3.67 (t, 4H), 2.75 (t, 2H), 2.46 (t, 4H), 2.09-2.03 (m, 4H), 1.61-1.53 (m, 4H), 1.45-1.38 (m, 2H); MS m / z 259, 480, 482 (M ⁺ )

< Example  18> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -3- (2- Morpholine Preparation of 4-yl-ethoxy) -phenylester

Tetrabutylammonium bromide (3.2 g) in a solution of 3-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (7.5 g) dissolved in toluene (100 ml). ), Sodium hydroxide (4.6 g) and 4- (2-chloroethyl) morpholine hydrochloride (5.67 g) were added, and the mixture was refluxed for 5 hours. Lowered to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, recrystallized with ethyl acetate, 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-3- 7.3 g (75%) of (2-morpholin-4-yl-ethoxy) -phenylester ( 18) ) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80 (d, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.45 (d, 1H), 7.22-6.74 (m, 4H), 4.10 ( t, 2H), 3.65-3.54 (m, 8H), 2.77 (t, 2H), 2.61-2.53 (m, 4H), 1.96-1.91 (m, 4H); MS m / z 259, 482, 484 (M ⁺ )

< Example 19 > 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- Benzyloxy - Phenyl Preparation of ester

Tetrabutylammonium bromide (1.3 g) in a solution of 2-hydroxyphenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.0 g) dissolved in toluene (50 ml). Sodium hydroxide (1.6 g) and benzyl bromide (0.96 ml) were added and refluxed for 6 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.2 g, 86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67-7.04 (m, 13H), 5.12 (s, 2H), 3.43 (t, 4H), 1.69 (t, 4H);

MS m / z 458 (M ⁺ )

< Example  20> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (4- Cyano - Benzyl Jade Of C) -phenylester

Tetrabutylammonium bromide (1.3 g) in a solution of 2-hydroxyphenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.0 g) dissolved in toluene (50 ml). , Sodium hydroxide (1.6 g) and α-bromo-p-tolunitrile (1.6 g) were added, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.5 g, 89%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82-6.89 (m, 12H), 5.15 (s, 2H), 3.55 (m, 4H), 1.67 (m, 4H);

MS m / z 500 (M ⁺ )

< Example  21> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (4- Chloro - Ben Preparation of oxyoxy) -phenyl ester

Tetrabutylammonium bromide (1.3 g) in a solution of 2-hydroxyphenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.0 g) dissolved in toluene (50 ml). , Sodium hydroxide (1.6 g) and 4-chlorobenzyl bromide (1.67 g) were added, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.4 g, 85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.66-7.06 (m, 12H), 5.09 (s, 2H), 3.55 (t, 4H), 1.72 (t, 4H);

MS m / z 509 (M ⁺ )

< Example  22> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (4- Bromo - Benzyl City Preparation of) -phenylester

Tetrabutylammonium bromide (1.3 g) in a solution of 2-hydroxyphenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.0 g) dissolved in toluene (50 ml). , Sodium hydroxide (1.6 g) and 4-bromobenzyl bromide (2.1 g) were added, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.9 g, 89%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.65 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.45 (d, 1H), 7.42 (d, 2H), 7.28 (d, 2H), 7.22 (t, 1H), 7.10-6.99 (m, 3H), 5.05 (s, 2H), 3.53 (t, 4H), 1.71 (t, 4H);

MS m / z 259, 537, 539 (M ⁺ )

< Example  23> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (pyridine-2- Work Preparation of Methoxy) -Phenyl Ester

Tetrabutylammonium bromide (0.8 g) in a solution of 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.3 g) dissolved in toluene (50 ml). ), Sodium hydroxide (1.7 g) and 2- (bromomethyl) pyridine hydrobromide (2.2 g) were added and refluxed for 10 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.7 g, 90%).

¹ H NMR (300 MHz, CDCl 3) δ 8.68 (d, 1H), 8.58 (d, 1H), 7.89 (d, 1H), 7.69-7.54 (m, 4H), 7.22-6.94 (m, 5H), 5.29 (s, 2H), 3.66-3.53 (m, 4H), 1.88-1.74 (m, 4H);

MS m / z 259, 460, 462 (M ⁺ )

< Example  24> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (pyridine-4- Work Preparation of Methoxy) -Phenyl Ester

Tetrabutylammonium bromide (0.8 g) in a solution of 2-hydroxyphenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (3.3 g) dissolved in toluene (50 ml). Sodium hydroxide (1.7 g) and 4- (bromomethyl) pyridine hydrobromide (2.2 g) were added, and the mixture was refluxed for 10 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.2 g, 78%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82-6.84 (m, 12H), 5.20 (s, 2H), 2.88 (m, 4H), 1.59 (m, 4H);

MS m / z 459 (M ⁺ )

< Example  25> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- (4- Morpholine Preparation of 4-yl-butoxy) -phenylester

7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2- (4-bromo-butoxy) -phenylester (0.3 g) was mixed with acetone and water (7: 3, Potassium carbonate (0.41 g) and morpholine (0.16 ml) were added to the solution dissolved in 20 ml), and the mixture was refluxed for 8 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (0.21 g, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (d, 1H), 7.89 (d, 1H), 7.67 (d, 1H), 7.57 (d, 1H), 7.24-7.18 (m, 1H), 7.11- 7.00 (m, 3H), 4.04 (t, 2H), 3.69-3.63 (m, 8H), 2.37-2.31 (m, 6H), 2.06-2.02 (m, 4H), 1.79 (q, 2H), 1.61 ( q, 2H);

MS m / z 252, 259, 510 (M ⁺ )

< Example  26> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- {2- [2- (2- Morpholine Preparation of -4-yl-ethoxy) -phenoxy] -ethoxy} -phenylester

Tetrabutylammonium in a solution of 2- (2-bromoethoxy) phenyl 7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate (9.8 g) dissolved in toluene (200 ml) Bromide (3.0 g), sodium hydroxide (3.7 g) and morpholinoethyl catechol (4.2 g) were added followed by reflux for 2 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (9.8 g, 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.26-7.20 (m, 1H), 7.11- 7.05 (m, 3H), 6.93-6.83 (m, 4H), 4.41-4.30 (m, 4H), 4.06 (t, 2H), 3.64-3.59 (m, 8H), 2.68 (t, 2H), 2.51- 2.43 (m, 4 H), 1.94-1.87 (m, 4 H);

MS m / z 259, 360, 618, 620 (M ⁺ )

< Example  27> 7- Chloro -3- Pyrrolidine -1-yl-quinolin-8- Carboxylic acid -2- {4- [3- (2- mother Preparation of Polin-4-yl-ethoxy) -phenoxy] -butoxy} -phenylester

Tetrabutylammonium bromide (0.43) in a solution of 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2-hydroxy-phenylester (1.0 g) dissolved in toluene (20 ml). g), sodium hydroxide (0.54 g) and 1,4-dibromobutane (1.7 g) were added and then refluxed for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed. The resulting solid compound was filtered, washed with hexane, and dried in vacuo. To the solution dissolved in toluene (20 ml) again, morpholinoethyl resorcinol (0.88 g), tetrabutylammonium bromide (0.32 g), and sodium hydroxide (0.4 g) were added and refluxed for 6 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a target compound (1.3 g, 74%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (d, 1H), 7.89 (d, 1H), 7.71 (d, 1H), 7.56 (d, 1H), 7.26-6.98 (m, 5H), 6.51- 6.41 (m, 3H), 4.13-4.03 (m, 4H), 3.94 (t, 2H), 3.76-3.61 (m, 8H), 2.77 (t, 2H), 2.62-2.51 (m, 4H), 2.06- 1.87 (m, 8 H);

MS m / z 259, 388, 646 (M ⁺ )

< Example  28> 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {4- [2- (2-morpholin-4-yl-ethoxy) -phenoxy]- Preparation of Butoxy} -phenylester

Tetrabutylammonium bromide (0.43) in a solution of 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2-hydroxy-phenylester (1.0 g) dissolved in toluene (20 ml). g), sodium hydroxide (0.54 g) and 1,4-dibromobutane (1.7 g) were added and then refluxed for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed. The resulting solid compound was filtered, washed with hexane, and dried in vacuo. To the solution again dissolved in toluene (20 ml), morpholinoethyl catechol (0.88 g), tetrabutylammonium bromide (0.32 g), and sodium hydroxide (0.4 g) were added and refluxed for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography after removal of solvent to obtain the target compound (1.1 g, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.73 (d, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.26-7.18 (m, 1H), 7.11- 7.02 (m, 4H), 6.90-6.81 (m, 3H), 4.13-3.96 (m, 6H), 3.71-3.59 (m, 8H), 2.66 (t, 2H), 2.55 (t, 4H), 2.07- 1.92 (m, 8 H);

MS m / z 259, 388, 646 (M ⁺ )

< Example  29> 7- Chloro 3-piperidin-1-yl-quinolin-8- Carboxylic acid -2- Hydroxy Preparation of Phenyl Ester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and piperidine (0.3 ml) were added followed by reflux for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (70 mg, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82-6.80 (m, 8H), 5.05 (s, 1H), 2.78 (m, 4H), 1.50 (m, 6H);

MS m / z 382 (M ⁺ )

< Example  30> 3- Butylamino -7- Chloro -Quinoline-8- Carboxylic acid -2- Hydroxy - Phenyl Preparation of ester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and butylamine (0.3 ml) were added and then refluxed for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (75 mg, 68%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 8H), 5.03 (s, 1H), 3.94 (s, 1H), 3.06 (t, 2H), 1.52 (m, 2H), 1.33 ( m, 2H), 0.96 (t, 3H);

MS m / z 370 (M ⁺ )

< Example  31> Preparation of 7-chloro-3- (2-hydroxy-ethylamino) -quinoline-8-carboxylic acid-2-hydroxy-phenylester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and ethanol amine (0.3 ml) were added followed by reflux for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (57 mg, 57%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 8H), 4.98 (s, 1H), 3.91 (s, 1H), 3.76 (t, 2H), 3.25 (t, 2H), 2.0 ( s, 1 H);

MS m / z 358 (M ⁺ )

< Example  32> Preparation of 7-chloro-3-phenethylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and phenethylamine (0.1 ml) were added followed by reflux for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (75 mg, 62%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 13H), 5.01 (s, 1H), 3.88 (s, 1H), 3.39 (t, 2H), 2.78 (t, 2H);

MS m / z 418 (M ⁺ )

< Example  33> 7- Chloro -3- Diisopropylamino -Quinoline-8- Carboxylic acid -2- Hyde Preparation of Roxy-phenyl Ester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and diisopropyl amine (0.3 ml) were added followed by reflux for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (61 mg, 51%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82-6.80 (m, 8H), 5.07 (s, 1H), 2.97 (m, 2H), 1.05 (d, 12H);

MS m / z 398 (M ⁺ )

< Example  34> Preparation of 7-chloro-3-cyclopentylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and cyclopentylamine (0.3 ml) were added followed by reflux for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (78 mg, 71%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 8H), 4.97 (s, 1H), 3.95 (s, 1H), 2.64 (m, 1H), 1.83-1.46 (m, 8H);

MS m / z 382 (M ⁺ )

< Example  35> 7- Chloro -3- Cyclohexylamino -Quinoline-8- Carboxylic acid -2- Hyde Preparation of Roxy-phenyl Ester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and cyclohexylamine (0.3 ml) were added followed by reflux for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (73 mg, 61%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 8H), 4.97 (s, 1H), 4.02 (s, 1H), 2.57 (m, 1H), 1.75-1.39 (m, 10H);

MS m / z 396 (M ⁺ )

< Example  36> 7- Chloro -3- Allylamino -Quinoline-8- Carboxylic acid -2- Hydroxy Preparation of Phenyl Ester

Zinc oxide (6 mg), tetra, in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.1 g) dissolved in N, N-dimethylformamide (5 ml). Keystriphenylphosphine palladium (0.03 g) and allylamine (0.3 ml) were added followed by reflux for 4 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (69 mg, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59-6.80 (m, 8H), 5.83 (m, 1H), 5.17-5.15 (m, 2H), 5.05 (s, 1H), 3.87 (s, 1H), 3.73 (d, 2 H);

MS m / z 354 (M ⁺ )

< Example  37> 7- Chloro -3-o- Tolyl -Quinoline-8- Carboxylic acid -2- Hydroxy - Phenyl ester  Produce

O-tolylboronic acid (2.2) in a solution of 3,7-dichloro-quinoline-8-carboxylic acid-2-hydroxy-phenyl ester (5.0 g) dissolved in acetone and a water mixture (1: 1, 100 ml) g), palladium acetate (0.34 g), triphenylphosphine (0.75 g) and potassium carbonate (4.1 g) were added and then refluxed for 8 hours. After cooling down to room temperature, the mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, solvent removed, and purified by silica gel column chromatography to obtain the target compound (3.9 g, 67%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 8.94 (d, 1H), 8.34 (d, 1H), 7.95 (d, 1H), 7.62 (d, 1H), 7.44-7.28 ( m, 4H), 7.18-7.05 (m, 2H), 6.89-6.79 (m, 2H), 2.24 (s, 3H);

MS m / z 280, 390, 392 (M ⁺ )

< Example  38> 7- Chloro -3-o- Tolyl -Quinoline-8- Carboxylic acid -2- (2- Morpholine -4- days- Etok Of C) -phenylester

Sodium hydroxide in a solution of 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2-hydroxy-phenylester (0.36 g) dissolved in acetonitrile and a water mixture (7: 3, 20 ml) (0.11 g) and 4- (2-chloroethyl) morpholine hydrochloride (0.21 g) were added, and the mixture was refluxed for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solvent was removed and recrystallized with a mixture of ethyl acetate and hexane to obtain the target compound (0.34 g, 73%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.94 (d, 1H), 8.23 (d, 1H), 7.88 (d, 1H), 7.53 (d, 1H), 7.45-7.25 (m, 4H), 7.14- 6.76 (m, 3H), 6.09 (d, 1H), 4.18-4.10 (m, 2H), 3.67-3.60 (m, 4H), 2.85 (t, 2H), 2.59-2.55 (m, 4H), 2.20 ( s, 3H);

MS m / z 280, 503, 505 (M ⁺ )

< Example  39> 7- Chloro -3-o- Tolyl -Quinoline-8- Carboxylic acid -2- {2- [3- (2- Morpholine Preparation of -4-yl-ethoxy) -phenoxy] -ethoxy} -phenylester

Tetrabutylammonium bromide (0.41 g), hydroxide in a solution of 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2-hydroxy-phenylester (1.0 g) dissolved in toluene (20 ml) Sodium (0.3 g), 1,2-dibromoethane (1.1 ml) were added and the mixture was refluxed for 3 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried under vacuum after removing the solvent. To the solution dissolved in toluene (30 ml), morpholinoethyl resorcinol (0.57 g), tetrabutylammonium bromide (0.41 g) and sodium hydroxide (0.3 g) were added and refluxed for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a target compound (1.3 g, 79%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71 (d, 1H), 8.17 (d, 1H), 7.86 (d, 1H), 7.51 (d, 1H), 7.38-7.11 (m, 5H), 7.03- 6.81 (m, 3H), 6.57-6.49 (m, 3H), 6.19 (d, 1H), 4.36 (s, 4H), 4.12-4.02 (m, 2H), 3.78-3.71 (m, 4H), 2.81- 2.74 (m, 2H), 2.61-2.51 (m, 4H), 2.21 (s, 3H);

MS m / z 639, 642 (M ⁺ )

< Example  40> 2- methyl -Quinoline-8- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy ) -Phenyl Ester Preparation

Triethyl amine (0.2 ml) and thionyl chloride (1.7 ml) were added to a solution of 2-methyl-8-quinolinecarboxylic acid (3 g) dissolved in chloroform (30 ml), and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and then dissolved in chloroform (30 ml). Triethyl amine (4.4 ml) and morpholinoethyl catechol (3.5 g) were added followed by reflux for 10 hours. After cooling to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (20 ml), and then the organic layer was separated and dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (4.3 g, 68%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71-6.84 (m, 9H), 4.04 (t, 2H), 3.67 (t, 4H), 2.78 (t, 2H), 2.55 (s, 3H), 2.37 ( t, 4H);

MS m / z 392 (M ⁺ )

< Example  41> 2- Butyl -Quinoline-8- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy Preparation of) -phenylester

Triethyl amine (0.2 ml) and thionyl chloride (1.7 ml) were added to the solution of 2-butyl-8-quinolinecarboxylic acid (3.6 g) in chloroform (30 ml), and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dissolved in chloroform (30 ml). Triethyl amine (4.4 ml) and morpholinoethyl catechol (3.5 g) were added followed by reflux for 10 hours. After cooling to room temperature, the reaction solution was washed with 5% aqueous sodium hydroxide solution (20 ml), and then the organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (5.4 g, 78%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71-6.84 (m, 9H), 4.04 (t, 2H), 3.67 (t, 4H), 2.88 (t, 2H), 2.78 (t, 2H), 2.37 ( t, 4H), 1.62 (m, 2H), 1.33 (m, 2H), 0.96 (t, 3H);

MS m / z 434 (M ⁺ )

< Example 42 > Quinoline-2- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (0.24 g), 4- (dimethylamino) pyridine (0.01 g), morpholinoethyl catenate in a solution of quinaldic acid (0.17 g) dissolved in methylene chloride (20 ml) After the call (0.24 g) was added, the mixture was stirred at room temperature for 8 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (0.27 g, 73%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.41-8.30 (m, 3H), 7.98-7.66 (m, 3H), 7.32-7.21 (m, 2H), 7.07-6.98 (m, 2H), 4.19-4.09 (m, 2H), 3.57-3.43 (m, 4H), 2.75-2.61 (m, 2H), 2.41-2.30 (m, 4H);

MS m / z 379 (M ⁺ )

< Example  43> Quinoline-2- Carboxylic acid -3- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (0.24 g), 4- (dimethylamino) pyridine (0.01 g), morpholinoethyl rezo in a solution of quinaldic acid (0.17 g) dissolved in methylene chloride (20 ml) Synol (0.24 g) was added and stirred at room temperature for 8 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (0.32 g, 86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37-8.27 (m, 3H), 7.90 (d, 1H), 7.84 (t, 1H), 7.68 (t, 1H), 7.33 (t, 1H), 6.91- 6.83 (m, 3H), 4.12 (t, 2H), 3.72 (t, 4H), 2.81 (t, 2H), 2.58 (t, 4H);

MS m / z 379 (M ⁺ )

< Example  44> Quinoline-2- Carboxylic acid -4- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (0.24 g), 4- (dimethylamino) pyridine (0.01 g), 4- (2- in a solution of quinaldic acid (0.17 g) dissolved in methylene chloride (20 ml) After adding morpholin-4-yl-ethoxy) -phenol (0.24 g), the mixture was stirred at room temperature for 8 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (0.31 g, 83%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.89-8.79 (m, 3H), 7.91 (d, 1H), 7.81 (t, 1H), 7.68 (t, 1H), 7.22 (d, 2H), 6.96 ( d, 2H), 4.13 (t, 2H), 3.74 (t, 4H), 2.82 (t, 2H), 2.58 (t, 4H);

MS m / z 224, 379 (M ⁺ )

< Example  45> quinoline-3- Carboxylic acid -3- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (1.2 g), 4- (dimethylamino) pyridine (0.07 g), in a solution of quinoline-3-carboxylic acid (1.0 g) dissolved in methylene chloride (20 ml), After adding morpholinoethyl resorcinol (1.28 g), the mixture was stirred at room temperature for 10 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (1.5 g, 68%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.58-6.85 (m, 10H), 4.14 (t, 2H), 3.72 (t, 4H), 2.84 (t, 2H), 2.57 (t, 4H);

MS m / z 378 (M ⁺ )

< Example  46> quinoline-3- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (1.2 g), 4- (dimethylamino) pyridine (0.07 g), in a solution of quinoline-3-carboxylic acid (1.0 g) dissolved in methylene chloride (20 ml), After adding morpholinoethyl catechol (1.28 g), the mixture was stirred at room temperature for 10 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (1.2 g, 55%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.59-7.06 (m, 10H), 4.16 (t, 2H), 3.53 (t, 4H), 2.68 (t, 2H), 2.40 (t, 4H);

MS m / z 378 (M ⁺ )

< Example  47> quinoline-4- Carboxylic acid -3- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (1.2 g), 4- (dimethylamino) pyridine (0.07 g), in a solution of quinoline-4-carboxylic acid (1.0 g) dissolved in methylene chloride (20 ml), After adding morpholinoethyl resorcinol (1.28 g), the mixture was stirred at room temperature for 10 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (1.6 g, 73%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.01-6.54 (m, 10H), 4.14 (t, 2H), 3.72 (t, 4H), 2.83 (t, 2H), 2.57 (t, 4H);

MS m / z 378 (M ⁺ )

< Example  48> quinoline-4- Carboxylic acid -2- (2- Morpholine -4- days- Ethoxy )- Phenyl ester  Produce

1,3-dicyclohexylcarbodiimide (1.2 g), 4- (dimethylamino) pyridine (0.07 g), in a solution of quinoline-4-carboxylic acid (1.0 g) dissolved in methylene chloride (20 ml), After adding morpholinoethyl catechol (1.28 g), the mixture was stirred at room temperature for 10 hours. The reaction solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and separation and purification by silica gel column chromatography to obtain the target compound (1.3 g, 59%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.12-7.05 (m, 10H), 4.19 (t, 2H), 3.50 (t, 4H), 2.71 (t, 2H), 2.40 (t, 4H);

MS m / z 378 (M ⁺ )

< Experimental Example  1> OPG  Expression level measurement

One. OPG  Expression level measurement method

Human osteosarcoma cell line MG63 was seeded in 96 well plates at 104 cells / well to determine OPG secretion by compound treatment. Twenty four hours after seeding, the compounds were treated by concentration, and 20 mM potassium chloride (CaCl ₂ ), which was found to promote more than twice the OPG secretion by positive control in order to increase the reliability of the experiment, was not treated with the compound. In unwell wells. After 24 hours of incubation in a 30 ° C. 5% Co ₂ incubator, the cell culture supernatant is recovered. The recovered supernatant was diluted 40-fold using Dulbecco's phosphate buffered saline (DPBS), and 100 µl each of the OPG capture antibody-coated ELISA plate was reacted for 2 hours. In order to remove the remaining material after the reaction, the plate was washed four times with PBS (phosphate buffered saline) containing 0.05% tween 20, and then the OPG detection antibody was added and reacted for 2 hours. After the reaction, the plate was washed four times with PBS containing 0.05% tween 20 again, and streptavidin-HRP was added and reacted for 30 minutes. After the reaction, the well plate was washed four times, TMB substrate (TMB substrate) was added, and the color reaction was performed for 15 minutes at 37 ° C. under light blocking. When the blue color reaction did not change any more, 50 μl of a stop solution was added to stop the reaction, and the amount of OPG was quantified using the absorbance reading at 450 nm using an ELISA-reader. Experimental Example The OPG expression effect of the compound is shown in Table 1 below.

Compound number OPG expression activity (%) 0.5 μM 2.0 μM 4.0 μM One 204 212 246 3 139 210 235 4 119 111 113 5 146 165 208 6 132 144 175 7 127 178 188 8 123 174 207 9 113 175 203 10 134 141 172 11 115 107 207 12 109 82 96 13 133 178 179 14 141 173 176 16 129 117 128 17 93 104 123 18 98 162 157 19 130 132 117 20 104 112 112 21 100 94 102 22 79 114 131 23 114 144 175 24 116 132 138 25 57 117 74 26 57 62 85 27 85 117 111 28 108 116 101 29 106 129 136 30 108 121 131 31 118 125 132 32 115 135 151 33 135 141 159 34 125 132 136 35 130 124 128 36 135 142 146 37 96 119 127 38 98 99 99 39 115 108 181 40 114 115 112 41 108 121 120 42 115 182 131 43 89 96 107 44 98 146 73 45 74 129 114 46 106 143 119 47 76 113 97 48 111 111 101

< Experimental Example  2> Clinical efficacy test

1. Ovariectomy

During ovarian ablation, general anesthesia was performed by administering a mixture of ketamine HCl (Ketamin, 10 mg / kg) and 2% xylazine (Rompun 0.15 mg / kg) to the abdominal cavity of the rats in the cage. Hair removal and aseptic treatment (10% povidone-iodine scrub followed by a 70% alcohol wipe) were performed according to the method.

A 1 cm incision was made in the center of the rat's abdomen and the ovaries were checked along the uterus, taking care not to damage major organs such as the diaphragm or liver. The ovary was ligated with sutures and ovarian resection was performed on both sides. After ovarian resection, each organ was relocated into the abdominal cavity and layered sutures were performed with suture thread. The antibiotic cefazoline (cefazolin 50 mg / mg) was injected to prevent infection after surgery.

2. Bone Mineral Density Measurement

BMD was measured using XCT540 Research SA, a pQCT method manufactured in Germany. The pixel size was set to 0.1 mm × 0.1 mm × 0.1 mm and threshold values for calculating bone density were set to 280 mg / cm 2 (cavernosal bone measurement) and 500 mg / cm 2 (dense bone measurement). A scout scan (30 mm / sec) was used to determine the proximal tibia measurement location, and a CT scan (7 mm / sec) measured the bone density values at three slices at the specified location. Two of them were selected and the bone mineral density of spongy bone was measured.

3. Statistical Processing

The BMD was compared with the preoperative value and tested. The experimental results were analyzed by t-test (SigmaPlot 2000, version 6.0) to verify statistical significance (P <0.05).

4. Bone Mineral Density Measurement and Drug Administration in Rats

Bone mineral density was measured before ovarian resection for 12 week-old rats (approximately 230 g of body weight). It was. Bone mineral density measurements were taken for 8 weeks at 2 week intervals. Examples 1, 6, 7, 13, 14 and 16 bone density changes of the compounds are shown in Tables 2a to 2c below

Compound number % Change in bone density Week 0 2 weeks 4 Weeks 6 Weeks 8 Weeks Control 0.0 -6.7 -17.9 -23.5 -24.3 One 0.0 -5.9 -16.5 -21.2 -29.1

Compound number % Change in bone density Week 0 2 weeks 4 Weeks 6 Weeks 8 Weeks Control 0.0 -8.2 -18.2 -22.5 -28.0 14 0.0 -4.3 -9.4 -13.2 -18.8

Compound number % Change in bone density Week 0 2 weeks 4 Weeks 6 Weeks 8 Weeks Control 0.0 -11.6 -21.5 -28.3 -35.0 6 0.0 -3.5 -9.4 -13.4 -19.2 7 0.0 -3.8 -10.2 -14.3 -17.8 13 0.0 -4.2 -13.8 -20.2 -25.8 16 0.0 -3.3 -13.6 -17.2 -25.9

< Experimental Example  3> Pharmacokinetics  Research

In magnetic white paper Pharmacokinetics Parameter  Calculation

1. Animal testing

After the magnetic white paper of about 250 g was anesthetized with ether, a catheter was inserted into the femoral vein and the artery, and the compounds of Examples 6 and 7 were intravenously injected at 5 mg / kg for 1 minute. 0.3 ml of blood was taken through the femoral artery at 0, 5, 10, 15 and 30 minutes and 1, 2, 4, 6, 9 and 12 hours, respectively, to determine the concentration of the compounds of Examples 6 and 7 in the serum. . The collected blood was immediately left in an ice bath for 30 minutes, centrifuged at 3,000 rpm for 10 minutes, and the upper serum was collected and stored in a -20 ° C freezer until analysis.

2. In serum  Determination of Concentration of Compounds of the Invention

Merck's HPLC grade methanol and acetonitrile were used as reagents, and the instrument used was Shimadzu's HPLC system (Shimaju LC-10AD). The drug used the compound of Examples 6 and 7 above.

1) Standard solution

The compounds of Examples 6 and 7 were dissolved in methanol to 1 mg / ml to make a standard stock solution. The standard stock solution was diluted sequentially with methanol to make standard solutions of 40, 20, 10, 2, 1 and 0.5 μg / ml.

2) Standard calibration curve

Calibration concentrations were prepared at 0.05, 0.1, 0.2, 1, 2 and 4 μg / ml.

10 μl of standard solution (40, 20, 10, 2, 1 and 0.5 μg / ml) was added to 100 μl of empty serum, followed by mixing. 250 μl of acetonitrile was added and mixed, followed by centrifugation for 10 minutes to obtain a supernatant. 300 μl of the supernatant was evaporated to dryness under nitrogen gas, and then 50 μl of methanol was added for reconstitution, and then 20 μl was injected into HPLC for analysis.

3) extraction

100 μl of each serum was dispensed into 1 ml microtubes, and then 10 μl of methanol was added and mixed. 250 µl of acetonitrile was added and mixed, followed by centrifugation for 10 minutes to obtain a supernatant. 300 μl of the supernatant was evaporated to dryness under nitrogen gas, and then 50 μl of methanol was added for reconstitution, and then 20 μl was injected into HPLC for analysis. In HPLC analysis, the mobile phase used methanol / water (90/10 (v / v)), the column used the Shimidage ODS2 (4.6 × 250 mm, 5 μm), the flow rate was 1.2 ml / min, and the detection was Absorbance measurements were taken at a wavelength of 240 nm.

3. Pharmacokinetics Parameter  Calculation

After the intravenous administration of the compounds of Examples 6 and 7 at 5 mg / kg in a magnetic white paper, the average concentration in serum over time was plotted on a semilog scale. Indicates. Each pharmacokinetic parameter was calculated using a non-compartment open model using the WinNonlin program.

As a result, Table 3 shows the average value of the pharmacokinetic parameters of each of the five magnetic white papers.

Compound number Dose (mg / kg) CL (L / hr.kg) Vd (L / kg) Dissipation Half Life (hr) AUC (ng.hr/mL) Bioavailability (%) 6 Vein (1) 0.9 ± 0.1 5.3 ± 0.7 3.9 ± 0.7 1,080.5 ± 147.3 80.2 Oral (10) 1.2 ± 0.3 8.8 ± 0.9 5.3 ± 2.0 8,659.7 ± 1,780.9 7 Vein (1) 1.4 ± 0.1 8.4 ± 1.3 4.0 ± 0.6 698.5 ± 58.0 52.3 Oral (10) 2.9 ± 0.3 42.2 ± 8.0 9.9 ± 1.7 3,646.7 ± 426.0

 AUC: Area under the curve of blood concentration over time

 CL: clearance

 Vd: volume of distribution

< Experimental Example  4> Oral Acute Toxicity in Mice

Acute toxicity experiments were performed using specific pathogen-free (SPF) mice at around 40 g of 10 weeks of age. The compounds of Examples 6, 7, 13, and 16 were dissolved in 5% poloxamer solution to make 20 mg / ml, and then diluted stepwise using 5% poloxamer solution to give 5, 2.5, 1.25 and 0.625. A solution of mg / ml was made, followed by a single intraperitoneal injection of 0.4 ml of this solution, 5 per group. For oral administration, the compounds of Examples 6, 7, 13, and 16 were dissolved in edible corn oil to make 180 mg / ml, and then diluted stepwise with edible corn oil to make solutions of 80, 20 and 5 mg / ml, 0.4 ml of this solution was orally administered once per group. After administration of the compounds of Examples 6, 7, 13, and 16, the mortality, clinical symptoms, and weight changes of the animals were observed for two weeks, and hematological and hematological and biochemical tests were performed. Abnormalities of thoracic organs were observed. Plot the mortality rate of animals by dose 4 is shown.

Compound number LD ₅₀ (mg / kg) Male Female 6 1479 1148 7 708 676 13 > 2000 > 2000 16 > 2000 > 2000

From the results of Experimental Examples 1 to 4, the quinoline acid ester compound according to the present invention does not exhibit the problems that the osteoporosis treatment agents used in the prior art do not exhibit cytotoxicity to osteoclast progenitor cells and osteoblasts, and generate osteoclasts. And it turns out that it shows the activity which suppresses activity.

Therefore, the novel quinoline acid ester derivative according to the present invention can be usefully used as a prophylactic and therapeutic agent for metabolic bone diseases such as osteoporosis and osteoarthritis. Furthermore, it can be usefully used for height growth of growing children.

Hereinafter, the formulation example for the composition containing the compound of this invention is illustrated.

Using the compounds of Examples 6, 7, 13 or 16, a pharmaceutical composition comprising the following ingredients was prepared.

200 mg of the compound of Example 6, 7, 13 or 16

Vitamin C 50 mg

Lactose 150 mg

Total amount 400 mg

The ingredients were mixed well and filled into hard gelatin capsules to a total of 400 mg per capsule. In addition to vitamin C, the compositions may further include other healthful ingredients, and various oral preparations, such as tablets, granules, powders, microcapsules, drinks, suspensions, emulsions, syrups, and other liquids, according to conventional general preparations. It can be prepared as.

According to the present invention, novel quinoline ester derivatives can be obtained. The novel quinoline ester derivative according to the present invention can be usefully used as an agent for preventing and treating diseases such as osteoporosis and osteoarthritis, which are metabolic bone diseases by promoting the amount of OPG secreted from osteoblasts and inhibiting the differentiation of osteoclasts. have. In addition, since the expression level of the OPG can be controlled, the OPG concentration in the blood can be controlled by stopping the dosing during the overexpression of the OPG. Furthermore, the quinoline ester derivatives of the present invention start from low molecular weight materials that are easy to synthesize, and thus are inexpensive to manufacture, easy to manage, stable, and oral, and have low toxicity. There is no advantage.

Claims (13)

A novel quinoline ester derivative represented by the following formula (1), a pharmaceutically acceptable salt or solvate thereof. <Formula 1>

In Chemical Formula 1, X is hydrogen or halogen; Z is hydrogen, halogen, straight or branched C ₁ to C ₁₀ alkyl, C ₅ to C ₁₀ aryl, C ₂ to C ₈ heterocyclyl, C ₁ to C ₁₀ alkylamine, C ₁ to C ₁₀ alkenylamine, C ₅ to C ₁₀ aryl C ₁ to C ₁₀ alkylamine, C ₅ to C ₁₀ cycloalkylamine and C ₁ to C ₁₀ hydroxyalkylamine; R is a phenylcarboxyl group substituted with U and Y represented by the following formula (2); <Formula 2>

In Chemical Formula 2, U is -O- (CH ₂ ) _m -V or -CH ₂ -O- (CH ₂ ) _m -V, where m is an integer from 0 to 10, provided that X is hydrogen and Z is hydrogen U is not -OCH ₃ ; V is any one selected from the group consisting of hydrogen, halogen, C ₅ -C ₁₀ aryl substituted with R ₁ , C ₂ -C ₈ heterocyclyl, C ₅ -C ₁₀ aryloxy and C ₅ -C ₁₀ arylamine ego; R ₁ is any one selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₂ -C ₈ heteroaryl and C ₂ -C ₈ heterocyclo C ₁ -C ₁₀ alkyloxy; Y is hydrogen, halogen, hydroxy, amino, nitro, unsubstituted or substituted straight or branched C ₁ -C ₁₀ alkyl, C ₂ -C ₈ heterocyclyl, C ₁ -C ₁₀ alkyl C ₅ -C ₁₀ aryl and Any one selected from the group consisting of C ₂ to C ₈ heteroaryl; The heterocyclyl, heteroaryl or heterocycloalkyloxy includes one or more hetero atoms selected from the group consisting of N, O and S. The method of claim 1, X is hydrogen or halogen; Z is hydrogen, halogen, straight or branched C ₁ -C ₄ alkyl, C ₅ -C ₇ aryl, C ₂ -C ₅ heterocyclyl, C ₁ -C ₄ alkylamine, C ₁ -C ₄ alkenylamine, C ₅ to C ₆ aryl C ₁ to C ₄ alkylamine, C ₅ to C ₁₀ cycloalkylamine, and C ₁ to C ₄ hydroxyalkylamine; U is -O- (CH ₂ ) _m -V or -CH ₂ -O- (CH ₂ ) _m -V, where m is an integer from 0 to 5, provided that X is hydrogen and Z is hydrogen U is not -OCH ₃ ; V is one selected from hydrogen, halogen, R ₁ substituted C ₅ ~ C ₆ aryl group, C ₂ ~ C ₅ heterocyclyl, C ₅ ~ C ₆ aryloxy and C ₅ ~ group consisting of a C ₆ aryl amines ego; R ₁ is any one selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₂ -C ₅ heteroaryl and C ₂ -C ₅ heterocyclo C ₁ -C ₄ alkyloxy; Y is hydrogen, halogen, hydroxy, amino, nitro, unsubstituted or substituted straight or branched C ₁ -C ₄ alkyl, C ₂ -C ₅ heterocyclyl, C ₁ -C ₄ alkyl C ₅ -C ₆ aryl and Any one selected from the group consisting of C ₂ to C ₅ heteroaryl; The heterocyclyl, heteroaryl or heterocycloalkyloxy is a novel quinoline ester derivative, pharmaceutically acceptable salt or solvent thereof, characterized in that it comprises at least one hetero atom selected from the group consisting of N, O and S. freight. The method of claim 1, X is hydrogen, chlorine or bromine; Z is hydrogen, chlorine, bromine, methyl, ethyl, propyl, butyl, o-tolyl, ethylphenyl, pyrrolidinyl, piperidinyl, ethylamine, propylamine, isopropylamine, diisopropylamine, diisobutylamine , Propenylamine, butenylamine, 2-butenylamine, phenylethylamine, phenylpropylamine, phenylbutylamine, cyclopentylamine, cyclohexylamine and hydroxyethylamine, hydroxypropylamine and hydroxybutylamine Any one selected from the group consisting of; V is any one selected from the group consisting of hydrogen, halogen, phenyl substituted with R ₁ , pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyloxy, or phenylamine; R ₁ is a novel quinoline, characterized in that any one selected from the group consisting of hydrogen, chlorine, bromine, nitro, cyano, pyridinyl and morpholinomethyloxy, morpholinoethyloxy, morpholinopropyloxy Ester derivatives, pharmaceutically acceptable salts or solvates thereof. The method according to claim 1, wherein in Formula 1 R is 2, 3, 4 or 8, Z is independently or selectively substituted at any one of position 2 or 3 of the quinoline ring Novel quinoline ester derivatives, pharmaceutically acceptable salts or solvates thereof. The method of claim 1, wherein U and Y of the formula (2) are each independently or selectively substituted at any one of positions 2, 3, 4, 5 or 6 of the benzene ring One quinoline ester derivative, a pharmaceutically acceptable salt or solvate thereof. The compound of claim 1, wherein (1) 2-hydroxyphenyl-3,7-dichloroquinoline-8-carboxylate; (2) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-bromo-ethoxy) -phenylester; (3) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-phenylamino-ethoxy) -phenylester; (4) 3,7-dichloro-quinoline-8-carboxylic acid-2- [2- (2-nitro-phenylamino) -ethoxy] -phenyl ester; (5) 3,7-dichloro-quinoline-8-carboxylic acid-2- [2- (2-fluoro-phenylamino) -ethoxy] -phenylester; (6) 3,7-dichloro-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (7) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-pyrrolidin-1-yl-ethoxy) -phenylester; (8) 3,7-dichloro-quinoline-8-carboxylic acid-2- (2-piperidin-1-yl-ethoxy) -phenylester; (9) 3,7-dichloro-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; (10) 3,7-dichloro-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxymethyl) -phenylester; (11) 3,7-dichloro-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxymethyl) -phenylester; (12) 3,7-dichloro-quinolin-8-carboxylic acid 4- (2-morpholin-4-yl-ethoxymethyl) -phenylester; (13) 3,7-dichloro-quinoline-8-carboxylic acid-2- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -ethoxy-phenylester; (14) 2-hydroxyphenyl-7-chloro-3- (pyrrolidin-1-yl) quinoline-8-carboxylate; (15) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2- (2-bromo-ethoxy) -phenylester; (16) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (17) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (2-piperidin-1-yl-ethoxy) -phenylester; (18) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; (19) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2-benzyloxy-phenylester; (20) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-cyano-benzyloxy) -phenylester; (21) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-chloro-benzyloxy) -phenylester; (22) 7-chloro-3-pyrrolidin-1-yl-quinoline-8-carboxylic acid-2- (4-bromo-benzyloxy) -phenylester; (23) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (pyridin-2-ylmethoxy) -phenylester; (24) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (pyridin-4-ylmethoxy) -phenyl ester; (25) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- (4-morpholin-4-yl-butoxy) -phenylester; (26) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {2- [2- (2-morpholin-4-yl-ethoxy) -phenoxy] -Ethoxy} -phenyl ester; (27) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {4- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -Butoxy} -phenyl ester; (28) 7-chloro-3-pyrrolidin-1-yl-quinolin-8-carboxylic acid-2- {4- [2- (2-morpholin-4-yl-ethoxy) -phenoxy] -Butoxy} -phenyl ester; (29) 7-chloro-3-piperidin-1-yl-quinolin-8-carboxylic acid-2-hydroxy-phenylester; (30) 3-butylamino-7-chloro-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (31) 7-chloro-3- (2-hydroxy-ethylamino) -quinoline-8-carboxylic acid-2-hydroxy-phenylester; (32) 7-chloro-3-phenethylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (33) 7-chloro-3-diisopropylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (34) 7-chloro-3-cyclopentylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (35) 7-chloro-3-cyclohexylamino-quinoline-8-carboxylic acid-2-hydroxy-phenyl ester; (36) 7-chloro-3-allylamino-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (37) 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2-hydroxy-phenylester; (38) 7-chloro-3-o-tolyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (39) 7-chloro-3-o-tolyl-quinoline-8-carboxylic acid-2- {2- [3- (2-morpholin-4-yl-ethoxy) -phenoxy] -ethoxy} -Phenyl ester; (40) 2-methyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (41) 2-butyl-quinolin-8-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (42) quinoline-2-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (43) quinoline-2-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; (44) quinoline-2-carboxylic acid-4- (2-morpholin-4-yl-ethoxy) -phenylester; (45) quinoline-3-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; (46) quinoline-3-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester; (47) quinoline-4-carboxylic acid-3- (2-morpholin-4-yl-ethoxy) -phenylester; And (48) quinolin-4-carboxylic acid-2- (2-morpholin-4-yl-ethoxy) -phenylester Novel quinoline ester derivatives, pharmaceutically acceptable salts or solvates thereof, characterized in that any one selected from the group consisting of: Dissolving the compound of Formula 3 in a suitable solvent to prepare a starting material (step 1); And A process for preparing the novel quinoline ester derivative of claim 1 comprising the step (step 2) of preparing a compound of formula 1 by reacting the starting material with a compound of formula 2 in the presence of a base. <Scheme 1>

Wherein U, X, Y and Z are as defined in Formula 1 of claim 1 The method of claim 7, wherein the solvent of step 1 is any one selected from the group consisting of chloroform, toluene, acetone, acetonitrile, N, N- dimethylformamide, methylene chloride and water or mixed solvents thereof. Process for preparing novel quinoline ester derivatives. 8. The method for preparing a novel quinoline ester derivative according to claim 7, wherein the base of step 2 is at least one selected from the group consisting of triethylamine, sodium hydroxide and potassium carbonate. A pharmaceutical composition for the prevention and treatment of osteoporosis or osteoarthritis, containing a quinoline derivative represented by Formula 1 as an active ingredient. The quinoline derivative of claim 1, wherein the quinoline derivative represented by Formula 1 promotes secretion of osteoprotegerin (OPG) secreted from osteoblasts, thereby preventing and treating osteoporosis or osteoarthritis. Pharmaceutical composition for the prevention and treatment of osteoporosis or osteoarthritis containing. The pharmaceutical composition for preventing and treating osteoporosis or osteoarthritis of claim 10, wherein the quinoline derivative represented by Formula 1 prevents and treats osteoporosis or osteoarthritis by inhibiting the differentiation of osteoclasts. Composition. delete