Quinoline compounds, preparation methods thereof, and uses thereof as urate transporter inhibitor drug

Abstract

Quinoline compounds and salts, hydrates or solvates serving as a selective uric acid reabsorption inhibitor, can be used in the treatment of hyperuricemia and gout by promoting uric acid to excrete from the body and reducing serum uric acid. Such compounds have the effect of reducing the uric acid in the animal body and human body.

Claims

1. A compound of formula (I) or optical isomers or solvates or pharmaceutically acceptable salts or pro-drugs thereof, ##STR00170## wherein, R.sub.1 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, OR.sup.d, S(O).sub.mR.sup.d, C(O)R.sup.d, C(O)OR.sup.d, C(O)NR.sub.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f, in which said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independently and optionally further substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, OR.sup.d, S(O).sub.mR.sup.d, C(O)R.sup.d, C(O)OR.sup.d, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f; R.sub.2 is hydrogen and R.sub.3 is methyl; or R.sub.2 is hydrogen and R.sub.3 is ethyl; or, R.sub.2 is hydrogen and R.sub.3 is isopropyl; or, R.sub.2 and R.sub.3 are independently selected from the group consisting of halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, OR.sup.d, S(O).sub.mR.sup.d, C(O)R.sup.d, C(O)OR.sup.d, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, or heteroaryl are independently and optionally further substituted by one or more substituents that are selected from the group consisting of halogen, cyano, nitro, oxo-, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, OR.sup.d, S(O).sub.mR.sup.d, C(O)R.sup.d, C(O)OR.sup.d, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f; R.sup.d is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl, or heteroaryl is independently and optionally further substituted by one or more substituents that are selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo-, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxyl, carboxylic ester, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f; R.sup.e, R.sup.f are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independently and optionally further substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo-, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxyl, and carboxylic ester group; and m is 0, 1 or 2; R.sub.4 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, and cycloalkyl, wherein said alkyl and cycloalkyl are independently and optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo-, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxyl, carboxylic ester group, C(O)NR.sup.eR.sup.f, NR.sup.eR.sup.f, and NR.sup.eC(O)R.sup.f.

2. The compound according to claim 1, wherein, R.sub.1 is selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl, R.sub.2 and R.sub.3 are independently selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl, R.sub.4 is hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6cycloalkyl.

3. The compound according to claim 1, or optical isomers or solvates or pharmaceutically acceptable salts or pro-drugs thereof, wherein, R.sub.1 is selected from the group consisting of halogen, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxdiazolyl, substituted or unsubstituted thiadiazolyl, and C.sub.3-C.sub.6 cycloalkyl.

4. The compound according to claim 1, or optical isomers or solvates or pharmaceutically acceptable salts or pro-drugs thereof, wherein, R.sub.2 and R.sub.3 are independently halogen or C.sub.1-C.sub.6 alkyl.

5. The compound according to claim 4, or optical isomers or solvates or chemically pharmaceutically salts or pro-drugs thereof, wherein the compound has the structure of formula (Id) or (Ie): ##STR00171##

6. The compound according to claim 5, or optical isomers or solvates or pharmaceutically acceptable salts or pro-drugs thereof, wherein, R.sub.1 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxdiazolyl, substituted or unsubstituted thiadiazolyl, and C.sub.3-C.sub.6 cycloalkyl.

7. The compound according to claim 1, or optical isomers or solvates or chemically acceptable salts or pro-drugs, that are selected from the group consisting of ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186##

8. The method for preparation of compounds according to claim 1, comprising: ##STR00187## or, ##STR00188##

9. A method of treating abnormal uric acid levels, comprising administering the compound according to claim 1 or the optical isomer or the solvate or the pharmaceutically acceptable salt or the pro-drugs thereof to a patient in need thereof.

10. A method of treating diseases characterized by abnormal uric acid levels, wherein the diseases are selected from gout, gout attack, gouty arthritis and hyperuricemia, comprising administering a compound according to claim 1 or the optical isomer or the solvate or the pharmaceutically acceptable salt or the prodrug thereof to a patient in need thereof.

11. The compound according to claim 2, wherein R.sub.1 is selected from the group consisting of F, Br, Cl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl, trifluoromethyl, and cyclopropyl, wherein said phenyl is optionally further substituted by one or more substituents selected from the group consisting of methoxy, ethoxy, fluorine, chlorine, bromine, and trifluoromethyl.

12. The compound according to claim 4, wherein R.sub.2 and R.sub.3 are both methyl; or, R.sub.2 and R.sub.3 are both ethyl; or, R.sub.2 and R.sub.3 are both n-propyl.

13. The compound according to claim 6, wherein R.sub.1 is selected from the group consisting of F, Br, Cl, trifluoromethyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl, and cyclopropyl, wherein said phenyl is optionally further substituted by one or more substituents selected from the group consisting of methoxy, ethoxy, fluorine, chlorine, bromine, and trifluoromethyl, wherein the pharmaceutically acceptable salts thereof include the salts formed with bases, and sodium salt is preferable; further includes the salts formed with the pharmaceutically acceptable acids.

Description

EMBODIMENTS

(1) The general reaction scheme was described as below:

(2) ##STR00027##

Synthesis of ethyl 2-((6-bromoquinolin-4-yl)thio)-2-methylpropanoate (Int. 2)

(3) ##STR00028##

(4) To a 100 mL reaction bottle, were added 6-bromo-4-chloroquinoline (2.42 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), and N-methylpyrrolidone (30 mL), and the mixture was heated to 120 C. and allowed to react for 2 hours, to which were then added Cs.sub.2CO.sub.3 (6.52 g, 20 mmol) and ethyl 2-bromo-2-methylpropanoate (2.15 g, 11 mmol). The mixture continued reacting at 100 C. for 2 hours. After completion of reaction, water (150 mL) was added, and the reaction mixture was extracted with ethyl acetate thrice (3100 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated by rotatory evaporator. The residue was purified by column chromatography to afford Int 2 (2.1 g, yield 60%), MS: 354, 356 (M+H.sup.+).

Synthesis of 2-((6-bromoquinolin-4-yl)thio)-2-methylpropanoic Acid (22)

(5) ##STR00029##

(6) To a 100 mL reaction bottle, were added Int. 2 (354 mg, 1 mmol), CH.sub.3OH (5 mL), and water (5 mL), and the mixture was allowed to react at room temperature for 16 hours. After completion of reaction, the mixture was adjusted to about pH 5 with 2N HCl in icewater bath, then filtered. The filter cake was washed with water (10 mL), and dried to provide compound 22 (228 mg, yield 70%). .sup.1H NMR (400 MHz, DMSO): (ppm) 13.09 (s, 1H), 8.89 (d, J=4.0 Hz, 1H), 8.51 (d, J=4.0 Hz, 1H), 7.96 (m, 2H), 7.64 (d, J=4.0 Hz, 1H), 1.55 (s, 6H). MS: 326.1, 328.1 (M+H.sup.+).

(7) The target products 23, 24, 83, 93, 94, 95, 96, 114, 128, 129 were synthesized according to the same method, using the corresponding reagents.

(8) ##STR00030##

(9) Product 23 (2-(6-bromoquinolin-4-ylthio)propanoic acid): 312.0, 314.0 (M+H.sup.+).

(10) ##STR00031##

(11) Product 24 (2-(6-bromoquinolin-4-ylthio)butanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.22 (s, 1H), 8.81 (d, J=4.8 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.99-7.94 (m, 2H), 7.65 (d, J=4.8 Hz, 1H), 4.29 (t, J=7.2 Hz, 1H), 2.01-1.90 (m, 2H), 1.06 (t, J=7.2 Hz, 3H); MS: 325.9, 327.9 (M+H.sup.+).

(12) ##STR00032##

(13) Product 83 (2-(6-bromoquinolin-4-ylthio)-2-ethylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.09 (s, 1H), 8.87 (d, J=4.0 Hz, 1H), 8.56 (d, J=4.0 Hz, 1H), 7.96 (m, 2H), 7.61 (d, J=4.0 Hz, 1H), 1.84-1.77 (m, 4H), 0.92 (t, 6H). MS: 354.0, 356.0 (M+H.sup.+).

(14) ##STR00033##

(15) Product 93 (2-(quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 8.60 (d, J=4.0 Hz, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.07 (d, J=4.0 Hz, 1H), 7.65 (m, 2H), 7.51 (t, J=4.0 Hz, 1H), 1.81 (t, 6H). MS: 324.1 (M+H.sup.+).

(16) ##STR00034##

(17) Product 94 (2-(6-bromoquinolin-4-ylthio)-3-methylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.10 (s, 1H), 8.79 (d, J=8.0 Hz, 1H), 8.29 (d, J=4.0 Hz, 1H), 7.96 (m, 2H), 7.61 (d, J=8.0 Hz, 1H), 4.13 (d, J=7.6 Hz, 1H), 2.27-2.24 (m, 1H), 1.14-1.10 (t, 6H). MS: 340.0, 342.0 (M+H.sup.+).

(18) ##STR00035##

(19) Product 95 (2-(6,7-dimethoxyquinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 8.62 (d, J=4.0 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.40 (1H, s), 3.94 (6H, s), 1.51 (6H, s); MS: 308.1 (M+H.sup.+).

(20) ##STR00036##

(21) Product 96 (2-(6-trifluoromethylquinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.10 (s, 1H), 8.96 (d, J=8.0 Hz, 1H), 8.28 (d, J=4.0 Hz, 1H), 8.05 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 1.5 (s, 6H); MS: 316.0 (M+H.sup.+).

(22) ##STR00037##

(23) Product 114 (2-(6-bromoquinolin-4-ylthio)-2-propylpentanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 8.84 (d, J=4.0 Hz, 1H), 8.54 (d, J=4.0 Hz, 1H), 7.94 (m, 2H), 7.61 (d, J=4.0 Hz, 1H), 1.78-1.65 (m, 4H), 1.46-1.29 (m, 4H), 0.89-0.82 (m, 6H); MS: 381.9, 383.9 (M+H.sup.+).

(24) ##STR00038##

(25) Product 128 (2-(6-trifluoromethyl-quinolin-4-ylthio)-2-propylpentanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 13.01 (s, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.47 (d, J=4.0 Hz, 1H), 7.94 (m, 2H), 7.59 (d, J=4.0 Hz, 1H), 1.77-1.62 (m, 4H), 1.45-1.27 (m, 4H), 0.87-0.80 (m, 6H); MS: 344.1 (M+H.sup.+).

(26) ##STR00039##

(27) Product 129 (2-(quinolin-4-ylthio)-2-propylpentanoic acid) MS: 276.1 (M+H.sup.+)

Example 2

(28) ##STR00040##
Synthesis of Product 87
To a 100 mL reaction bottle, were added Int. 2 (325 mg, 1 mmol), dichloromethane (10 mL), DMF (20 mg), and then oxalyl chloride (1 g, 8 mmol) was added. The mixture was heated to 40 C. and allowed to react for 1 hour, and concentrated to dry. Then, CH.sub.2Cl.sub.2 (10 mL) and triethylamine (500 mg, 5 mmol) were added, and 4-aminopyridine (190 mg, 2 mmol) was finally added. The mixture was heated to 40 C. and reacted for 1 hour. After completion of reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (350 mL) thrice. The organic layers were combined, washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated by rotatory evaporator. The residue was purified by column chromatography to afford the product 87 (160 mg, yield 40%). MS: 401.0, 403.0 (M+H.sup.+).
The target products 88, 89, 90, 91, 92 were synthesized as the same method, using corresponding reagents.

(29) ##STR00041##

(30) Product 88 (2-(6-bromoquinolin-4-ylthio)-2-methylpropionyl-(2-aminopyridine)): MS: 401.0, 403.0 (M+H.sup.+).

(31) ##STR00042##

(32) Product 89 (2-(6-bromoquinolin-4-ylthio)-2-methylpropionyl-(3-aminopyridine)): MS: 401.0, 403.0 (M+H.sup.+).

(33) ##STR00043##

(34) Product 90 (2-(quinolin-4-ylthio)-2-methylpropionyl-(4-aminopyridine)): MS: 324.1 (M+H.sup.+).

(35) ##STR00044##

(36) Product 91 (2-(quinolin-4-ylthio)-2-methylpropionyl-(2-aminopyridine)): MS: 324.1 (M+H.sup.+).

(37) ##STR00045##

(38) Product 92 (2-(quinolin-4-ylthio)-2-methylpropionyl-(3-aminopyridine)): MS: 324.1 (M+H.sup.+).

Example 3

(39) ##STR00046##
To a 50 mL reaction bottle, were added Int. A-1 (112 mg, 0.33 mmol), cyclopropanesulfonamide (52 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol), DIPEA (129 mg, 1 mmol), and DMF (3 mL), and stirred at room temperature for 16 hours. After completion of reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL3) and dried by rotatory evaporator. The residue was purified by prep-HPLC to afford compound 105 (50 mg, yield 34%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.70 (d, J=4.6 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.85 (m, 1H), 6.95 (d, J=4.8 Hz, 1H), 3.18-3.10 (m, 2H), 2.83-2.73 (m, 2H), 2.42 (dd, J=11.2 Hz, 2H), 2.26-2.14 (m, 1H), 1.18-1.12 (m, 2H), 0.91-0.84 (m, 2H). MS: 440.8, 442.8 (M+H.sup.+).
Compounds 106 and 107 were prepared according to the same preparative way, using the corresponding starting materials.

(40) ##STR00047##

(41) Product 106 2-(6-bromoquinolin-4-ylthio)-N-(cyclopropylsulfonyl)-2-methylpropanamide: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.78 (d, J=4.7 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.85 (m, 1H), 7.33 (d, J=4.6 Hz, 1H), 2.98-2.90 (m, 2H), 1.73 (s, 6H), 2.26-2.14 (m, 1H), 1.38-1.31 (m, 2H); MS: 428.8, 430.8 (M+H.sup.+).

(42) ##STR00048##

(43) Product 107 1-(6-bromoquinolin-4-ylthio)-N-(methylsulfonyl)cyclobutyl-1-formamide (107): MS: 414.8, 416.8 (M+H.sup.+).

Example 4

(44) ##STR00049##
Synthesis of Int. 4

(45) ##STR00050##
To a 50 mL reaction bottle, were added Int. 3 (241 mg, 1 mmol), 2-methoxyphenylboronic acid (152 mg, 1 mmol), Na.sub.2CO.sub.3 (212 mg, 2 mmol), Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol), dioxane (6 mL), and water (3 mL), and then nitrogen was purged. The mixture was heated to 110 C. under protection of N.sub.2 and allowed to react for 2 hours. After completion of reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (350 ml) thrice. The organic layers were combined, washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and rotatory evaporated. The residue was purified by column chromatography to afford Int. 4 (190 mg, yield 50%). MS: 270.0, 272.0 (M+H.sup.+).
Synthesis of Int. 5

(46) ##STR00051##
To a 100 mL reaction bottle, were added Int. 4 (2.69 g, 10 mmol), Na.sub.2S (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL), and the mixture was heated to 120 C. and allowed to react for 2 hours. Then, to the reaction bottle, were added Cs.sub.2CO.sub.3 (6.52 g, 20 mmol) and ethyl 2-bromo-2-methylpropanoate (2.15 g, 11 mmol), and the reaction mixture was continued being heated to 100 C. for 2 hours. After completion of reaction, 150 mL water was added, and the reaction mixture was extracted with ethyl acetate (3100 ml) thrice. The organic layers were combined, washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and rotatory evaporated. The residue was purified by column chromatography to afford Int. 5 (2.1 g, yield 60%). MS: 382.0 (M+H.sup.+).
Synthesis of 19

(47) ##STR00052##

(48) To a 100 mL reaction bottle, were added Int. 5 (381 mg, 1 mmol), CH.sub.3OH (5 mL), and water (5 mL), and the mixture was allowed to react at room temperature for 16 hours. After completion of reaction, the reaction mixture was adjusted to about pH 5 with 2N HCl in icewater bath and filtered. The filter cake was washed with water (10 mL), and dried to provide compound 19 (247 mg, yield 70%). MS: 354.1 (M+H.sup.+).

(49) Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 84, 85, 86, 100, 101, 102, 103, 104, 108, 109, 110, 111, 112, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 138, 139, 140, 141, 142 were synthesized according to the same method, using the corresponding reagents.

(50) ##STR00053##

(51) Product 1 (2-(6-cyclopropylquinolin-4-ylthio)-2-methylpropanoic acid: .sup.1H NMR (400 MHz, DMSO): (ppm) 12.97 (s, 1H), 8.72 (d, J=4.0 Hz, 1H), 8.03 (d, J=4.0 Hz, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.52-7.47 (m, 2H), 2.20-2.09 (m, 1H), 1.55 (s, 6H), 1.10-1.02 (m, 2H), 0.83-0.75 (m, 2H). MS: 288.1 (M+H.sup.+).

(52) ##STR00054##

(53) Product 2 (2-(6-(pyridin-2-yl)quinolin-4-ylthio)-2-methylpropanoic acid): MS: 325.1 (M+H.sup.+).

(54) ##STR00055##

(55) Product 3 (2-(6-(pyridin-3-yl)quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (400 MHz, DMSO): (ppm) 12.94 (s, 1H), 9.04 (d, J=4.0 Hz, 1H), 8.88 (m, 1H), 8.66-8.62 (m, 2H), 8.22-8.16 (m, 3H), 7.66 (d, J=4.0 Hz, 1H), 7.58 (m, 1H), 1.58 (s, 6H). MS: 325.1 (M+H.sup.+).

(56) ##STR00056##

(57) Product 4 (2-(6-(pyridin-4-yl)quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (400 MHz, DMSO): (ppm) 13.00 (s, 1H), 8.90 (d, J=4.0 Hz, 1H), 8.74-8.70 (m, 3H), 8.22-8.20 (m, 2H), 7.86 (m, 2H), 7.67 (d, J=4.0 Hz, 1H), 1.58 (s, 6H). MS: 325.1 (M+H.sup.+).

(58) ##STR00057##

(59) Product 5 (2-(6-cyclopropylquinolin-4-ylthio)propanoic acid: MS: 274.1 (M+H.sup.+).

(60) ##STR00058##

(61) Product 6 (2-(6-cyclopropylquinolin-4-ylthio)butanoic acid): MS: 288.1 (M+H.sup.+).

(62) ##STR00059##

(63) Product 7 (2-(6-(pyridin-2-yl)quinolin-4-ylthio)propanoic acid): MS: 311.1 (M+H.sup.+).

(64) ##STR00060##

(65) Product 8 (2-(6-(pyridin-2-yl)quinolin-4-ylthio)butanoic acid): MS: 325.1 (M+H.sup.+).

(66) ##STR00061##

(67) Product 9 (2-(6-(pyridin-3-yl)quinolin-4-ylthio)propanoic acid): MS: 311.1 (M+H.sup.+).

(68) ##STR00062##

(69) Product 10 (2-(6-(pyridin-3-yl)quinolin-4-ylthio)butanoic acid): MS: 325.1 (M+H.sup.+).

(70) ##STR00063##

(71) Product 11 2-((6-(pyridin-4-yl)quinolin-4-ylthio)propanoic acid): MS: 311.1 (M+H.sup.+).

(72) ##STR00064##

(73) Product 12 (2-(6-(pyridin-4-yl)quinolin-4-ylthio)butanoic acid): MS: 325.1 (M+H.sup.+).

(74) ##STR00065##

(75) Product 13 (2-(6-(2-methoxyphenyl)-quinolin-4-ylthio)propanoic acid): MS: 340.1 (M+H.sup.+).

(76) ##STR00066##

(77) Product 14 (2-(6-(2-methoxyphenyl)quinolin-4-ylthio)butanoic acid): MS: 354.1 (M+H.sup.+).

(78) ##STR00067##

(79) Product 15 (2-(6-(3-methoxyphenyl)-quinolin-4-ylthio)propanoic acid): MS: 340.1 (M+H.sup.+).

(80) ##STR00068##

(81) Product 16 (2-(6-(3-methoxyphenyl)-quinolin-4-ylthio)butanoic acid): MS: 354.1 (M+H.sup.+).

(82) ##STR00069##

(83) Product 17 (2-(6-(4-methoxyphenyl)-quinolin-4-ylthio)propanoic acid): MS: 340.1 (M+H.sup.+).

(84) ##STR00070##

(85) Product 18 (2-(6-(4-methoxyphenyl)quinolin-4-ylthio)butanoic acid): MS: 354.1 (M+H.sup.+).

(86) ##STR00071##

(87) Product 19 (2-(6-(2-methoxyphenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 12.98 (s, 1H), 8.84 (d, J=4.0 Hz, 1H), 8.43 (d, J=4.0 Hz, 1H), 8.06 (d, J=4.0 Hz, 1H), 7.95 (m, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.44-7.41 (m, 2H), 7.19 (d, J=4.0 Hz, 1H), 7.13-7.09 (m, 1H), 3.87 (s, 3H), 1.56 (s, 6H); MS: 354.1 (M+H.sup.+).

(88) ##STR00072##

(89) Product 20 (2-(6-(3-methoxyphenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 8.92 (d, J=4.9 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.22 (dt, J=22.3, 5.3 Hz, 2H), 7.67 (d, J=4.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.42-7.31 (m, 2H), 7.05 (dd, J=8.1, 1.8 Hz, 1H), 3.87 (s, 3H), 1.64 (s, 6H); MS: 354.1 (M+H.sup.+).

(90) ##STR00073##

(91) Product 21 (2-(6-(4-methoxyphenyl)quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 12.99 (s, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.10 (m, 2H), 7.77 (d, J=4.0 Hz, 2H), 7.60 (d, J=4.0 Hz, 1H), 7.11 (d, J=4.0 Hz, 2H), 3.84 (s, 3H), 1.57 (s, 6H); MS: 354.1 (M+H.sup.+).

(92) ##STR00074##

(93) Product 25 (2-(6-(2-fluorophenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.02 (s, 1H), 8.88 (d, J=4.0 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.02-8.0 (m, 1H), 8.00-7.99 (m, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.54-7.49 (m, 1H), 7.43-7.38 (m, 2H), 1.57 (s, 6H); MS: 342.0 (M+H.sup.+).

(94) ##STR00075##

(95) Product 26 (2-(6-(2-fluorophenyl)-quinolin-4-ylthio)propanoic acid): MS: 328.0 (M+H.sup.+).

(96) ##STR00076##

(97) Product 27 (2-(6-(2-fluorophenyl)-quinolin-4-ylthio)butanoic acid): MS: 342.0 (M+H.sup.+).

(98) ##STR00077##

(99) Product 28 (2-(6-(3-fluorophenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 12.97 (s, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.59 (s, 1H), 8.18-8.13 (m, 2H), 7.69-7.60 (m, 4H), 7.32-7.27 (m, 1H), 1.58 (s, 6H); MS: 342.0 (M+H.sup.+).

(100) ##STR00078##

(101) Product 29 (2-(6-(3-fluorophenyl)quinolin-4-ylthio)propanoic acid): MS: 328.0 (M+H.sup.+).

(102) ##STR00079##

(103) Product 30 (2-(6-(3-fluorophenyl)-quinolin-4-ylthio)butanoic acid): MS: 342.0 (M+H.sup.+).

(104) ##STR00080##

(105) Product 31 (2-(6-(4-fluorophenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 342.0 (M+H.sup.+).

(106) ##STR00081##

(107) Product 32 (2-(6-(4-fluorophenyl)quinolin-4-ylthio)propanoic acid): MS: 328.0 (M+H.sup.+).

(108) ##STR00082##

(109) Product 33 (2-(6-(4-fluoro-phenyl)-quinolin-4-ylthio)butanoic acid): MS: 342.0 (M+H.sup.+).

(110) ##STR00083##

(111) Product 34 (2-(6-(4-(trifluoromethyl)phenyl)quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 12.98 (s, 1H), 8.89 (d, J=4.0 Hz, 1H), 8.64 (s, 1H), 8.19 (d, J=4.0 Hz, 2H), 8.06 (d, J=4.0 Hz, 2H), 7.91 (d, J=4.0 Hz, 2H), 7.66 (d, J=4.0 Hz, 1H), 1.57 (s, 6H); MS: 392.0 (M+H.sup.+).

(112) ##STR00084##

(113) Product 35 (2-(6-(4-trifluoromethyl-phenyl)-quinolin-4-ylthio)propanoic acid): MS: 378.0 (M+H.sup.+).

(114) ##STR00085##

(115) Product 36 (2-(6-(4-trifluoromethyl-phenyl)-quinolin-4-ylthio)butanoic acid): MS: 392.0 (M+H.sup.+).

(116) ##STR00086##

(117) Product 37 (2-(6-(2-(trifluoromethyl-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm) 13.02 (s, 1H), 8.89 (d, J=4.0 Hz, 1H), 8.25 (d, J=4.0 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.78-7.70 (m, 3H), 7.61-7.55 (m, 2H), 1.53 (s, 6H); MS: 392.0 (M+H.sup.+).

(118) ##STR00087##

(119) Product 38 (2-(6-(2-trifluoromethyl-phenyl)-quinolin-4-ylthio)propanoic acid): MS: 378.0 (M+H.sup.+).

(120) ##STR00088##

(121) Product 39 (2-(6-(2-trifluoromethyl-phenyl)-quinolin-4-ylthio)butanoic acid): MS: 392.0 (M+H.sup.+).

(122) ##STR00089##

(123) Product 40 (2-(6-(3-trifluoromethyl-phenyl)quinolin-4-ylthio)-2-methylpropanoic acid): MS: 392.0 (M+H.sup.+).

(124) ##STR00090##

(125) Product 41 (2-(6-(3-trifluoromethyl-phenyl)-quinolin-4-ylthio)propanoic acid): MS: 378.0 (M+H.sup.+).

(126) ##STR00091##

(127) Product 42 (2-(6-(3-trifluoromethyl-phenyl)-quinolin-4-ylthio)butanoic acid): MS: 392.0 (M+H.sup.+).

(128) ##STR00092##

(129) Product 84 (2-(6-(3,4-dimethoxy-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 384.0 (M+H.sup.+).

(130) ##STR00093##

(131) Product 85 (2-(6-(3,4-dimethoxy-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 412.0 (M+H.sup.+).

(132) ##STR00094##

(133) Product 86 (2-(6-cyclopropylquinolin-4-ylthio)-2-ethylbutanoic acid): MS: 316.0 (M+H.sup.+).

(134) ##STR00095##

(135) Product 100 (2-(6-(4-cyano-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 349.0 (M+H.sup.+).

(136) ##STR00096##

(137) Product 101 (2-(6-(3-trifluoromethoxy-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid (101): MS: 408.0 (M+H.sup.+).

(138) ##STR00097##

(139) Product 102 (2-(6-(3-ethoxy-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 368.0 (M+H.sup.+).

(140) ##STR00098##

(141) Product 103 (2-(6-(3-isopropoxy-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 382.0 (M+H.sup.+).

(142) ##STR00099##

(143) Product 104 (2-(6-(3-(difluoromethoxy-phenyl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 390.0 (M+H.sup.+).

(144) ##STR00100##

(145) Product 108 (2-(6-(3-ethoxy-phenyl)-quinolin-4-ylthio)-2-propylpentanoic acid): MS: 424.1 (M+H.sup.+).

(146) ##STR00101##

(147) Product 109 (2-(6-(3-cyclopropyloxy-phenyl)-quinolin-4-ylthio)-2-propylpentanoic acid): MS: 436.1 (M+H.sup.+).

(148) ##STR00102##

(149) Product 110 (2-(6-(3-cyclobutyloxy-phenyl)-quinolin-4-ylthio)-2-propylpentanoic acid): MS: 450.1 (M+H.sup.+).

(150) ##STR00103##

(151) Product 111 (2-(6-(3-cyclobutyloxy-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 422.1 (M+H.sup.+).

(152) ##STR00104##

(153) Product 112 (2-(6-(3-cyclopropyloxy-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 408.1 (M+H.sup.+).

(154) ##STR00105##

(155) Product 113 (2-(6-(3-ethoxy-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 396.1 (M+H.sup.+).

(156) ##STR00106##

(157) Product 115 (2-(6-(2-methoxypyridin-4-yl)quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 13.02 (s, 1H), 8.95 (d, J=4.0 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.36 (d, J=4.0 Hz, 1H), 8.20 (m, 2H), 7.66 (d, J=4.0 Hz, 1H), 7.47 (m, 1H), 7.24 (s, 1H), 3.94 (s, 3H), 0.95-0.85 (m, 6H); MS: 355.1 (M+H.sup.+).

(158) ##STR00107##

(159) Product 116 (2-(6-(2-methoxypyridin-4-yl)quinolin-4-ylthio)-2-ethylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 12.96 (s, 1H), 8.87 (d, J=4.0 Hz, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.33 (d, J=4.0 Hz, 1H), 8.18 (m, 2H), 7.64 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.24 (s, 1H), 3.94 (s, 3H), 1.91-1.82 (m, 4H), 0.95-0.85 (m, 6H); MS: 383.2 (M+H.sup.+).

(160) ##STR00108##

(161) Product 117 (2-(6-(2-fluoropyridin-4-yl)-quinolin-4-ylthio)-2-methylpropanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 13.02 (s, 1H), 8.95 (d, J=4.0 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.36 (d, J=4.0 Hz, 1H), 8.20 (m, 2H), 7.66 (d, J=4.0 Hz, 1H), 7.47 (m, 1H), 7.24 (s, 1H), 0.93 (m, 6H); MS: 343.0 (M+H.sup.+).

(162) ##STR00109##

(163) Product 118 (2-(6-(2-fluoropyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 12.96 (s, 1H), 8.87 (d, J=4.0 Hz, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.33 (d, J=4.0 Hz, 1H), 8.18 (m, 2H), 7.64 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.24 (s, 1H), 3.94 (s, 3H), 1.89 (m, 4H), 0.91 (m, 6H); MS: 371.0 (M+H.sup.+).

(164) ##STR00110##

(165) Product 119 (2-(6-(pyridin-4-yl)quinolin-4-ylthio)-2-ethylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 13.00 (s, 1H), 8.90 (d, J=8.0 Hz, 1H), 8.72 (m, 3H), 8.21 (m, 2H), 7.86 (m, 2H), 7.67 (d, J=4.0 Hz, 1H), 1.93 (m, 4H), 1.58 (m, 6H); MS: 353.1 (M+H.sup.+).

(166) ##STR00111##

(167) Product 120 (2-(6-(2-methylpyridin-4-yl)quinolin-4-ylthio)-2-methylpropanoic acid): 13.03 (s, 1H), 8.87 (d, J=4.0 Hz, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.33 (d, J=4.0 Hz, 1H), 8.18 (m, 2H), 7.64 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.24 (s, 1H), 2.71 (s, 3H), 1.52 (m, 6H); MS: 339.1 (M+H.sup.+).

(168) ##STR00112##

(169) Product 121 (2-(6-(2-methylpyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid): .sup.1H NMR (DMSO, 400 MHz): (ppm): 12.99 (s, 1H), 8.85 (d, J=4.0 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.15 (m, 2H), 7.69 (d, J=4.0 Hz, 1H), 7.47 (m, 1H), 7.26 (s, 1H), 3.94 (s, 3H), 1.92 (m, 4H), 0.9 (m, 6H); MS: 367.1 (M+H.sup.+).

(170) ##STR00113##

(171) Product 122 (2-(6-(3-fluoropyridin-4-yl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 343.1 (M+H.sup.+).

(172) ##STR00114##

(173) Product 123 (2-(6-(3-fluoropyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 371.1 (M+H.sup.+).

(174) ##STR00115##

(175) Product 124 (2-(6-(3-chloropyridin-4-yl)-quinolin-4-ylthio)-2-methylpropanoic acid): MS: 359.0 (M+H.sup.+).

(176) ##STR00116##

(177) Product 125 (2-(6-(3-chloropyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid (125): MS: 387.0 (M+H.sup.+).

(178) ##STR00117##

(179) Product 126 (2-(6-(2-hydroxypyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 369.0 (M+H.sup.+).

(180) ##STR00118##

(181) Product 127 (2-(6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-quinolin-4-ylthio)-2-ethylbutanoic acid (127): MS: 383.0 (M+H.sup.+).

(182) ##STR00119##

(183) Product 138 (2-(6-(3-cyano-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 377.1 (M+H.sup.+).

(184) ##STR00120##

(185) Product 139 (2-(6-(3-trifluoromethyl-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid (139): MS: 420.1 (M+H.sup.+).

(186) ##STR00121##

(187) Product 140 (2-(6-(3-fluoro-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 370.1 (M+H.sup.+).

(188) ##STR00122##

(189) Product 141 (2-(6-(2-fluoro-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 370.1 (M+H.sup.+).

(190) ##STR00123##

(191) Product 142 (2-(6-(4-fluoro-phenyl)-quinolin-4-ylthio)-2-ethylbutanoic acid): MS: 370.1 (M+H.sup.+).

Example 2 Biological Assay of Compounds According to the Present Invention

(192) Test example: Determination of the inhibitory activity of compounds according to the present invention against URAT1
Experimental Materials FBS (Invitrogen, Cat. No. 10099141) Trypsin (Invitrogen, Cat. No. 25200056) DPBS (Invitrogen, Cat. No. 14190250) DMEM (Invitrogen, Cat. No. 10564) Penicillin-Streptomycin (Invitrogen, Cat. No. 15070-063) TransIT-293 Transfection Reagent (MIRUS BIO, Cat. No. MIR2706) Opti-MEM I Reduced Serum Medium (Invitrogen, Cat. No. 31985-070) URAT1 plasmid (Genecopoeia, Cat. No. EX-T4563-M03) Uric acid [8-14C] (ARC, Cat. No. ARC0513-250UCI) Ultima Gold XR (PerkinElmer, Cat. No. 6013111) Benzbromarone (J&K Scientific, Cat. No. 3562-84-3) D-Gluconic acid sodium salt (Aladdin, Cat. No. 527-07-1) Potassium D-gluconate (Aladdin, Cat. No. 299-27-4) Calcium gluconate (Aladdin, Cat. No. 299-28-5) DMSO (Sigma, Cat. No. D2650) Tube, 15 ml (Greiner, Cat. No. 07030115) Tube, 50 ml (BD Falcon, Cat. No. 352098) Poly-D-lysine 96-well microplates (BD, Cat. No. 356461) Isoplate-96 Microplate (PERKIN ELMER, Cat. No. 6005040)
Experimental Method:

(193) Buffer Preparation

(194) TABLE-US-00001 Cl free HBSS buffer Cell lysate solution 100 mM NaOH 125 mM Sodium gluconate 4.8 mM Potassium gluconate 1.3 mM Calcium gluconate 1.2 mM KH.sub.2PO.sub.4 1.2 mM MgSO.sub.4 5.6 mM Glucose 25 mM HEPES (pH 7.4)

(195) Cell Culture: 1. The HEK-293t cells that expressed the stable expression of hURAT1 were cultured in DMEM medium containing 10% FBS and 1% P/S, and incubated overnight in the incubator at 37 C. under 5% carbon dioxide. 2. the culture medium was removed, and the cells were washed with PBS, and then the pancreatin was added to digest for 2 minutes. After the cell is separated from the dish, 10 ml of medium was added to terminate digestion. 3. The cells were placed into a centrifugal apparatus and centrifugated for 2 minutes at the speed of 1000 rpm, followed by the addition of fresh 10 mL medium to resuspend the cells, and calculate the number of cells. The number of cells was adjusted to 410.sup.5 cells/mL. 4. the above counted cells were inoculated into the 96-well plate at 100 L/well. 5. The 96-well plate with inoculated cells was placed in a 37 C. cell incubator and cultivated overnight.

(196) The uric acid absorption experiment labeled with isotope C14: 1. 5 mL of Cl-free HBSS buffer was added to a 15 mL centrifuge tube, followed by the addition of the uric acid labeled with C14, and the concentration of uric acid was 2 uCi/ml. 2. The medium in the 96-well plate that was previously cultivated overnight was removed, and the plate was washed three times with 100 mL preheated Cl-free HBSS buffer. 3. The buffer in the well-washed 96-well plate was removed. 4. 50 mL Cl-free HBSS buffer containing C-14 labeled uric acid was added into each well in the cleaned 96-well plate, and then DMSO solution of the compound that needs to be tested was added. 5. After the 96-well plate stood for 5 minutes at room temperature, all the liquid in it was removed. 6. 100 mL precooled Cl-free HBSS buffer was added to wash the plate three times. 7. After the remained liquid in the plates was completely removed, 50 L cell lysis was added to each well, and the plate was agitated on the mixer at a speed of 600 revolutions/min for 10 minutes. 8. After 50 L Ultima Gold XR scitillation cocktail fluid was added, the plate was continued to agitate for 10 minutes. The well-agitated plate was sealed, and the data was read on MicroBeta Trilux. 9. The test compound was dissolved in DMSO, and DMSO at the same concentration was added to the HEK293/hURAT1 cell well without test compounds. The uric acid uptake of cells at each test concentration was expressed as the average percentage inhibition ratio, comparable to the control DMSO. The radiation value obtained from the well containing DMSO is considered to be 100% of the cell uptake. The IC.sub.50 values of compounds can be calculated by the inhibition rate at different concentrations.

(197) The IC.sub.50 values (nM) of hURAT1 inhibitory activity for compounds according to the present invention are shown in table 1. Among them, reference compound 1 was synthesized according to the method described in patent WO 2011/159839 A2. Reference compound 2 and reference compound 3 were synthesized according to the method described in patent WO 2014/183555 A1, and they were head-to-head tested with compounds 83 and 129 respectively under the same conditions. The IC.sub.50 values of the reference compound 2 and compound 83 are the average of the multiple head-to-head comparison tests. The IC.sub.50 values of the reference compound 3 and 129 are the average of two comparison tests.

(198) TABLE-US-00002 TABLE 1 Compound No. Structure IC.sub.50 (nM) Ref cpd 1 (RDEA3170) 153.8 Ref Cpd 2 137.7 Ref Cpd 3 794 1 486 3 514 4 127 19 0 472 20 21 21 1896 24 6000 22 159 25 812 96 772 83 70.6 129 201 93 2400 114 0 203 117 272 118 36 105 1779 106 235 37 325 100 8140 101 710 28 351 34 4600 37 0 325 115 79 116 98 107 336 94 4300 95 >30000 128 74 109 722 110 2858 102 32 103 0 37 104 238 108 523 112 147 113 109 119 133 123 1400 111 267 120 1235 121 360

(199) It can be seen from the above table that the compounds according to the present invention have an obvious inhibitory effect on uric acid transporter URAT1.

(200) Reference compounds 1 and 2 are known to be high active inhibitors against uric acid transporter URAT1. Compound 83 showed a better inhibitory activity against the uric acid transporter than compound 1. Meanwhile, the statistical analysis on the activity data of compound 83 and the reference compound 2 obtained by multiple head to head tests is shown in table 2, and the results demonstrated that the activity of compound 83 was significantly different from that of reference compound 2. Combined with the structure and activity comparison of compound 129 and compounds 3, obviously, in the present invention, that the cycloalkyls at certain position of the compounds are substituted by ring-opened alkyl, especially the diethyl substituent, significantly increased the inhibitory activity of the compound against uric acid transporter URAT1.

(201) TABLE-US-00003 TABLE 2 Ref cpd2 (nM) Cpd 83 (nM) Multiple 72.9, 185, 172, 42.5, 117, 89, determination data 164, 144, 127, 99 93, 56, 58, 38.9 Average 137.7 70.6 SD 29.3 26.6 p values (Ref cpd 2) 0.00008

(202) Various compounds and salts, hydrates or solvates provided in the present invention are a uric acid reuptake inhibitor with higher selectivity than the typical compounds in this art. They can promote the uric acid excretion from the body and reduce serum uric acid to treat or prevent diseases characterized by abnormal uric acid levels. Amongst, the diseases are selected from the group of gout, recurrent gout symptoms, hyperuricemia, cardiovascular disease, Lesch-Nyhan syndrome, Kearns-Sayre Syndrome, kidney disease, arthritis, urinary stone disease, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyl transferase deficiency, with a characteristic of, with an effect of reducing uric acid in animal and human body.