P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

R 1 is aryl, heteroaryl, acrylaryl, acrylheteroaryl, heterocycloalkenyl, or carbocyclo, which is optionally substituted with one or more substituents selected from the group consisting of C 1-5 alkyl, hydroxy, C 1-5 alkoxy, halogen, trifluoromethyl, nitro and amino;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, nitro, C 1-5 alkyl or alkoxy, R 6 and R 11 being optionally fused together to form a 4 to 8-membered ring;

m and n are each independently an integer ranging from 0 to 4; and

X is CH 2 , O or S.

2. The compound of claim 1 , wherein R 1 is unsubstituted or substituted phenyl, pyridine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, pyrazole, imidazole, triazole, oxazole, thiazole, oxadiazole, thiadiazole, benzothiazole, benzoxazole, chromone, quinolone, cinnamic or quinoline acryl.

3. The compound of claim 2 , which is selected from the group consisting of:

quinoline-3-carboxylic acid [2-(2-4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

quinoline-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

isoquinoline-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

quinoline-8-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

isoquinoline-1-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

quinoline-4-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

4-methoxy-quinoline-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

quinoxaline-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

pyridine-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-nicotinamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-isonicotinamide;

pyrazine-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-benzamide;

naphthalene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-2-fluoro-benzamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-3-fluoro-benzamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-4-fluoro-benzamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-3,4-difluoro-benzamide;

thiophene-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

furan-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

6-methyl-4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

5-hydroxy-4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

5-methoxy-4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

6-fluoro-4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

6-bromo-4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

cinoline-4-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

4-oxo-4H-chromene-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

quinoline-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-difluoro-phenyl]-amide;

quinoline-3-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylsulfanyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide;

N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-3-phenyl-acrylamide;

N-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-3-quinolin-3-yl-acrylamide; and

4-oxo-4H-chromene-2-carboxylic acid (2-{2-[4-(2-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amino}-ethyl)-phenyl]-2H-tetrazol-5-yl}-4,5-dimethoxy-phenyl)-amide.

4. A process for preparing a compound of formula (I), which comprises the steps of:

(i) cyclizing a compound of formula (V) with a compound of formula (VI) in the presence of a base to obtain a compound of formula (IV);

(ii) hydrogenating the compound of formula (IV) in the presence of a catalyst to obtain a compound of formula (II); and

(iii) acylating the compound of formula (II) with a compound of formula (III) in the presence of a base or a condensing agent to give the compound of formula (I):

wherein,

R 1 is aryl, heteroaryl, acrylaryl, acrylheteroaryl, heterocycloalkenyl, or carbocyclo, which is optionally substituted with one or more substituents selected from the group consisting of C 1-5 alkyl, hydroxy, C 1-5 alkoxy, halogen, trifluoromethyl, nitro and amino;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, nitro, C 1-5 alkyl or alkoxy, R 6 and R 11 being optionally fused together to form a 4 to 8-membered ring:

m and n are each independently an integer ranging from 0 to 4:

X is CH 2 , O or S;

R′ is OH, Cl or Br; and

L is benzyl or tolyl.

5. The process of claim 4 , wherein the compound of formula (V) is prepared by reacting a compound of formula (VII) with toluenesulfonyl chloride or benzenesulfonyl chloride:

wherein,

R 2 , R 3 , R 4 , R 5 and L have the meanings as defined in claim 4 .

6. The process of claim 4 , wherein the compound of formula (VI) is prepared by reacting a compound of formula (X) with a compound of formula (XI) in the presence of a base, to obtain a compound of formula (IX); hydrogenating the compound of formula (IX) in the presence of a catalyst, to obtain a compound of formula (VIII); and reacting the compound of formula (VIII) with sodium nitrite and HCl:

wherein,

R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n and X have the same meanings as defined in claim 4 ; and

R″ is OH, Cl or Br.

7. A pharmaceutical composition for inhibiting the activity of p-glycoprotein comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier:

wherein,

R 1 is aryl, heteroaryl, acrylaryl, acrylheteroaryl, heterocycloalkenyl, or carbocyclo, which is optionally substituted with one or more substituents selected from the group consisting of C 1-5 alkyl, hydroxy, C 1-5 alkoxy, halogen, trifluoromethyl, nitro and amino;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, nitro, C 1-5 alkyl or alkoxy, R 6 and R 11 being optionally fused together to form a 4 to 8-membered ring;

m and n are each independently an integer ranging from 0 to 4; and

X is CH 2 , O or S.

8. The composition of claim 7 , which further comprises an anticancer agent.

9. The composition of claim 8 , wherein the anticancer agent is selected from the group consisting of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbin, daunomycin, doxorubicin, topotecan, irinotecan, actinomycin and etopocid.