1,3,6-substituted indole derivatives having inhibitory activity for protein kinase
View Patent ↗Disclosed are a 1,3,6-substituted indole compound having inhibitory activity for protein kinases, a pharmaceutically acceptable thereof, and a pharmaceutical composition for prevention and treatment of diseases caused by abnormal cell growth including the compound as an active ingredient. Since the novel indole compound exhibits superior inhibitory activity for various protein kinases involved in growth factor signal transduction, it is useful as an agent for preventing or treating cancers caused by abnormal cell growth.
1. A 1,3,6-substituted indole compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
wherein
X and Y are independently selected from N or CH;
Z is selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; cyano; OR 1 ; —SR 1 ; NHR 1 ; —C(O)NHR 1 ; —NHC(O)R 1 ; —NHC(O)NHR 1 ; —S(O)R 1 ; and —S(O) 2 R 1 ;
G is selected from the group consisting of halogen; 5- to 7-membered substituted or unsubstituted aryl; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
L 1 is selected from the group consisting of 5- to 7-membered substituted or unsubstituted aryl; biaryl resulting from two fused 5- to 7-membered substituted or unsubstituted aryls; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
L 2 is nonexistent or selected from the group consisting of —NR 2 C(O)—; —C(O)NR 2 —; —NR 2 C(O)NR 3 —; —S(O)NR 2 —; and —S(O) 2 NR 2 —;
E is selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; —NO 2 ; —OR 3 ; —NR 3 R 4 ; —NHC(O)R 3 ; —C(O)OR 3 ; 5- to 7-membered substituted or unsubstituted aryl; biaryl resulting from two fused 5- to 7-membered substituted or unsubstituted aryls; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
R 1 is selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; saturated or unsaturated C 1 -C 6 alkyl substituted with heteroaryl or heterocyclic ring selected from the group consisting of pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and aziridinyl;
R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen; and linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl;
wherein the above aryl, heteroaryl, biaryl or heterocyclic is independently substituted or unsubstituted with 1 to 3 substituent(s) selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; C 1 -C 6 haloalkyl containing 1 to 10 halogen atoms; cyano; —NO 2 ; —OBoc; —OR 5 ; —O(CH 2 ) n NR 6 R 7 (where n is an integer from 1 to 6); —NR 6 R 7 ; —NR 5 COR 6 ; —NR 5 C(O)NR 6 R 7 ; —C(O)R 6 ; —C(O)OR 6 ; —C(O)NR 6 R 7 ; —C(O)NH(CH 2 ) n NR 6 R 7 ; —S(O)R 6 ; —S(O) 2 R 6 ; —S(O) 2 NR 6 R 7 ; 5- to 7-membered aryl; biaryl resulting from two fused 5- to 7-membered aryls; 5- to 7-membered heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and
R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; 5- to 7-membered aryl; biaryl resulting from two fused 5- to 7-membered aryls; 5- to 7-membered heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; or NR 6 R 7 forms a 5- to 7-membered heteroaryl or a heterocyclic ring by further including 1 to 3 other heteroatom(s); wherein the aryl, biaryl, heteroaryl or heterocyclic ring may be substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl containing 1 to 10 halogen atom(s).
2. A 1,3,6-substituted indole compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
wherein
X and Y are independently selected from N or CH;
Z is selected from the group consisting of hydrogen, halogen, —SR 1 , NHR 1 and —S(O)R 1 ;
G is selected from the group consisting of halogen, indolyl and substituted or unsubstituted aryl;
L 1 is selected from the group consisting of substituted or unsubstituted aryl; and a substituted or unsubstituted heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
L 2 is nonexistent or selected from the group consisting of —NR 2 C(O)— and —NR 2 C(O)NR 3 —;
E is selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; —NO 2 ; —OR 3 ; —NR 3 R 4 ; —NHC(O)R 3 ; and substituted or unsubstituted aryl;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; and substituted or unsubstituted aryl;
wherein the above substituted aryl or heterocyclic ring is independently aryl or a heterocyclic ring substituted with 1 to 3 substituent(s) selected from the group consisting of halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; C 1 -C 6 haloalkyl containing 1 to 10 halogen atoms; cyano; —NO 2 ; —OBoc; —OR 5 ; —O(CH 2 ) n NR 6 R 7 (where n is an integer from 1 to 6); —NR 6 R 7 ; —NR 5 COR 6 ; —NR 5 C(O)NR 6 R 7 ; —C(O)R 6 ; —C(O)OR 6 ; —C(O)NR 6 R 7 ; —C(O)NH(CH 2 ) n NR 6 R 7 ; substituted or unsubstituted aryl; and a heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
R 3 , R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl and substituted or unsubstituted aryl, or NR 6 R 7 forms a heterocyclic ring by optionally further including 1 to 3 other heteroatom(s), wherein the aryl or heterocyclic ring may be substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl containing 1 to 10 halogen atoms;
the aryl is phenyl; and
the heterocyclic ring is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and N-protected piperazinyl.
3. A 1,3,6-substituted indole compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
wherein
X and Y are independently N or CH;
Z is hydrogen, Cl, —SCH 3 , NH 2 , NHCH 3 , NH-cyclopropyl, NHCH 2 CH 2 -morpholinyl or —S(O)CH 3 ;
G is Br, indolyl or substituted or unsubstituted phenyl;
L 1 is substituted or unsubstituted phenyl, piperazinyl or N-Boc-piperazinyl;
L 2 is nonexistent or —NHC(O)— or —NHC(O)NH—;
E is hydrogen, cyclohexyl, —NO 2 , —OH, —OCH 3 , —NH 2 , —NHC(O)CH 3 or substituted or unsubstituted phenyl; and
wherein the above substituted phenyl is phenyl substituted with 1 to 3 substituent(s) selected from the group consisting of —Cl, —F, —CH 3 , —CF 3 , —CN, —NO 2 , —OH, —OBoc, —OCH 3 , —OCH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHC(O)CH 3 , —NHC(O)Ph, —NHC(O)-Ph(4-Cl,3-CF 3 ), NHSO 2 -cyclopropyl, —C(O)OH, —C(O)OCH 2 CH 3 , —C(O)NH-cyclopropyl, —C(O)NHCH 2 CH 2 -morpholinyl, morpholinyl, 4-ethylpiperazinyl and 4-methylimidazolyl.
4. A 1,3,6-substituted indole compound,
wherein the 1,3,6-substituted indole compound is selected from the group consisting of:
tert-butyl 4-(3-bromo-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate;
4-(3-bromo-1-(pyridin-4-yl)-1H-indol-6-yl)phenol;
3-bromo-6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole;
3-bromo-1-(2-(methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole;
3-bromo-1-(6-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole;
6-(3-bromo-6-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
3-bromo-1-(6-chloropyrimidin-4-yl)-6-(4-methoxyphenyl)-1H-indole;
6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
tert-butyl 4-(3-(4-methoxyphenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate;
3-(4-methoxyphenyl)-6-(piperazin-1-yl)-1-(pyridin-4-yl)-1H-indole;
4-(6-(piperazin-1-yl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol;
tert-butyl 4-(3-(4-(tert-butoxycarbonyloxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate;
tert-butyl 4-(3-(4-hydroxyphenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate;
tert-butyl 4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate;
N,N-dimethyl-2-(4-(6-(piperazin-1-yl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenoxy)ethanamine;
3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole;
4-(6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol;
4-(6-(3-aminophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol;
N,N-dimethyl-2-(4-(6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenoxy)ethanamine;
3-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)benzenamine;
N-(3-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)phenyl)acetamide;
6-(6-(4-methoxyphenyl)-3-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
N-(3-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)phenyl)acetamide;
ethyl 4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate;
4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate;
4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)-N-(2-morpholinoethyl)benzamide;
3-(4-methoxyphenyl)-1-(2-(methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole;
3-(4-methoxyphenyl)-1-(2-(methylsulfinyl)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole;
4-(3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1H-indol-1-yl)pyrimidin-2-amine;
6-(3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
6-(6-(3-aminophenyl)-3-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-(3,4-dichlorophenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-(2-methoxyphenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methy)amino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-(2-fluorophenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-cyclohexyl-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
N-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-methyl-3-nitrobenzamide;
N-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-3-morpholino-5-(trifluoromethyl)benzamide;
N-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide;
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)phenyl)urea;
4-chloro-N-(3-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)phenyl)-3-(trifluoromethyl)benzamide;
N-cyclopropyl-4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzamide;
1-(2,6-dimethylphenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
1-(5-chloro-2,4-dimethoxyphenyl)-3-(3-(3-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-6-yl)phenyl)urea;
N-(3-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)phenyl)cyclopropanecarboxamide;
N-(3-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)phenyl)cyclopropanesulfonamide;
6-(6-(4-methoxyphenyl)-1H,1′H-3,6′-biindol-1-yl)-N-methylpyrimidin-4-amine;
6-(6-(4-methoxyphenyl)-3-(4-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
6-(3-(4-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine;
6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-(2-morpholinoethyl)pyrimidin-4-amine;
6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-cyclopropylpyrimidin-4-amine;
6-(6-(4-methoxyphenyl)-3-(3-nitrophenyl)-1H-indol-1-yl)-N-(2-morpholinoethyl)pyrimidin-4-amine;
N-cyclopropyl-6-(6-(4-methoxyphenyl)-3-(3-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine;
6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-(2-morpholinoethyl)pyrimidin-4-amine;
6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-cyclopropylpyrimidin-4-amine; and
ethyl 4-(6-(4-methoxyphenyl)-1-(6-(2-morpholinoethylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate.
5. A pharmaceutical composition comprising an active ingredient that is a 1,3,6-substituted indole compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
wherein
X and Y are independently selected from N or CH;
Z is selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; cyano; OR 1 ; —SR 1 ; NHR 1 ; —C(O)NHR 1 ; —NHC(O)R 1 ; —NHC(O)NHR 1 ; —S(O)R 1 ; and —S(O) 2 R 1 ;
G is selected from the group consisting of halogen; 5- to 7-membered substituted or unsubstituted aryl; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
L 1 is selected from the group consisting of 5- to 7-membered substituted or unsubstituted aryl; biaryl resulting from two fused 5- to 7-membered substituted or unsubstituted aryls; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
L 2 is nonexistent or selected from the group consisting of —NR 2 C(O)—; —C(O)NR 2 —; —NR 2 C(O)NR 3 —; —S(O)NR 2 —; and —S(O) 2 NR 2 —;
E is selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; —NO 2 ; —OR 3 ; —NR 3 R 4 ; —NHC(O)R 3 ; —C(O)OR 3 ; 5- to 7-membered substituted or unsubstituted aryl; biaryl resulting from two fused 5- to 7-membered substituted or unsubstituted aryls; 5- to 7-membered substituted or unsubstituted heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur;
R 1 is selected from the group consisting of hydrogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; saturated or unsaturated C 1 -C 6 alkyl substituted with heteroaryl or heterocyclic ring selected from the group consisting of pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and aziridinyl;
R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen; and linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl;
wherein the above aryl, heteroaryl, biaryl or heterocyclic is independently substituted or unsubstituted with 1 to 3 substituent(s) selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; C 1 -C 6 haloalkyl containing 1 to 10 halogen atoms; cyano; —NO 7 ; —OBoc; —OR 5 ; —O(CH 2 ) n NR 6 R 7 (where n is an integer from 1 to 6); —NR 6 R 7 ; —NR 5 COR 6 ; —NR 5 C(O)NR 6 R 7 ; —C(O)R 6 ; —C(O)OR 6 ; —C(O)NR 6 R 7 ; —C(O)NH(CH 2 ) n NR 6 R 7 ; —S(O)R 6 ; —S(O) n R 6 ; —S(O) 2 NR 6 R 7 ; 5- to 7-membered aryl; biaryl resulting from two fused 5- to 7-membered aryls; 5- to 7-membered heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and
R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen; halogen; linear, branched or cyclic saturated or unsaturated C 1 -C 6 alkyl; 5- to 7-membered aryl; biaryl resulting from two fused 5- to 7-membered aryls; 5- to 7-membered heteroaryl containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; and a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur; or NR 6 R 7 forms a 5- to 7-membered heteroaryl or a heterocyclic ring by further including 1 to 3 other heteroatom(s); wherein the aryl, biaryl, heteroaryl or heterocyclic ring may be substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl containing 1 to 10 halogen atom(s).
6. A method for preparing a 1,3,6-substituted indole compound represented by Chemical Formula 1, comprising performing a Suzuki coupling reaction of a bromine compound represented by Chemical Formula 2 with a boronic acid compound represented by Chemical Formula 3 using an organometallic compound:
wherein
X, Y, Z, G, L 1 , L 2 and E are the same as defined in claim 1 .
7. The preparation method according to claim 6 , wherein the bromine compound represented by Chemical Formula 2 is prepared by:
performing a Suzuki coupling reaction of a 6-bromoindole compound using an organometallic compound to prepare a 6-substituted indole compound represented by Chemical Formula 4:
wherein L 1 , L 2 and E are the same as defined in claim 1 ;
performing a coupling reaction of the 6-substituted indole compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 8 using a metal including palladium to prepare a compound represented by Chemical Formula 5a:
wherein X, Y, Z, L 1 , L 2 and E are the same as defined in claim 1 and R is halogen or a leaving group; and
brominating the compound represented by Chemical Formula 5a to prepare the bromine compound represented by Chemical Formula 2:
wherein X, Y, Z, L 1 , L 2 and E are the same as defined above.
8. The preparation method according to claim 6 , wherein the bromine compound represented by Chemical Formula 2 is prepared by:
performing a Suzuki coupling reaction of a 6-bromoindole compound using an organometallic compound to prepare a 6-substituted indole compound represented by Chemical Formula 4:
wherein L 1 , L 2 and E are the same as defined in claim 1 ;
brominating the 6-substituted indole compound represented by Chemical Formula 4 to prepare a compound represented by Chemical Formula 5b:
wherein L 1 , L 2 and E are the same as defined above; and
performing a coupling reaction of the compound represented by Chemical Formula 5b with a compound represented by Chemical Formula 8 using a base to prepare the bromine compound represented by Chemical Formula 2:
wherein X, Y, Z, L 1 , L 2 and E are the same as defined in claim 1 and R is halogen or a leaving group.
9. A pharmaceutical composition comprising the compound according to claim 2 as an active ingredient.
10. A pharmaceutical composition comprising the compound according to claim 3 as an active ingredient.
11. A pharmaceutical composition comprising the compound according to claim 4 as an active ingredient.