Indole compound as inhibitor of necrosis

1. An indole compound of the following Formula (1) or a pharmaceutically acceptable salt or isomer thereof, wherein the isomer is an R or S isomer, a racemate, a mixture of diastereomers, or an individual diastereomer:

in which

m denotes a number of 1 to 3;

n denotes a number of 0 to 2;

R1 represents hydrogen, C 1 -C 6 -alkyl, —(CH 2 ) n —C 3 -C 6 -cycloalkyl or —(CH 2 ) n -heterocyclyl, wherein heterocyclyl is a 4- to 8-membered ring having 1 to 3 heteroatoms selected from N, O and S;

R2 represents C 1 -C 6 -alkyl or —(CH 2 ) n -A-R6, wherein A represents C 4 -C 8 -cycloalkyl, or represents 4- to 8-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, or represents 6- to 10-membered aryl, R6 represents hydrogen, C 1 -C 6 -alkyl, halogen, hydroxy, nitrile, nitro, —C(O)—R7 or —SO 2 R7, and R7 represents C 1 -C 6 -alkyl or allyl, or represents 6- to 10-membered aryl, or represents 4- to 8-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N and S, and is optionally substituted with oxo;

R3 represents hydrogen, halogen, hydroxy, —O—R7, —NH—R7 or —(CH 2 ) n —R7;

R4 represents hydrogen or XR8R9, wherein X represents CH or N, R8 and R9 independently of one another represent hydrogen or Z—R10, Z represents —(CH 2 ) n —, —C(O)—, —C(O)(CH 2 ) n — or —(CH 2 ) n C(O)—, R10 represents hydrogen, amino, C 3 -C 6 -cycloalkyl or —(NH) r C(═NH)NH 2 , or represents 4- to 8-membered heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms selected from N, O and S, and r denotes a number of 0 or 1;

R5 represents hydroxy or 6- to 10-membered aryl, or represents —(CH 2 ) n -4- to 9-membered heterocyclyl which has 1 to 4 heteroatoms selected from N, O and S, and optionally contains oxo; and

where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy and oxo.

2. The compound according to claim 1 , wherein

m denotes a number of 1 to 3;

n denotes a number of 0 to 2;

R1 represents hydrogen, C 1 -C 6 -alkyl, —(CH 2 ) n —C 3 -C 6 -cycloalkyl or —(CH 2 ) n -heterocyclyl, wherein heterocyclyl is a 4- to 8-membered ring having 1 to 3 heteroatoms selected from N, O and S;

R2 represents C 1 -C 6 -alkyl or —(CH 2 ) n -A-R6, wherein A represents C 4 -C 6 -cycloalkyl, or represents 5- or 6-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, or represents 6- to 10-membered aryl, R6 represents hydrogen, C 1 -C 6 -alkyl, halogen, hydroxy, —C(O)—R7 or —SO 2 R7, and R7 represents C 1 -C 6 -alkyl, or represents 6- to 10-membered aryl, or represents 5- or 6-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N and S, and is optionally substituted with oxo;

R3 represents hydrogen, halogen, —O—R7, —NH—R7 or —(CH 2 ) n —R7;

R4 represents hydrogen or XR8R9, wherein X represents CH or N, R8 and R9 independently of one another represent hydrogen or Z—R10, Z represents —(CH 2 ) n —, —C(O)—, —C(O)(CH 2 ) n — or —(CH 2 ) n C(O)—, R10 represents hydrogen, amino, C 3 -C 6 -cycloalkyl or —(NH) r C(═NH)NH 2 , or represents 4- to 8-membered heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms selected from N, O and S, and is optionally substituted with amino, and r denotes a number of 0 or 1; and

R5 represents hydroxy or 6- to 10-membered aryl, or represents —(CH 2 ) n -4- to 9-membered heterocyclyl which has 1 to 4 heteroatoms selected from N, O and S, and optionally contains oxo and is optionally substituted with halogeno-C 1 -C 6 -alkyl.

3. The compound according to claim 1 , which is the following Formula (1a):

wherein X, m, n, R1, R2, R3, R5, R8 and R9 are the same as defined in claim 1 .

4. The compound according to claim 1 , wherein R1 is hydrogen, C 1 -C 6 -alkyl or 5- or 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S.

5. The compound according to claim 4 , wherein R1 is hydrogen, isopentyl or tetrahydropyran.

6. The compound according to claim 1 , wherein R2 is C 1 -C 6 -alkyl or —(CH 2 ) n -A-R6, wherein n denotes a number of 0 to 2, A represents C 4 -C 6 -cycloalkyl, or represents 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms selected from N and O, or represents phenyl, R6 represents hydrogen, —C(O)—R7 or —SO 2 R7, and R7 represents C 1 -C 3 -alkyl.

7. The compound according to claim 6 , wherein R2 is isopentyl, cyclopentyl, benzyl, tetrahydropyran, tetrahydropyran-4-ylmethyl, 1-acetyl-piperidine, tetrahydropyran-2-ylmethyl or piperidin-4-ylmethyl.

8. The compound according to claim 1 , wherein R3 is hydrogen, halogen or —(CH 2 ) n —R7, wherein n denotes a number of 0 to 2, R7 represents C 1 -C 6 -alkyl, or represents 5- or 6-membered heterocyclyl which has 1 or 2 heteroatoms selected from N and S, and is optionally substituted with oxo.

9. The compound according to claim 8 , wherein R3 is hydrogen, methyl, chloro or 1,1-dioxothiomorpholin-4-ylmethyl.

10. The compound according to claim 1 , wherein R5 is hydroxyl, 6- to 10-membered aryl or —(CH 2 ) n -4- to 9-membered heterocyclyl which has 1 to 4 heteroatoms selected from N, O and S, and optionally contains oxo and is optionally substituted with halogeno-C 1 -C 3 -alkyl, wherein n denotes a number of 0 to 2.

11. The compound according to claim 10 , wherein R5 is hydroxy, 1,1-dioxothiomorpholine, 2-oxopiperazine, 3 -trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl, morpholine or phenyl.

12. The compound according to claim 1 , wherein R8 is hydrogen or Z—R10, wherein Z represents —(CH 2 ) n —, —C(O)—, —C(O)(CH 2 ) n — or —(CH 2 ) n C(O)—, n denotes a number of 0 to 2, R10 represents hydrogen, amino, C 4 -C 6 -cycloalkyl or —(NH) r C(═NH)NH 2 , or represents 5- or 6-membered heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms selected from N and S, and is optionally substituted with amino, and r denotes a number of 0 or 1.

13. The compound according to claim 1 , wherein R8 is hydrogen, cyclohexyl-ethyl, 2-amino-pyridin-3-ylmethyl, pyrrolidine, 3-amino-triazol-5-carbonyl, aminomethyl-carbonyl, NH 2 (NH═)C—, NH 2 (NH═)C—NH—CH 2 —C(O)—, 2-amino-thiazol-4-ylmethyl, cyclopentyl-methyl, NH 2 (NH═)C—NH—C(O)—CH 2 — or acetyl.

14. An indole compound, which is selected from the group consisting of:

4-(5-Chloro-7-cyclopentylamino-1H-indol-2-ylmethyl)-piperazin-2-one;

4-{2-[5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-yl]-ethyl}-piperazin-2-one;

4-{2-[7-(1-Acetyl-piperidin-4-ylamino)-5-chloro-1H-indol-2-yl]-ethyl}-piperazin-2-one;

(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-methanol;

2-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-ethanol;

4-{5-Methyl-7-[(piperidin-4-ylmethyl)-amino]-1H-indol-2-ylmethyl}-piperazin-2-one;

[2-(1,1-Dioxothiomorpholin-4-ylmethyl)-5 -methyl-1H-indol-7-yl]-(tetrahydropyran-4-ylmethyl)-amine;

Cyclopentyl-[2-(1,1-dioxothiomorpholin-4-ylmethyl)-5-methyl-1H-indol-7-yl]-amine;

4-[5-Methyl-7-(tetrahydropyran-4-ylmethylamino)-1H-indol-2-ylmethyl)-piperazin-2-one;

{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol -7-yl}-(tetrahydrofuran-2-ylmethyl)-amine;

{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol-7-yl}-(tetrahydropyran-2-ylmethyl)-amine;

{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol-7-yl}-(1-methanesulfonyl-piperidin-4-yl)-amine;

1-(4-{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol-7-yl}-piperidin-1-yl)-ethanone;

4-[2-(7-Benzylamino-5-chloro-1H-indol-2-yl)-ethyl]-piperazin-2-one;

4-(2-{5-Chloro-7-[(tetrahydrofuran-2-ylmethyl)-amino]-1H-indol-2-yl)-ethyl]-piperazin-2-one;

4-(2-{5-Chloro-7-[(tetrahydropyran-2-ylmethyl)-amino]-1H-indol-2-yl)-ethyl]-piperazin-2-one;

4-{5-Chloro-7-[(tetrahydropyran-4-ylmethyl)-amino]-1H-indol-2-ylmethyl}-piperazin-2-one;

{5-Chloro-2-[2-(1,1-dioxothiomorpholin-4-yl)-ethyl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)-amine;

{5-Chloro-2-[2-(1,1-dioxothiomorpholin-4-yl)-ethyl]-1H-indol-7-yl}-cyclopentyl-amine;

{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol-7-yl}-cyclopentyl-amine;

{5-Chloro-2-[2-(1,1-dioxothiomorpholin-4-yl)-ethyl]-1H-indol-7-yl}-(tetrahydropyran-4-ylmethyl)-amine;

4-(2-{5-Chloro-7-[(tetrahydropyran-4-ylmethyl)-amino]-1H-indol-2-yl}-ethyl)-piperazin-2-one;

{5-Chloro-2-[2-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-1-yl)-ethyl]-1H-indol-7-yl}-(tetrahydropyran-4-ylmethyl)-amine;

[5-Chloro-2-(2-morpholin-4-yl-ethyl)-1H-indol-7-yl-(tetrahydropyran-4-ylmethyl)-amine;

Cyclopentyl-(5-methyl-2-morpholin-4-ylmethyl-1H-indol-7-yl)-amine;

[2-((R)-1-amino-2-phenyl-ethyl)-5-methyl-1H-indol-7-yl]-cyclopentyl-amine;

{2-[(R)-1-(2-cyclohexyl-ethylamino)-2-phenyl-ethyl]-5-methyl-1H-indol-7-yl}-cyclopentylamine;

Benzyl-{5-chloro-2-[(R)-2-phenyl-1-(pyrrolidin-3-ylamino)-ethyl]-1H-indol-7-yl}-amine;

2-Amino-N-[(R)-1-(7-benzylamino-5-chloro-1H-indol-2-yl)-2-phenylethyl]-acetamide;

N-[(R)-1-(7-Benzylamino-5-chloro-1H-indol-2-yl)-2-phenyl-ethyl]-guanidine;

{2-[(R)-1-(cyclohexylmethyl-amino)-2-phenyl-ethyl]-5-methyl-1H-indol-7-yl}-cyclopentyl-amine;

(2-{(S)-1-[(2-amino-pyridin-3-ylmethyl)-amino]-2-phenyl-ethyl}-5-chloro-1H-indol-7-yl)-(3-methyl-butyl)-amine;

3-Amino-4H-[1,2,4]triazol-4-carboxilic acid [(S)-1-(7-benzylamino-5-chloro-1H-indol-2-yl)-2-phenyl-ethyl]-amide;

2-Amino-N-{(S)-1-[5-chloro-7-(3-methyl-butylamino)-1H-indol-2-yl]-2-phenyl-ethyl}-acetamide;

N-[(R)-1-(7-benzylamino-5-chloro-1H-indol-2-yl)-2-phenyl-ethyl]-2-guanidino-acetamide; and

(S)-2-Amino-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-ethanol;

or a pharmaceutically acceptable salt or isomer thereof, wherein the isomer is an R or S isomer, a racemate, a mixture of diastereomers, or an individual diastereomer.

15. A method of preparing a composition for the prevention or treatment of necrosis and necrosis-associated diseases, which comprises the step of mixing the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof as defined in claim 1 as an active ingredient together with a pharmaceutically acceptable carrier.

16. A composition comprising a therapeutically effective amount of the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof as defined in claim 1 as an active ingredient together with a pharmaceutically acceptable carrier or diluent.