US 9,868,731 B2Granted

Indole amide compound as inhibitor of necrosis

AssigneeLG Chem, Ltd.

InventorsHeui Sul Park, Sun Young Koo, Hyoung Jin Kim, Sung Bae Lee, Hyo Shin Kwak, Seung Yup Paek, Soon Ha Kim

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Abstract

The present invention relates to an indole amide compound represented by formula (1), a pharmaceutically acceptable salt or isomer thereof, a composition for prevention or treatment of necrosis and necrosis-associated diseases, and a method for preparing the composition, the composition comprising the indole compound or the pharmaceutically acceptable salt or isomer thereof as an active ingredient.

Claims18

Dependent claims

An indole amide compound of the following Formula (1) or a pharmaceutically acceptable salt or isomer thereof:

in which
R1 represents hydrogen, C1—C6-alkyl or —CH2)n—C3-C8-cycloalkyl;
n denotes a number of 0 to 2;
R2 represents —X—CH2)n-A-R6, wherein X represents a direct bond, A represents a direct bond, or represents C3-C8-cycloalkyl or C6-C10 aryl, or represents 4- to 8-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, R6 represents hydrogen, C1-C6-alkyl, halogen, hydroxy, amino, nitrile, nitro or —CO2—R7, and R7 represents hydrogen, C1-C6-alkyl, C6-C10 aryl or C6-C10 aryl-C1-C6-alkyl, or represents 5- or 6-membered heterocyclyl or heteroaryl each of which optionally contains oxo, and has 1 to 3 heteroatoms selected from N, O and S, provided that R2 is not hydrogen;
R1 and R2 may together represent —(CH2)r—, wherein r denotes a number of 4 to 6;
R3 represents halogen, hydroxy, —NH—R7 or —(CH2)m—R7, wherein m denotes a number of 0 to 3, provided that when m is 0, R7 is not hydrogen;
R4 represents —(CHR7)n—B—(Z—R8)(Z′—R9), wherein B represents a direct bond, or represents C6-C10 aryl, or represents 4- to 9-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, Z and Z′ independently of one another represent a direct bond, —(CH2)m—, —O—or —N—, and R8 and R9 independently of one another represent hydrogen, halogen, hydroxy, amino, di(C1-C6-alkyl)amino, C1-C6-alkyl, —CO2R7, C3-C8-cycloalkyl, C6-C10-aryl, C6-C10-aryloxy, C6-C10-aryl-C1-C6-alkyl or C6-C10-aryl-C1-C6-alkylamino, or represents 4- to 8-membered heterocyclyl which has 1 to 3 heteroatoms selected from N, O and S, provided that when B is direct bond, (Z′—R9) does not exist;
R5 represents —(CH2)m—R10, wherein R10 represents hydrogen, C1-C6-alkyl or C6-C10-aryl;
Z′ and R5 may be connected with an atom(s) to which they are attached to form the structure
provided that when Z′ is —O—, R9 does not exist;
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, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, arylalkoxy and oxo.

8 more elements

An indole amide compound which is selected from the following group:

5-Chloro-7-cyclopentylamino-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
5-Chloro-7-(pyrrolidin-3-ylamino)-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid [4-(3,4-difluoro-phenoxy)-phenyl]-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (3-phenoxy-phenyl)-amide;
5-Chloro-7-[(pyrrolidin-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid benzylamide;
5-Chloro-7-(piperidin-3-ylamino)-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
5-Chloro-7-[(pyrrolidin-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid (3-phenoxy-phenyl)-amide;
5-Chloro-7-[(pyrrolidin-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid (3-cyclopentyloxy-5-phenoxy-phenyl)-amide;
5-Chloro-7-[(pyrrolidin-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
7-[(2-Amino-pyridin-3-ylmethyl)-amino]-5-chloro-1H-indol-2-carboxylic acid [4-(3,4-difluoro-phenoxy)-phenyl]-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (3-cyclopentyloxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (3-morpholin-4-ylmethyl-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid biphenyl-3-ylamide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (3-benzyloxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (4-trifluoromethoxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid [4-(3,5-dimethyl-phenoxy)-phenyl]-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide;
5-Chloro-7-[(thiazol-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid (3-phenoxy-phenyl)-amide;
5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-carboxylic acid (4-isopentyloxy-phenyl)-amide;
5-Chloro-7-[(pyrrolidin-2-ylmethyl)-amino]-1H-indol-2-carboxylic acid [4-(3,4-dimethyl-phenoxy)-phenyl]-amide;
(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-pyrrolidin-1-yl-methanone;
(R)-1-(5-chloro-7-cyclopentylamino-1H-indol-2-carbonyl)-pyrrolidin-3-carboxylic acid methyl ester;
(S)-1-(5-chloro-7-cyclopentylmethylamino-1H-indol-2-carbonyl)-pyrrolidin-3-carboxylic acid methyl ester;
(R)-1-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-carbonyl]-pyrrolidin-3-carboxylic acid methyl ester;
(S)-1-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-carbonyl]-pyrrolidin-3-carboxylic acid methyl ester;
(5-Bromo-7-cyclohexylamino-1H-indol-2-yl)-morpholin-4-yl-methanone;
(7-Cyclopentylamino-5-methyl-1H-indol-2-yl)-morpholin-4-yl-methanone;
(7-Cyclopentylamino-5-methyl-1H-indol-2-yl)-piperazin-4-yl-methanone;
5-Chloro-7-cyclopentylamino-1H-indol-2-carboxylic acid (1-benzyl-pyrrolidin-3-ylmethyl)-amide;
7-Cyclopentylamino-5-methyl-1H-indol-2-carboxylic acid (2-dimethylamino-ethyl)-amide;
7-Cyclopentylamino-5-methyl-1H-indol-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
(4-Benzyl-piperazin-1-yl)-[5-chloro-7-(piperidin-4-ylamino)-1H-indol-2-yl]-methanone;
[5-Chloro-7-(piperidin-4-ylamino)-1 H-indol-2-yl]-[(R)-3-(3,4-difluoro-phenoxymethyl)-pyrrolidin-1-yl]-methanone;
[5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-yl]-((R)-3-phenoxymethyl-pyrrolidin-1-yl]-methanone;
(R)-1-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-carbonyl]-pyrrolidin-3-carboxylic acid;
[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-((R)-3-hydroxymethyl-pyrrolidin-1-yl)-methanone;
(S)-1-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-carbonyl]-pyrrolidin-3-carboxylic acid;
7-(2-Amino-acetylamino)-5-chloro-1H-indol-2-carboxylic acid (4-phenoxy-phenyl)-amide;
(3-Aminomethyl-pyrrolidin-1-yl)-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-methanone;
(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-(3-piperidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
[5-Chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-(3-piperidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-methanone;
((R)-3-amino-pyrrolidin-1-yl)-[5-chloro-7-cyclopentylamino-1H-indol-2-yl]-methanone;
(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-{3-[(3-dimethylamino-benzylamino)-methyl]-pyrrolidin-1-yl}-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-[5-chloro-7-(3-methyl-butylamino)-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-[5-chloro-7-(cyclopentylmethyl-amino)-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-(5-chloro-7-piperidin-1-yl-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-(5-chloro-7-penethylamino-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-(5-chloro-7-pentylamino-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl-(5-chloro-7-cyclohexylamino-1H-indol-2-yl]-methanone;
(3-Aminomethyl-piperidin-1-yl)-(5-chloro-7-cyclopentylamino-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-[7-(bis-cyclopropylmethyl-amino)-5-chloro-1H-indol-2-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-{7-[bis-(3-methyl-butyl)-amino]-5-chloro-1H-indol-2-yl}-methanone;
((S)-3-amino-pyrrolidin-1-yl)-(5-chloro-7-cyclopentylamino-1H-indol-2-yl}-methanone;
{7-[Bis-(3-methyl-butyl)-amino]-5-chloro-1H-indol-2-yl}-[3-(4-fluoro-benzylaminomethyl)-pyrrolidin-1-yl]-methanone;
{7-[Bis-(3-methyl-butyl)-amino]-5-chloro-1H-indol-2-yl}-[3-(3 ,4-difluoro-benzylaminomethyl)-pyrrolidin-1-yl]-methanone;
(3-Aminomethyl-pyrrolidin-1-yl)-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-methanone;
7-Cyclopentylamino-5-methyl-1H-indol-2-carboxylic acid (pyrrolidin-3-ylmethyl)-amide;
{7-[Bis-(3-methyl-butyl)-amino]-5-chloro-1H-indol-2-yl}-[(3R,4R)-3-(2,4-difluoro-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;
{7-[Bis-(3-methyl-butyl)-amino]-5-chloro-1H-indol-2-yl}-[(3R,4R)-3-(4-chloro-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;
(5-Chloro-7-cyclopentylamino-1H-indol-2-yl}-[(3R,4R)-3-(2,4-difluoro-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;
(5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl}-[(3R,4R)-3-(2,4-difluoro-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;
(5-Chloro-7-(piperidin-4-ylamino)-1H-indol-2-yl}-[(3R,4R)-3-(2,4-difluoro-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;
(5-Chloro-7-cyclopentylamino)-1H-indol-2-carboxylic acid ((R)-2-phenyl-1-pyrrolidin-1-ylmethyl-ethyl)-amide;
[5-Methyl-2-(pyrrolidin-1-carbonyl)-1H-indol-7-ylamino]-acetic acid;
and
[7-Cyclopentylamino-5-(1,1-dioxo-thiomorpholin-4-yl-methyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone,
or a pharmaceutically acceptable salt or isomer thereof.

66 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/913,140Filed 21 Aug 2014
Priority: KR 10-2013-009996722 Aug 2013
Published: US 2016/0194313 A17 Jul 2016
Granted: 16 Jan 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/4045
Indoles, e.g. pindolol: indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Family

US 2016/0194313 A1Pre-grant publication · published 7 Jul 2016
US 9,868,731 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

An indole amide compound of the following Formula (1) or a pharmaceutically acceptable salt or isomer thereof:

in which
R1 represents hydrogen, C1—C6-alkyl or —CH2)n—C3-C8-cycloalkyl;
n denotes a number of 0 to 2;
R2 represents —X—CH2)n-A-R6, wherein X represents a direct bond, A represents a direct bond, or represents C3-C8-cycloalkyl or C6-C10 aryl, or represents 4- to 8-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, R6 represents hydrogen, C1-C6-alkyl, halogen, hydroxy, amino, nitrile, nitro or —CO2—R7, and R7 represents hydrogen, C1-C6-alkyl, C6-C10 aryl or C6-C10 aryl-C1-C6-alkyl, or represents 5- or 6-membered heterocyclyl or heteroaryl each of which optionally contains oxo, and has 1 to 3 heteroatoms selected from N, O and S, provided that R2 is not hydrogen;
R1 and R2 may together represent —(CH2)r—, wherein r denotes a number of 4 to 6;
R3 represents halogen, hydroxy, —NH—R7 or —(CH2)m—R7, wherein m denotes a number of 0 to 3, provided that when m is 0, R7 is not hydrogen;
R4 represents —(CHR7)n—B—(Z—R8)(Z′—R9), wherein B represents a direct bond, or represents C6-C10 aryl, or represents 4- to 9-membered heterocyclyl or heteroaryl each of which has 1 to 3 heteroatoms selected from N, O and S, Z and Z′ independently of one another represent a direct bond, —(CH2)m—, —O—or —N—, and R8 and R9 independently of one another represent hydrogen, halogen, hydroxy, amino, di(C1-C6-alkyl)amino, C1-C6-alkyl, —CO2R7, C3-C8-cycloalkyl, C6-C10-aryl, C6-C10-aryloxy, C6-C10-aryl-C1-C6-alkyl or C6-C10-aryl-C1-C6-alkylamino, or represents 4- to 8-membered heterocyclyl which has 1 to 3 heteroatoms selected from N, O and S, provided that when B is direct bond, (Z′—R9) does not exist;
R5 represents —(CH2)m—R10, wherein R10 represents hydrogen, C1-C6-alkyl or C6-C10-aryl;
Z′ and R5 may be connected with an atom(s) to which they are attached to form the structure
provided that when Z′ is —O—, R9 does not exist;
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, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, arylalkoxy and oxo.

8 more elements

Facts

Application

14/913,140Filed 21 Aug 2014

Priority

KR 10-2013-009996722 Aug 2013

Published

US 2016/0194313 A17 Jul 2016

Granted

16 Jan 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/4045
Indoles, e.g. pindolol: indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole