US 12,180,185 B2Granted

Compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof

AssigneeHk Inno.N Corporation

InventorsJi-Yeon Park, Seung Chan Kim, So Young Ki, Ye-Ri Shim

Life of this patent

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Abstract

The present invention provides a novel compound having a protein kinase inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof. The compound according to the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof are effective in preventing or treating protein kinase-related diseases such as cancers, autoimmune diseases, neurological diseases, metabolic diseases, infections or the like by showing a protein kinase inhibitory activity.

Claims10

Dependent claims

A compound represented by a following Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof:

in Formula 1,
R1 is H, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, hydroxy, cyano, halogen, C(═O)—OH, C(═O)—O—C1-6 alkyl, S(═O)2—C1-6 alkyl, aryl or heteroaryl;
X-Y-Z is C═CA2-NA5, N—CA2═CA3 or C═N—NA5;
A2, A3 and A5 are each independently H, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C(═O)—OH, C(═O)—O—C1-6 alkyl, S(═O)2—C1-6 alkyl, —C(═O)—NH—C1-6 haloalkyl, aryl or heteroaryl;
R2 is H, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, hydroxy, cyano, halogen, C(═O)—OH, C(═O)—O—C1-6 alkyl, S(═O)2—C1-6 alkyl, aryl or heteroaryl;
n and m are each independently 0, 1, 2 or 3;
B1 is —C(═O);
B2 is cyclopropyl;
B3 is H;
D1 is —NR3—;
D2 is —C(═O)—, —C(═S)—,—S(═O)2- or a single bond;
D3 is —NR3—,
or a single bond;
D4 is H, C1-6 alkyl, C1-6 alkenyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C3-7 cycloalkyl, 5-6-membered heterocycloalkyl, C1-6 alkyl, in which one H is substituted with methylpiperazinyl, aryl or heteroaryl;
wherein when D4 is C1-6 alkyl in which one H is substituted with methylpiperazinyl, then D1 is NH, D2 is C(═O) and D3 is a single bond,
wherein at least one H of C1-6 alkyl, C1-6 alkenyl, C1-6 haloalkyl or C1-6 cyanoalkyl may be substituted with C3-7 cycloalkyl, aryl, heteroaryl or cyano,
at least one H of C3-7 cycloalkyl or 5-6-membered heterocycloalkyl may be substituted with C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, cyano or halogen, and
at least one H of aryl or heteroaryl may be substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 thioalkyl, hydroxy, cyano, nitro or halogen;
and
R3 and R4 are each independently H, C1-6 alkyl or C1-6 haloalkyl.

17 more elements

A compound selected from the group consisting of the following compounds (1) to (63), stereoisomers thereof or pharmaceutically acceptable salts thereof:

1)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
2)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3,5-
difluorobenzamide
3)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-
yl)cyclohexanecarboxamide
4)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-2-
fluoroisonicotinamide
5)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3,5-
dimethylbenzamide
6)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)thiazole-5-
carboxamide
7)
N-(4-(7-butyramido-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide
8)
N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)-5-methylpyridin-2-
yl)cyclopropanecarboxamide
9)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-6-methylpyridin-2-
yl)cyclopropanecarboxamide
10)
N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
11)
4-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-
yl)tetrahydro-2H-pyran-4-carboxamide
12)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-5-methylpyridin-2-
yl)cyclopropanecarboxamide
13)
N-(4-(7-(2-(1-cyanocyclopropyl)acetamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
14)
N-(4-(7-(2-cyanopropanamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
15)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-5-methyl-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
16)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-methyl-1H-indol-7-yl)-5-
methylpyrazine-2-carboxamide
17)
N-(4-(7-(2,3-dimethylbut-2-enamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
18)
N-(4-(7-(2-(4-methylpiperazin-1-yl)propanamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
19)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-6-methoxypyridin-
2-yl)cyclopropanecarboxamide
20)
N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)-6-methoxypyridin-2-
yl)cyclopropanecarboxamide
21)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-
(trifluoromethyl)thiazole-2-carboxamide
22)
(E)-N-(4-(7-(2-cyano-3-phenylacrylamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
23)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1H-pyrrole-2-
carboxamide
24)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-
methylnicotinamide
25)
(E)-N-(4-(7-(2-cyano-3-(thiophen-2-yl)acrylamido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
26)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1-methyl-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
27)
4-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-
yl)benzamide
28)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-6-
methylnicotinamide
29)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-6-
(trifluoromethyl)nicotinamide
30)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-5,6-
difluoronicotinamide
31)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-5-
fluoronicotinamide
32)
6-chloro-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-
yl)nicotinamide
33)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1H-pyrazole-
3-carboxamide
34)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1-methyl-2-
oxo-1,2-dihydropyridine-3-carboxamide
35)
2-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-
yl)isonicotinamide
36)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-ethyl-1H-
pyrrole-2-carboxamide
37)
3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-7-(3-
(2,2,2-trifluoroethyl)ureido)-1H-indole-1-carboxamide
38)
N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3-
fluorobenzamide
39)
N-(4-(7-(3-(2,2,2-trifluoroethyl)ureido)-1H-indol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide
40)
N-(4-(4-(2-cyano-3-methylbut-2-enamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
41)
N-(4-(4-(2-cyanoacetamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
42)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1H-pyrrole-2-
carboxamid
43)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2-
methylthiazole-5-carboxamid
44)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-3,5-
difluorobenzamide
45)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1-methyl-2-
oxo-1,2-dihydropyridine-3-carboxamide
46)
N-(4-(4-(2-cyano-3-(thiophen-2-yl)acrylamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
47)
4-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-
yl)benzamide
48)
N-(4-(4-(2-cyano-3-phenylacrylamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
49)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl-1H-indol-4-yl)-1-methyl-1H-
indole-2-carboxamide
50)
4-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-
yl)tetrahydro-2H-pyran-4-carboxamide
51)
2-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-
yl)isonicotinamide
52)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2-
fluoroisonicotinamide
53)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2,3-
difluoroisonicotinamide
54)
N-(4-(4-(2-cyanopropanamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
55)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1H-pyrazole-
3-carboxamide
56)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-3-fluoro-4-
methoxybenzamide
57)
(1R,2S)-2-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-
yl)cyclopropane-1-carboxamide
58)
N-(4-(4-(2-(1-cyanocyclopropyl)acetamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
59)
N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-6-
methylnicotinamide
60)
N-(4-(4-(2,3-dimethylbut-2-enamido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
61)
N-(4-(4-(3-(2,4-difluorophenyl)ureido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
62)
N-(4-(4-(3-(2,2,2-trifluoroethyl)ureido)-1H-indol-1-yl)pyridin-2-
yl)cyclopropanecarboxamide
63)
N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indazol-3-yl)pyridin-2-
yl)cyclopropanecarboxamide.

185 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/294,226Filed 14 Nov 2019
Priority: KR 10-2018-014057815 Nov 2018
Published: US 2022/0009902 A113 Jan 2022
Granted: 31 Dec 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…

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US 2022/0009902 A1Pre-grant publication · published 13 Jan 2022
US 12,180,185 B2This patent

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

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Abstract

Facts

Application

17/294,226Filed 14 Nov 2019

Priority

KR 10-2018-014057815 Nov 2018

Published

US 2022/0009902 A113 Jan 2022

Granted

31 Dec 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…