# US 12,180,185 B2 · Compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof

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- Number: US 12,180,185 B2
- Document ID: US12180185B2
- Status: Granted
- Kind: B2
- Application number: 17/294,226
- Filed: 2019-11-14
- Published: 2022-01-13
- Granted: 2024-12-31
- Earliest claimed: 2018-11-15
- Assignees: Hk Inno.N Corporation
- Applicants: HK INNO.N Corporation
- Inventors: Ji-Yeon Park; Seung Chan Kim; So Young Ki; Ye-Ri Shim
- Web page: https://patentgrep.com/patent/US12180185B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound represented by Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound represented by Formula 1 is the compound represented by the following Formula 2:
in Formula 2,
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 or 1;
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 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 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.

### Claim 3 (depends on 1)

The compound represented by Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein:
R1 is H, C1-6 alkyl or C1-6 alkoxy;
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 or —C(═O)—NH—C1-6 haloalkyl;
R2 is H, C1-6 alkyl or C1-6 heteroaryl;
n and m are each independently 0 or 1;
D2 is —C(═O)—;
D3 is —NR3—,
or a single bond;
D4 is H, C1-6 alkyl, C1-6 alkenyl, 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 or C1-6 cyanoalkyl may be substituted with C3-7 cycloalkyl, aryl, heteroaryl or cyano,
at least one H of C3-7 cycloalkyl or 4-6-membered heterocycloalkyl may be substituted with C1-6 alkyl, C1-6 cyanoalkyl or cyano, and
at least one H of aryl or heteroaryl may be substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or cyano; and
R3 and R4 are each independently H, C1-6 alkyl or C1-6 haloalkyl.

### Claim 4 (depends on 3)

The compound represented by Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3, wherein:
R1 is H;
X-Y-Z is N—CH═CH;
R2 is H;
n and m are each independently 0;
D2 is —C(═O)—;
D3 is —NR3—,
or a single bond;
D4 is H, C1-6 alkyl, C1-6 alkenyl, C1-6 cyanoalkyl, C3-7 cycloalkyl, 5-6-membered heterocycloalkyl, aryl or heteroaryl;
wherein at least one H of C1-6 alkyl, C1-6 alkenyl or C1-6 cyanoalkyl may be substituted with aryl, heteroaryl or cyano,
at least one H of C3-7 cycloalkyl or 5-6-membered heterocycloalkyl may be substituted with C1-6 cyanoalkyl or cyano, and
at least one H of aryl or heteroaryl may be substituted with C1-6 alkyl, C1-6 alkoxy, cyano, nitro or halogen; and
R3 and R4 are each independently H or C1-6 alkyl.

### Claim 5 (depends on 4)

The compound represented by Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 4, wherein:
R1 is H, C1-6 alkyl or C1-6 alkoxy;
X-Y-Z is C═CA2-NA5;
A2 and A5 are each independently H, C1-6 alkyl or —C(═O)—NH—C1-6 haloalkyl;
R2 is H or C1-6 alkyl;
n and m are each independently 0 or 1;
D2 is —C(═O)—;
D3 is —NR3—,
or a single bond;
D4 is H, C1-6 alkyl, C1-6 alkenyl, 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 or C1-6 cyanoalkyl may be substituted with C3-7 cycloalkyl, heteroaryl or cyano,
at least one H of C3-7 cycloalkyl or 5-6-membered heterocycloalkyl may be substituted with C1-6 alkyl or cyano, and
at least one H of aryl or heteroaryl may be substituted with C1-6 alkyl, C1-6 haloalkyl or cyano; and
R3 and R4 are each independently H, C1-6 alkyl or C1-6 haloalkyl.

### Claim 6 (depends on 3)

The compound represented by Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3, wherein:
R1 is H;
X-Y-Z is C═N—NH;
R2 is H;
n and m are each independently 0;
D2 is —C(═O)—;
D3 is a single bond;
D4 is C1-6 alkenyl wherein at least one H of C1-6 alkenyl may be substituted with cyano; and
R3 is H.

### Claim 7

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.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, as an active ingredient.

### Claim 9 (depends on 1)

A method for preventing or treating protein kinase-related diseases, comprising a step of administering a therapeutically effective amount of the compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, into a subject.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the protein kinase-related diseases are selected from the group consisting of cancers, autoimmune diseases, neurological diseases, metabolic diseases and infections.