# US 7,745,641 B2 · Nitrogen-containing heterocyclic compound

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- Number: US 7,745,641 B2
- Document ID: US7745641B2
- Status: Granted
- Kind: B2
- Application number: 11/918,778
- Filed: 2006-04-19
- Published: 2009-02-26
- Granted: 2010-06-29
- Earliest claimed: 2005-04-19
- Assignees: Kyowa Hakko Kirin Co., Ltd.
- Inventors: Chikara Murakata; Nobuyoshi Amishiro; Toshiyuki Atsumi; Yoshinori Yamashita; Takeshi Takahashi; Ryuichiro Nakai; Hisashi Tagaya; Hiroko Takahashi; Jun Funahashi; Junichiro Yamamoto; Yuichi Fukuda
- Web page: https://patentgrep.com/patent/US7745641B2

## CPC

- C07D 209/46: with an oxygen atom in position 1
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a nitrogen-containing heterocyclic compound represented by formula (I): {wherein W represents a nitrogen atom or —CH—; X represents —C(═O)— or —CHR4— (wherein R4 represents a hydrogen atom, or the like}; R1 represents a group represented by the following formula: [wherein Q1 represents a nitrogen atom or —CR8— (wherein R8 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like). Q2 represents —NR15— (wherein R15 represents a hydrogen atom, or the like) and R5 and R6 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like]; and R2 and R3 may be the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or the like} or a pharmaceutically acceptable salt thereof, and the like.

## Claims

### Claim 1

A nitrogen-containing heterocyclic compound represented by formula (I):
wherein W represents —CH—;
X represents —CHR4— (wherein R4 represents a hydrogen atom);
R1 represents a group represented by the following formula:
{wherein Q1 represents —CR8— (wherein R8 represents a hydrogen atom),
Q2 represents —NR15— (wherein R15 represents a hydrogen atom),
R5 represents methyl substituted with NR35bR36b (wherein R35b and R36b may be the same or different and each represents a hydrogen atom, C1-10 alkyl, C1-10 alkyl substituted with hydroxy or C1-10 alkoxy), pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin-1-ylmethyl, piperazin-1-ylcarbonyl, or 4-methylpiperazin-1-yl, and
R6 represents a hydrogen atom},
R2 represents a hydrogen atom or C1-10 alkoxy, and
R3 represents hydroxy, halogen, or —OS(O)2R24a (wherein R24a represents C1-10 alkyl, thienyl, pyridyl, amino, or dimethylamino),
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R5 is methyl substituted with NR35aR36a (wherein R35a and R36a may be the same or different and each represents a hydrogen atom or C1-10 alkyl).

### Claim 3

A nitrogen-containing heterocyclic compound represented by formula (Ia):
{wherein R2A represents methoxy,
R3A represents methylsulfonyloxy, and
R5A represents (methylamino)methyl, (ethylamino)methyl, (propylamino)methyl, (2,2-dimethylethylamino)methyl, (cyclopropylamino)methyl, (cyclohexylamino)methyl, (dimethylamino)methyl, (diethylamino)methyl, [di(2-hydroxyethyl)amino]methyl, (2-methoxyethylamino)methyl, [di(2-methoxyethyl)amino]methyl, pyrrolidin-1-ylmethyl, piperidinomethyl, (4-piperidinopiperidino)methyl, morpholinomethyl, 4-methylpiperazin-1-ylmethyl or 4-(2-hydroxyethyl)piperazin-1-ylmethyl},
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

A pharmaceutical composition comprising, as an active ingredient, the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in claim 3 together with a pharmaceutically acceptable carrier.

### Claim 5 (depends on 1, 2)

The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R2 is methoxy.

### Claim 6 (depends on 1, 2)

The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R3 is methylsulfonyloxy.

### Claim 7 (depends on 5)

The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to claim 5, wherein R3 is methylsulfonyloxy.

### Claim 8

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(methylaminomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(ethylaminomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(1-propylaminomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(cyclopropylaminomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(cyclohexylaminomethyl)indol-2-yl]isoindolinone, and
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(2-methoxyethylaminomethyl)indol-2-yl]isoindolinone.

### Claim 9

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the compound is:
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(dimethylaminomethyl)indol-2-yl]isoindolinone, or
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(diethylaminomethyl)indol-2-yl]isoindolinone.

### Claim 10

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the compound is:
4-Methanesulfonyloxy-5-methoxy-7-{1H-5-[di(2-hydroxyethyl)aminomethyl]indol-2-yl}isoindolinone, or
4-Methanesulfonyloxy-5-methoxy-7-{1H-5-[di(2-methoxyethyl)aminomethyl]indol-2-yl}isoindolinone.

### Claim 11

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(piperidinomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(4-piperidinopiperidinomethyl)indol-2-yl] isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(morpholinomethyl)indol-2-yl]isoindolinone,
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-(4-methylpyperazin-1-ylmethyl)indol-2-yl]isoindolinone, and
4-Methanesulfonyloxy-5-methoxy-7-[1H-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone.

### Claim 12 (depends on 8, 9, 10, 11)

A pharmaceutical composition comprising, as an active ingredient, the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claim 8 to 11 together with a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for inhibiting a protein kinase comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 14 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for inhibiting a fibroblast growth factor receptor comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 15 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for inhibiting an Aurora comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 16 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for inhibiting a fms-like tyrosine kinase 3 comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 17 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for treating a hematopoietic tumor comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 18 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for treating leukemia, myeloma, or lymphoma comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 19 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for treating multiple myeloma comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 20 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for treating stomach cancer comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.

### Claim 21 (depends on 1, 2, 3, 8, 9, 10, 11)

A method for treating colon cancer comprising a step of administering the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of claims 1, 2, 3, 8, 9, 10 or 11.