# US 2013/0158030 A1 · Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof

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- Number: US 2013/0158030 A1
- Document ID: US20130158030A1
- Status: Published application
- Kind: A1
- Application number: 13/702,956
- Filed: 2011-03-31
- Published: 2013-06-20
- Earliest claimed: 2010-06-08
- Assignees: Qilu Pharmaceutical Co., Ltd.
- Inventors: Jingyi Wang; Chuanwen Fan; Long Zhang; Boyan Xu; Shousheng Yan; Zongru Guo; Minghui Zhang; Dong Lin; Zhantao Zhang; Haojie Zhou
- Web page: https://patentgrep.com/patent/US20130158030A1

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are pyrrolyl substituted dihydroindol-2-one derivatives represented by formula (I), pharmaceutically acceptable salts or solvates of said derivatives, or solvates of said salts, which are effective tyrosine kinase inhibitors. Also provided are the preparation methods of the above compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in manufacturing drugs useful for the treatment or adjunctive treatment of tumors medicated by tyrosine kinases or proliferation or migration of tumor cells driven by tyrosine kinases in mammals (including human).

## Claims

### Claim 1

A pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt,
wherein,
R1 is selected from the group consisting of hydrogen atom, C1-4 alkyl;
R2 is selected from the group consisting of C1-4 alkyl, C1-4 alkyl substituted with one or more halogen or hydroxyl groups, allyl, propargyl, —(CH2)mNR11R12, —SOjR11, —(CH2)mSOj(CH2)nNR11R12, —CO(CH2)kNR11R12, —SOj(CH2)mCH═CH(CH2)nNR11R12, —CO(CH2)mCH═CH(CH2)nNR11R12; wherein R11 and R12 are each independently selected from the group consisting of hydrogen atom, C1-4 alkyl, cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl can be substituted with one or more halogen, alkyl, hydroxy, amino, alkoxy groups; or R11, R12 together with N atom can form a 4- to 8-membered heterocycle, the heterocycle can further comprise 0 to 2 heteroatoms selected from N, S, O, and the heterocycle can be substituted at any other positions, except S or O atom, and the substituent is selected from the group consisting of C1-4 alkyl, hydroxy-substituted C1-4 alkyl, —(CH2)mNR11R12; m, n each independently can be an integer of 0 to 4, k is an integer of 1 to 4, and j is 1 or 2;
R3, R4 are each independently selected from the group consisting of hydrogen atom, halogen, C1-4 alkyl;
R5, R6, R7, R8 are each independently selected from the group consisting of hydrogen atom, halogen, C1-4 alkyl, C1-4 alkyl substituted with one or more halogens, C1-4 alkoxy, alkoxy substituted with one or more halogens, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy, —NR9R10, —SOR9, —SO2R9, —NR9SO2R10, —SO2NR9R10, —COR9, —NR9COR10, —OCOR9, —CN, —NO2, wherein the aryl, heteroaryl, cycloalkyl groups can be further substituted at any positions with alkyl, halogen or haloalkyl, alkoxy, haloalkoxy;
R9 and R10 are each independently selected from the group consisting of hydrogen atom, C1-4 alkyl, C1-4 alkyl substituted with one or more halogens, cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or heteroaryl can be substituted with one or more halogens, alkyl, hydroxy, amino, or haloalkyl, alkoxy, haloalkoxy;
the above halogens can be independently selected from the group consisting of fluorine, chlorine and bromine.

### Claim 2 (depends on 1)

The pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1, wherein R1 is hydrogen atom.

### Claim 3 (depends on 1)

The pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1, wherein R5, R6, R7, R8 are each independently selected from the group consisting of hydrogen atom, halogen, C1-4 alkyl, C1-4 alkyl substituted with one or more halogens, C1-4 alkoxy, C1-4 alkoxy substituted with one or more halogens, alkenyl, alkynyl, hydroxy, —NR9R10, —SOR9, —SO2R9, —NR9SO2R10, —SO2NR9R10, —OCOR9, —CN, —NO2.

### Claim 4 (depends on 1)

The pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1, wherein the pyrrolyl substituted dihydroindol-2-one derivative is selected from the group consisting of the following compounds:
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(N,N-diethylamino)propionamide;
N-{5-[5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(N,N-diethylamino)propionamide;
N-{5-[5-bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(N,N-diethylamino)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-4-(N,N-dimethylamino)-(2E)-crotonamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-4-(N,N-dimethylamino)butyramide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(N,N-dimethylamino)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acrylamide;
N-{5-[5-methylsulfonylamino-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(N,N-diethylamino)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)ethylsulfonamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(4-ethylpiperazin-1-yl)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(4-methylpiperazin-1-yl)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(morpholin-4-yl)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(piperidin-1-yl)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-(tetrahydropyrrol-1-yl)propionamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(4-methylpiperazin-1-yl)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(piperidin-1-yl)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(tetrahydropyrrol-1-yl)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(4-ethylpiperazin-1-yl)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(morpholin-4-yl)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-dimethylamino)acetamide;
N-{5-[6-methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[6-trifluoromethyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[5-methylsulfonylamino-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[5-nitro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[6-methyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide;
N-{5-[5-acetylamino-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-2-(N,N-diethylamino)acetamide.

### Claim 5 (depends on 1)

A pharmaceutical composition, comprising the pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1, and a pharmaceutically acceptable carrier and/or excipient.

### Claim 6 (depends on 1)

A method for preparing a pyrrolyl substituted dihydroindol-2-one derivative according to claim 1, comprising the following steps:
1) synthesizing a substituted 4-nitro-2-formylpyrrole compound from suitable raw materials:
synthesizing the substituted 4-nitro-2-formylpyrrole compound directly from substituted 2-formylpyrrole by nitration using a suitable nitrating agent:
or synthesizing the substituted 4-nitro-2-formylpyrrole compound indirectly from 2-ester group substituted pyrrole via nitration, decarboxylation and oxidization:
2) synthesizing compound A from the substituted 4-nitro-2-formylpyrrole compound:
3) synthesizing the target compound directly from compound A and a corresponding raw material via a suitable reaction:
or synthesizing a corresponding halogenated intermediate B first from compound A, and then synthesizing the target compound via a further step of reaction:
wherein, R3, R4, R11, R12 are as defined in claim 1; X is selected from the group consisting of Cl, Br or I; R is optionally selected from one or more of R5—R8 as defined in claim 1; n is integer of 0 to 4, and T is selected from the group consisting of OH or Cl.

### Claim at position 7

7-10. (canceled)

### Claim 11 (depends on 1)

A method of treating and/or preventing diseases associated with the inhibition of tyrosine kinase activity in a mammal comprising administering the mammal in such need an effective amount of the pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the mammal is a human.

### Claim 13 (depends on 1)

A method of treating and/or preventing diseases associated with tyrosine kinase in a mammal comprising administering the mammal in such need an effective amount of the pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the mammal is a human.

### Claim 15 (depends on 1)

A method of treatment or adjunctive treatment and/or prevention of a tumor mediated by tyrosine kinase or tumor cell proliferation and migration driven by tyrosine kinase in a mammal comprising administering the mammal in such need an effective amount of the pyrrolyl substituted dihydroindol-2-one derivative of formula I, a pharmaceutically acceptable salt thereof, a solvate of said derivative, or a solvate of said salt according to claim 1.

### Claim 16 (depends on 13)

The method according to claim 13, wherein the mammal is a human.