RU2008130458A

RU2008130458A - PYRROLO [3,2-c] PYRIDIN-4-OH 2-INDOLINONE DERIVATIVES AS PROTEINKINASE INHIBITORS

Info

Publication number: RU2008130458A
Application number: RU2008130458/04A
Authority: RU
Inventors: Пэн Чо ТАН (CN); Пэн Чо ТАН; Идун СУ (CN); Идун СУ; Лэй ЧЖАН (CN); Лэй Чжан; Лу СЯО (CN); Лу СЯО
Original assignee: Шанхай Хэнжуй Фармасьютикал Со. Лтд (Cn); Шанхай Хэнжуй Фармасьютикал Со. Лтд
Priority date: 2006-01-27
Filing date: 2007-01-24
Publication date: 2010-03-10
Also published as: CN101007814A; RU2410387C2

Abstract

1. Соединение формулы (I) или его фармацевтически приемлемые соли: ! ! где представляет собой одинарную связь или двойную связь; ! Х и Y независимо друг от друга выбраны из С или N; ! Х и Y представляют собой N, тогда R5 и R7 отсутствуют; ! R1 и R2 независимо друг от друга выбраны из Н, алкила, циклоалкила, гетероциклоалкила, арила, гетероарила, алкоксила, арилоксила, -COOR9, -CONR9R10, -C(=S)NR9R10, -COR9, -SOR9, -SO2R9, -SO2NR9R10 и -P(=O)(OR9)(OR10); ! R3 выбран из алкила, трифторметила, арила и аралкила, где указанный алкил, арил или аралкил замещен одним или более галогенами и гидроксилами; ! R4 выбран из алкила, циклоалкила, гетероциклоалкила, арила, гетероарила, гетероарила, алкенила, алкинила, -(CH2)n(OCH2CH2)rR11, -[CH2CH(OH)]rCH2NR9R10 и -(CH2)nNR9R10, где указанный алкил, циклоалкил, арил, гетероарил или гетероциклоалкил возможно замещен одной или более группами, выбранными из группы, состоящей из арила, гидроксила, амино, амидной группы, аминокарбонила, алкоксила, арилоксила, аминоалкила, гидроксиалкила, гетероциклоалкила, карбоновой кислоты, эфира карбоновой кислоты и -NR9R10; ! Х и Y представляют собой С, тогда R5, R6, R7, R8 независимо друг от друга выбраны из водорода, гало, галоалкоксила, алкила, циклоалкила, гетероциклоалкила, алкенила, алкинила, арила, гетероарила, гидроксила, -OR9, -O[CH2CH2O]rR11, -SR9, -NR9R10, -SOR9, -SO2R9, -NSO2R9, -SO2NR9R10, -(CH2)nCO2R9, -(CH2)nCONR9R10, -C(=S)NR9R10, -COR9, -NR9COR10, -NHCO2R10, -OCO2R9, -OCO2NR9R10, -CN и -NO2, где указанные арил, гетероарил, циклоалкил, гетероциклоалкил замещены одной или более группами, состоящими из алкила, алкоксила и галогена; ! R9 и R10 независимо друг от друга выбраны из водорода, алкила, циклоалкила, гетероарила и гетероциклоалкила, где указанные алкил, циклоалкил, арил, гетероарил и гетероциклоалкил незави�1. The compound of formula (I) or its pharmaceutically acceptable salts:! ! where is a single bond or double bond; ! X and Y are independently selected from C or N; ! X and Y are N, then R5 and R7 are absent; ! R1 and R2 are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, -COOR9, -CONR9R10, -C (= S) NR9R10, -COR9, -SOR9, -SO2R9, -SO2NR9R and -P (═O) (OR9) (OR10); ! R3 is selected from alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is substituted with one or more halogens and hydroxyls; ! R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, alkenyl, alkynyl, - (CH2) n (OCH2CH2) rR11, - [CH2CH (OH)] rCH2NR9R10 and - (CH2) nNR9R10, where the specified alkyl, cycloalkyl aryl, heteroaryl or heterocycloalkyl is optionally substituted with one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and -NR9R10; ! X and Y are C, then R5, R6, R7, R8 are independently selected from hydrogen, halo, haloalkoxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, -OR9, -O [CH2CH2O ] rR11, -SR9, -NR9R10, -SOR9, -SO2R9, -NSO2R9, -SO2NR9R10, - (CH2) nCO2R9, - (CH2) nCONR9R10, -C (= S) NR9R10, -COR9, -NR9COR10, -NHCO2, -OCO2R9, -OCO2NR9R10, -CN and -NO2, wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl are substituted with one or more groups consisting of alkyl, alkoxyl and halogen; ! R9 and R10 are independently selected from hydrogen, alkyl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are independently

Claims

1. The compound of formula (I) or its pharmaceutically acceptable salts:

Where

represents a single bond or double bond;

X and Y are independently selected from C or N;

X and Y are N, then R5 and R7 are absent;

R ₁ and R _{2 are} independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, —COOR ₉ , —CONR ₉ R ₁₀ , —C (= S) NR ₉ R ₁₀ , —COR ₉ , -SOR ₉ , -SO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ and -P (= O) (OR ₉ ) (OR ₁₀ );

R _{3 is} selected from alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is substituted with one or more halogens and hydroxyls;

R _{4 is} selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, alkenyl, alkynyl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂₎ _n NR ₉ R _10, wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substituted with one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

X and Y are C, then R ₅ , R ₆ , R ₇ , R _{8 are} independently selected from hydrogen, halo, haloalkoxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, -OR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -SR ₉ , -NR ₉ R ₁₀ , -SOR ₉ , -SO ₂ R ₉ , -NSO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ , - ( ₂ CH) _n CO ₂ R _9, - (CH ₂₎ _n CONR ₉ R _10, -C (= S) NR ₉ R _10, -COR _9, -NR ₉ COR _10, -NHCO ₂ R _10, -OCO ₂ R ₉ , —OCO ₂ NR ₉ R ₁₀ , —CN and —NO 2, wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl are substituted with one or more groups consisting of alkyl, alkoxyl and halogen;

R ₉ and R _{10 are} independently selected from hydrogen, alkyl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are independently substituted by one or more groups consisting of alkyl, aryl, hydroxyl, amino, amide group, aminocarbonyl, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid and carboxylic acid ester;

R ₉ and R ₁₀ together with the atom to which they are attached form 4-8 membered rings, where 5-8 membered rings may, in addition, contain one to three heteroatoms selected from the group consisting of N, O and S, and each 4-8 membered ring thus formed is optionally substituted with one or more groups consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxyl, hydroxyl, amino, amide groups, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, halogen and —NR ₉ R ₁₀ ;

R ₁₁ represents hydrogen or alkyl;

n represents 2-6 and

r represents 1-6.

2. The compound of formula (I) or its pharmaceutically acceptable salts according to claim 1, where the compound has the formula (Ia):

Where

represents a single bond or double bond;

X and Y are independently selected from C and N;

X and Y are N, then R5 and R7 are absent;

R3 is selected from alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl and aralkyl are independently substituted with one or more halogens and hydroxyls;

R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, alkenyl, alkynyl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ where each said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

X and Y are C, then R5, R6, R7 and R8 are independently selected from hydrogen, halo, haloalkoxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, —OR ₉ , —O [ CH ₂ CH ₂ O] _r R ₁₁ , -SR ₉ , -NR ₉ R ₁₀ , -SOR ₉ , -SO ₂ R ₉ , -NSO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ , - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n CONR ₉ R ₁₀ , -C (= S) NR ₉ R ₁₀ , -COR ₉ , -NR ₉ COR ₁₀ , -NHCO ₂ R ₁₀ , -OCO ₂ R ₉ , - OCO ₂ NR ₉ R _10, -CN and -NO _2, wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl independently substituted with one or more groups consisting of alkyl, alkoxy and halogen;

R ₉ and R _{10 are} independently selected from hydrogen, alkyl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl are independently substituted by one or more groups consisting of alkyl, aryl, hydroxyl, amino, amide group, aminocarbonyl, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid and carboxylic acid ester;

R ₉ and R ₁₀ together with the atom to which they are attached form 4-8 membered rings, where 5-8 membered rings, in addition, may contain one to three heteroatoms selected from the group consisting of N, O and S, and each 4-8 membered ring thus formed is optionally substituted with one or more groups consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxyl, hydroxyl, amino, amide groups, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, halogen and —NR ₉ R ₁₀ ;

R ₁₁ represents hydrogen or alkyl;

n represents 2-6 and

r represents 1-6.

3. The compound of formula (I) or its pharmaceutically acceptable salts according to claim 1, where the compound has the formula (Ib):

Where

represents a single bond or double bond;

R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, alkenyl, alkynyl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are independently independently substituted by one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide groups, aminocarbonyl, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

X and Y are C, then R ₅ , R ₆ , R ₇ , R _{8 are} independently selected from hydrogen, halo, haloalkoxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, -OR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -SR ₉ , -NR ₉ R ₁₀ , -SOR ₉ , -SO ₂ R ₉ , -NSO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ , - ( CH ₂₎ _n CO ₂ R _9, - (CH ₂₎ _n CONR ₉ R _10, -C (= S) NR ₉ R _10, -COR _9, -NR ₉ COR _10, -NHCO ₂ R _10, -OCO ₂ R ₉ , —OCO ₂ NR ₉ R ₁₀ , —CN and —NO ₂ , wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl are independently substituted by one or more groups consisting of alkyl, alkoxyl and halogen;

R ₉ and R ₁₀ together with the atom to which they are attached form 4-8 membered rings, where 5-8 membered rings, in addition, may contain one to three heteroatoms selected from the group consisting of N, O and S, and 4-8 membered rings thus formed are optionally substituted with one or more groups consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxyl, hydroxyl, amino, amide groups, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carbon acid, carboxylic acid ester, halogen and —NR ₉ R ₁₀ ;

R ₁₁ represents hydrogen or alkyl;

n represents 2-6 and

r represents 1-6.

4. The compound of formula (I) or its pharmaceutically acceptable salts according to claim 1, where the compound has the formula (IB):

Where

represents a single bond or double bond;

R _{3 is} selected from alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl and aralkyl are independently substituted with one or more halogens and hydroxyls;

R _{4 is} selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, alkenyl, alkynyl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl are optionally substituted with one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

X and Y are C, then R ₅ , R ₆ , R ₇ , R _{8 are} independently selected from hydrogen, halo, haloalkoxyl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, -OR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -SR ₉ , -NR ₉ R ₁₀ , -SOR ₉ , -SO ₂ R ₉ , -NSO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ , - ( CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n CONR ₉ R ₁₀ , -C (= S) NR ₉ R ₁₀ , -COR ₉ , -NR ₉ COR ₁₀ , -NHCO ₂ R ₁₀ , -OCO ₂ R _9, -OCO ₂ NR ₉ R _10, -CN and -NO _2, wherein each said aryl, heteroaryl, cycloalkyl, heterocycloalkyl substituted with one or more groups consisting of alkyl, alkoxy and halogen;

R ₉ and R _{10 are} independently selected from hydrogen, alkyl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are independently substituted by one or more groups consisting of alkyl, aryl, hydroxyl, amino, amide group, aminocarbonyl, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid and carboxylic acid ester;

R ₉ and R ₁₀ together with the atom to which they are attached form 4-8 membered rings, where 5-8 membered rings may, in addition, contain one to three heteroatoms selected from the group consisting of N, O and S, and 4-8 membered rings thus formed are optionally substituted with one or more groups consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxyl, hydroxyl, amino, amide groups, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carbon acid, carboxylic acid ester, halogen and —NR ₉ R ₁₀ ;

R ₁₁ represents hydrogen or alkyl;

n represents 2-6 and

r represents 1-6.

5. The compound of formula (I) or its pharmaceutically acceptable salts according to claim 1, where the specified compound is selected from the group consisting of:

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- (7-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl} -acetamide

2- (6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -formamide

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -acetamide

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} methanesulfonamide

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

4- (3-Chloro-4-fluoro-phenylamino) -5- [5- (2-diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3 , 2-c] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -acetamide

N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -acetamide

2- (6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (7-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} methanesulfonamide

N- {3- [3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

4- (3-Chloro-4-fluoro-phenylamino) -5- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H -pyrrolo [3,2-c] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

4- (3-Chloro-4-fluoro-phenylamino) -5- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H -pyrrolo [3,2-c] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

N- {3- [3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

2- (4-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -3-methyl-2- (2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-diethylamino-ethyl) -3-methyl-1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -formamide

2- [4- (4-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -5- (2-diethylamino-ethyl) -3-methyl-1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- (5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- [4- (3-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -5- (2-diethylamino-ethyl) -3-methyl-1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- [4- (2-hydroxy-ethyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-1,5,6, 7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- [5- (4-methoxy-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-1,5,6, 7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- [4- (2,3-difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-phenyl-1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4- she

2- [4- (2-Hydroxy-ethyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl) -1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (4-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (2,3-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3- (4-fluoro-phenyl) -1,5,6,7-tetrahydro-pyrrolo [3,2- c] pyridin-4-one

4- (3-Chloro-4-fluoro-phenylamino) -5- [3- (4-fluoro-phenyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-s ] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

2- [4- (3-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (4-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-pyrrolo [2,3-b] pyridin-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-5- (2-morpholin-4-yl-ethyl) -2- (2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenomethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxy-acetamide

2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -formamide

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-phenyl-1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4- she

5- (2-Diethylamino-ethyl) -3-methyl-2- (4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3- (4-fluoro-phenyl) -1,5,6,7-tetrahydro-pyrrolo [3,2- c] pyridin-4-one

2- [4- (2,3-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxy-acetamide

N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-acetamide

2- (6-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (2,6-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (3-Fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) -1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3- (4-fluoro-phenyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-acetamide

N- {3- [3- (4-Fluoro-phenyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo -2,3-dihydro-1H-indol-5-yl} -2-hydroxy-acetamide

N- {5-Fluoro-3- [3- (4-fluoro-phenyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxy-acetamide

2- [4- (3-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (4-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-pyrrolidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl) -5- (2-pyrrolidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxy-acetamide

N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-acetamide

2- [4- (4-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (2-Hydroxy-ethyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-pyrrolo [2,3-b] pyridin-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- [5-Fluoro-2-oxo-3- (4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene) -2 , 3-dihydro-1H-indol-6-yl] -2-hydroxy-acetamide

2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -formamide

2- [5-Fluoro-6- (4-fluoro-benzylamino) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3- (4-fluoro-phenyl) -1.5,6, 7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [3- (4-Fluoro-phenyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo -2,3-dihydro-1H-indol-5-yl} -2-methoxy-acetamide

2- [4- (2,3-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (2-Hydroxy-ethyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) -1, 5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (4-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (3-Chloro-2-fluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenemethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (4-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl) -5- (2-piperidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {3- [3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -formamide

2- (5-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-pyrrolo [2,3-b] pyridin-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) - 1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [5-Fluoro-6- (4-fluoro-benzylamino) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl ) -1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-2- (2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl) -5- (2-piperidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

3-Methyl-5- (2-morpholin-4-yl-ethyl) -2- (2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenomethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

(S) -N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [ 3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-propionamide

(S) -N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine- 2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-propionamide

(S) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [ 3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-propionamide

(S) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [ 3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-propionamide

3-Methyl-2- (2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl) -5- (2-pyrrolidin-1-yl-ethyl) -1.5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methyl-propionamide

N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methyl-propionamide

N- {3- [5- (2-Diethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methyl-propionamide

5- (2-Ethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (4-hydroxy-1-methyl-piperidin-4-ylmethyl) -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- [4- (2,3-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -5- (4-hydroxy-1-methyl-piperidin-4-ylmethyl) - 3-methyl-1,5,6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (4-hydroxy-1-methyl-piperidin-4-ylmethyl) -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (4-hydroxy-1-methyl-piperidin-4-ylmethyl) -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5-dihydro-pyrrolo [3,2- c] pyridin-4-one

5- (2-Dimethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

2- [4- (2,3-Difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -5- (2-dimethylamino-ethyl) -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one

2- (5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -5- (2-dimethylamino-ethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

4- (3-Chloro-4-fluoro-phenylamino) -5- [5- (2-dimethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3 , 2-c] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

N- {3- [5- (2-Dimethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -formamide

N- {3- [5- (2-Dimethylamino-ethyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methyl-propionamide

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-hydroxymethyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

5- (2-Dimethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-1,5-dihydro-pyrrolo [3,2- c] pyridin-4-one

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5-dihydro-pyrrolo [ 3,2-c] pyridin-4-one

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-trifluoromethyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one

4- (3-Chloro-4-fluoro-phenylamino) -5- [5- (2-diethylamino-ethyl) -4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrrolo [3 , 2-c] pyridin-2-ylmethylene] -5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-yl-demmethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one malate

2- (5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -1,5,6,7- tetrahydro-pyrrolo [3,2-c] pyridin-4-one malate

5- (2-Diethylamino-ethyl) -2- [4- (2,3-difluoro-phenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-1,5, 6,7-tetrahydro-pyrrolo [3,2-c] pyridin-4-one malate

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one lactate

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one maleate and

5- (2-Diethylamino-ethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-1,5,6,7-tetrahydro-pyrrolo [ 3,2-c] pyridin-4-one of mesylate.

6. The compound of formula (I) or its pharmaceutically acceptable salts according to claim 1, where the pharmaceutically acceptable salts are salts formed with acids selected from the group of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid.

7. A pharmaceutical composition comprising at least a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, as well as a pharmaceutically acceptable carrier.

8. The compound having the following formula (II), or its pharmaceutically acceptable salts, which are an intermediate in the synthesis of compounds according to claim 1:

where R _{2 is} selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, —COOR ₉ , —CONR ₉ R ₁₀ , —C (= S) NR ₉ R ₁₀ , —COR ₉ , —SOR ₉ , -SO ₂ R ₉ , -SO ₂ NR ₉ R ₁₀ and -P (= O) (OR ₉ ) (OR ₁₀ );

R _{3 is} selected from alkyl, trifluoromethyl, aryl and aralkyl, wherein each said alkyl, aryl and aralkyl is optionally substituted with one or more halogens and hydroxyls;

R _{4 is} selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein each said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R _{10 are} independently selected from hydrogen, alkyl, cycloalkyl, heteroaryl and heterocycloalkyl, where each specified alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl is substituted with one or more groups consisting of alkyl, aryl, hydroxyl, amino, amide groups, aminocarbonyl, cyano, alkoxyl, aryloxyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid and carboxylic acid ester;

R ₁₁ represents hydrogen or alkyl;

R ₁₂ represents hydrogen or an aldehyde;

n represents 2-6 and

r represents 1-6.

9. A method of manufacturing a compound according to claims 1-5, wherein the oxindole is reacted with an aldehyde or ketone in the presence of a base, including piperidine or triethylamine, in a solvent of 1-2 ml / mol of 2-oxindole, and then the mixture is heated for about 2 up to about 12 hours, where the aldehyde has the following structure:

and oxindole has the following structure:

where the definitions of R1, R2, R3, R4, R5, R6, R7 and R8 are as described in paragraph 1, respectively.

10. A method of treating a mammal for a protein kinase-associated disease that responds to modulation of one or more protein kinases, according to which a therapeutically effective amount of a compound or its pharmaceutically acceptable salts thereof is administered to a mammal according to claims 1-5.

11. A method of treating a mammal for a protein kinase-associated disease that responds to modulation of one or more protein kinases, according to which a therapeutically effective amount of a pharmaceutical composition according to claim 7 is administered to a mammal.

12. The use of a compound according to claims 1-5 in the manufacture of drugs for the treatment of a protein kinase-related disease in a mammal that responds to modulation of one or more protein kinases.

13. The use of claim 12, wherein the drugs are combined with another antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic substances, antihormones, antiandrogens and mixtures thereof, for the treatment of protein kinase-associated diseases.

14. The use of the composition according to claim 7 in the manufacture of a medicament for the treatment of a protein kinase-related disease in a mammal that responds to modulation of one or more protein kinases.

15. The use of claim 14, wherein said composition further comprises an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, modifiers biological responses, antibodies, cytotoxic substances, antihormones, antiandrogens and mixtures thereof, for the treatment of protein kinase-associated diseases.

16. The method of claim 10, where at least one protein kinase is selected from the group consisting of EGFR, HER-2, HER-3, HER-4, FGFR, Cdk, c-Met, c-Ret, PDGFR, VEGFR- 2, Aurora, Raf, Flt3, c-Kit, Chk, Pim-1, Plk-1, Pyk-2, Src, Frk, Btk, Csk, AY, Zap70, Fes / Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk, as well as their aberrant forms.

17. The method according to clause 16, where at least one protein kinase is selected from the group consisting of HER-2, PDGFR, VEGFR-2, EGFR, c-Kit, c-Met, FGFR, Flt3, as well as their aberrant forms.

18. The method according to 17, where the aberrant forms include mutant forms and allelic variants.

19. The method of claim 10, wherein said mammal is a human.

20. The method according to claim 10, where the diseases associated with protein kinases are selected from the group consisting of leukemia, especially chronic myelogenous leukemia, acute myelogenous leukemia, acute myeloid leukemia with myelodysplasia of three sprouts of blood formation, acute lymphoblastic leukemia, myelodysplastic syndrome, undifferentiated leukemia; various solid tumors, including tumors of a benign or especially malignant type, preferably sarcoma, gastrointestinal stromal tumors, seminomas, carcinoids, mast cell tumors, lung carcinomas, bronchial carcinomas, seminomas, dysgermines, testicular intraepithelial neoplasias, melanomas, breast papillomas, breast carcinomas thyroid carcinomas, malignant lymphomas, non-Hodgkin’s lymphomas, type 2 endocrine neoplasias, pheochromocytomas, shield carcinomas of the ovarian gland, parathyroid hyperplasia / adenoma, breast carcinoma, colon cancer, colorectal adenoma, ovarian cancer, breast cancer, prostate carcinoma, glioblastoma, brain tumors, prostate carcinoma, including adenocarcinomas and bone metastases, malignant gliomas, anaplasts astrocytoma / glioblastoma, pancreatic cancer, pleural malignant mesothelioma, hemangioblastoma, hemangioma, carcinoma of the kidney, liver, adrenal gland, bladder, stomach, including tumors Oli stomach, rectum, vagina, cervix, endometrium, multiple myeloma, tumors of the neck and head, including neoplasias, especially of epithelial character, malignant nephrosclerosis; other hyperplasia or proliferative diseases, including mastocytosis, concomitant myeloproliferative syndrome, pigmented urticaria, epidermal hyperproliferation, especially psoriasis; prostatic hyperplasia; inflammatory diseases, especially rheumatoid or rheumatic inflammatory diseases, preferably arthritis, more preferably rheumatoid arthritis, other chronic inflammatory diseases, including chronic asthma, arterial or post-transplant atherosclerosis, other diseases associated with unregulated angiogenesis, including fibrosis, angiogenesis, smooth muscle proliferation vessels, including stenosis or restenosis after angioplasty; retinopathies, macular degeneration, other eye diseases, especially diabetic retinopathies or non-vascular glaucoma; kidney diseases, including glomerulonephritis; diabetic nephropathy; inflammatory bowel disease, Crohn's disease, thrombotic microangiopathic syndromes; transplant rejection or glomerulopathy; fibrotic diseases, including cirrhosis; mesangial cell proliferative diseases and damage to nerve tissue; and / or diseases that respond to the action of said compound or pharmaceutically acceptable salts as immunosuppressants, as a means for healing wounds that do not leave scars, and for treating senile spots and contact dermatitis.

21. The method of claim 10, wherein said protein kinase-associated disease is cancer.

22. The method of claim 21, wherein said cancer is at least one disease selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer , ovarian cancer, colon cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer stems, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma , renal pelvis carcinomas, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal tumors, glioma of the brain stem, pituitary adenoma, and combinations thereof.

23. The method of claim 22, wherein said cancer is selected from gastrointestinal stromal tumors, renal cell carcinoma, breast cancer, colorectal cancer, non-small cell lung cancer, neuroendocrine tumor, thyroid cancer, small cell lung cancer, mast cell, glioma, sarcoma acute myeloid leukemia, prostate cancer, lymphoma, or combinations thereof.

24. The method according to claim 10, according to which at least one antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors is co-administered, biological response modifiers, antibodies, cytotoxic substances, antihormones, antiandrogens and their mixtures.

25. A method of manufacturing an intermediate compound of formula (II) according to claim 8, according to which:

the pyrrole IIa triester is selectively hydrolyzed under the action of the first base at a certain temperature to form the pyrrole carboxylic acid diester IIb and

aminopyrrole IIc ether is heated with a second base in a solvent to form a cyclized product condensed with pyrrole lactam IIg

wherein said first base is selected from aqueous lithium hydroxide, sodium hydroxide or potassium hydroxide; and said second base is selected from lithium hydroxide, triethylamine, t-BuOK or trimethylaluminum; and the definitions of R2, R3, R4 and R12 are as described in claim 8.

26. The method according A.25, where the solvent is toluene or glycol.

27. The method according A.25, where the temperature of the selective hydrolysis of the pyrrole IIa triester is 10 ° C ~ 50 ° C.

28. A method of manufacturing an intermediate compound of formula (II) according to claim 8, according to which:

aminopyrrole IIe ether is heated with a base in 95% ethanol at the reaction temperature to form a cyclized pyrrolo-lactam IIe product

wherein said base is selected from lithium hydroxide or potassium carbonate; and the definitions of R2, R3, R4 and R12 are as described in claim 8.

29. The method according to p, where the reaction temperature is 35 ° C ~ 80 ° C.

30. A method of manufacturing an intermediate compound of formula (II) according to claim 8, according to which:

aminopyrrole IIg ether is heated with a base in 95% ethanol at the reaction temperature to form the cyclized product of pyrrolo-lactam IIh

wherein said base is selected from lithium hydroxide, potassium carbonate; and the definitions of R2, R3, R4 and R12 are as described in claim 8.

31. The method according to clause 30, where the reaction temperature is 35 ° C ~ 80 ° C.

32. A method of manufacturing an intermediate compound of formula (II) according to claim 8, according to which:

trifluoromethyl amine IIi and lactam-ketone IIk in acetic acid are reacted during Knorr cyclization to form trifluoromethylpyrrolo-lactam IIl

trifluoromethylpyrrole-lactam IIl selectively alkylates with sodium hydride and R ₄ Br in dimethylformamide to give compound IIm

Compound IIm is reacted with a reducing agent, such as lithium aluminum hydride or DIBAL-H, in tetrahydrofuran or dichloromethane at a certain temperature to form hydroxypyrrololactam IIn

hydroxypyrrolo-lactam IIn is oxidized with 2-iodoxybenzoic acid (IBX) as an oxidizing agent and para-toluenesulfonic acid in DMSO to form pyrrolo-lactam IIo aldehyde

definitions of R2, R3, R4 and R12 are as described in claim 8.

33. The method according to p, where the cyclization temperature according to Knorr is 100 ° C ~ 140 ° C.

34. The method according to claim 33, wherein the determined reduction temperature is -5 ° C ~ 25 ° C.