RU2003120442A

RU2003120442A - MACROHETEROCYCLIC COMPOUNDS USEFUL AS KINASE INHIBITORS

Info

Publication number: RU2003120442A
Application number: RU2003120442/04A
Authority: RU
Inventors: Гее-Хонг КУО; Кэтрин ПРОУТИ; АНДЖЕЛИС Алан ДЕ; Хан-Ченг ЗАНГ; Петер КОННОЛЛИ; Уилльям В. МЮРРЭЙ; Чандра Р. ШАХ; Брюс Е. Марьянофф; Кимберли Б. УАЙТ; Лан Шен; Брюс КОНВЭЙ; Кейт ДЕМАРЕСТ
Original assignee: Орто-Макнейл Фармасьютикал, Инк.
Priority date: 2000-12-08
Filing date: 2001-12-06
Publication date: 2004-12-27

Claims

1. The compound of formula (I)

Where

A and E are independently selected from the group consisting of a hydrogen substituted carbon atom and a nitrogen atom; Where

independently selected from the group consisting of 1H-indole, 1H-pyrrolo [2,3-b] pyridine, 1H-pyrazolo [3,4-b] pyridine and 1H-indazole;

Z is selected from O or dihydro; where if Z is a dihydro, each hydrogen atom is attached by a single bond;

R ₄ and R _{5 are} independently selected from C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl, where R ₄ and R _{5 are} optionally substituted with oxo;

R _{2 is} selected from the group consisting of -C _1-8 alkyl-, -C _2-8 alkenyl-, -C _2-8 alkynyl, -O- (C _1-8 ) alkyl-O-, -O- ( C _2-8 ) alkenyl-O-, -O- (C _2-8 ) alkynyl-O-, -C (O) - (C _1-8 ) alkyl-C (O) - (where any of the above alkyl, alkenyl and alkynyl linking groups is a linear carbon chain, optionally substituted with one to four substituents,

independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, -C (O) O- (C _1-8 ) alkyl, -C _1-8 alkyl-C (O) O- (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _{1 -3} (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl, heteroaryl (C _1-8 ) alkyl, spirocycloalkyl and spiroheterocyclyl (where any of the above cycloalkyl, heterocyclic, aryl and heteroaryl substituents is optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _{1 -8} alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _{1- 3} (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where any of the above heterocyclic substituents is optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (where cycloalkyl, heterocycle il, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _{1 -8} ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where heterocyclyl is optionally substituted with oxo), - (O- (CH ₂ ) _1-6 ) _0-5 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- , -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _0-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 --NR ₆ -, - (O- (CH ₂ ) _1-6 ) _0-5 -S-, -O- (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O-, - O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -S-, -NR ₆ -, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 -NR ₈ -, -NR _{6 =} C (O) -, -C (O) -NR ₆ -, - C (O) - (CH ₂ ) _0-6 -NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 -NR ₇ -, -NR ₆ -C (O) -NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, - O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, - S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -NR ₆ - (CH ₂ ) _1-6 -S - (CH ₂ ) _1-6 --NR ₇ - and -SO ₂ - (wherein R _6, R ₇ and R ₈ are independently selected from the group consisting of hydrogen, C _1-8 -alk la, C _1-8 alkoxy (C _1-8) alkyl, carboxy (C _1-8) alkyl, amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _{1- 4} alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl and heteroaryl (C _1-8 ) alkyl (where the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino ( substituted will Lemma independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl; (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; where heterocyclyl is optionally substituted by oxo)),

provided that if A and E are selected from a hydrogen substituted carbon atom, then R _{2 is} selected from the group consisting of -C _2-8 alkynyl-, -O- (C _1-8 ) alkyl-O-, -O- (C _2-8 ) alkenyl-O-, -O- (C _2-8 ) alkynyl-O-, -C (O) - (C _1-8 ) alkyl-C (O) - (where any of the above alkyl, alkenyl and alkynyl linking groups is a linear carbon chain optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl , carboxyl (C _1-8 ) alkyl, -C (O) O- (C _1-8 ) alkyl, -C _1-8 alkyl-C ( O) O- (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy, hydroxy (C _{1- 8} ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroar sludge, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl, heteroaryl (C _1-8 ) alkyl, spirocycloalkyl and spiroheterocyclyl (where any of the above cycloalkyl, heterocyclic, aryl and heteroaryl substituents is optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent, independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted Subst Telem independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _1-8) alkyl, (halo) _1-3 (C _1-8) alkoxy, hydroxy, and hydroxy (C _1-8 ) alkyl, and where any of the above heterocyclic substituents is optionally substituted with oxo), cycloalkyl (where cycloalkyl is optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8) alkyl, carboxyl, carboxyl _(C1-8) alkyl, amino (substituted with a substituent independently selected from the group consisting and hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _{1 -8} ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl, - (O- (CH ₂ ) _1-6 ) _1-5 -O-, - O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _1-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O -, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -NR ₆ -, - (O- (CH ₂ ) _1-6 ) _0-5 -S-, -O- ( CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -S-, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 -NR ₈ -, -NR _{9 =} C (O) -, -C (O) -NR ₉ -, -C (O) - (CH ₂ ) _0-6 --NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 --NR ₇ -, -NR ₆ -C (O) - NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S- and -NR ₆ - (CH ₂ ) _1-6 -S - (CH ₂ ) _1-6 --NR ₇ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-8 alkyl, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl (C _1-8 ) alkyl, amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8) alkyl, aryl (C _1-8) alkyl and heteroaryl (C _1-8) alkyl (wherein the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four I substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8) alkyl, carboxyl, carboxyl _(C1-8) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, ( halogen) _1-3 (C _1-8 ) alkyl; (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where heterocyclyl is optionally substituted by oxo)); and where R _{9 is} selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl (C _1-8 ) alkyl, amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl and heteroaryl (C _1-8 ) alkyl (where the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl car oxyl (C _1-8) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting from hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl ; and where heterocyclyl is optionally substituted by oxo)), and

R ₁ and R _{3 are} independently selected from the group consisting of hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl (where alkyl, alkenyl and alkynyl are optionally substituted with a substituent selected from the group consisting of C _{1 -8} alkoxy, alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _{1- 8} ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), (halogen) _1-3 , (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _{1 -3} (C _1-8 ) alkoc si, hydroxy, hydroxy (C _1-8 ) alkyl and oxo), C _1-8 alkoxy, C _1-8 alkoxycarbonyl, (halogen) _1-3 (C _1-8 ) alkoxy, C _1-8 alkylthio, aryl, heteroaryl (where aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino ( substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen , (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl), amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), cyano, halogen, hydroxy and nitro;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where R ₄ and R _{5 are} independently selected from C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, optionally substituted with oxo.

3. The compound according to claim 1, where R ₄ and R _{5 are} independently selected from C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl.

4. The compound according to claim 1, where R ₄ and R _{5 are} independently selected from C _1-6 alkyl.

5. The compound according to claim 1, where R ₂ selected from the group consisting of -C _1-8 alkyl-, -C _2-4 alkenyl-, -C _2-4 alkynyl-, -O- (C _1-4 ) alkyl-O-, -O- (C _2-4 ) alkenyl-O-, -O- (C _2-4 ) alkynyl-O-, -C (O) - (C _1-4 ) alkyl-C (O ) - (where any of the above alkyl, alkenyl and alkynyl linking groups are linear carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, -C (O) O- (C _1-4 ) alkyl, -C _1-4 alkyl-C (O) O- (C _1-4 ) alkyl, amino (substituted a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen , (halogen) _1-3 (C _1-4 ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy, hydroxy (C _1-4 ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl linking groups optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl (C _1-4 ) alkyl , aryl (C _1-4 ) alkyl, heteroaryl (C _1-4 ) alkyl, spirocycloalkyl and spiroheterocyclyl (where any of the above cycloalkyl, heterocyclic, aryl and heteroaryl substituents is optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-4 ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy and hydroxy (C _{1 -4} ) alkyl; and where any of the above heterocyclic substituents is optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4) alkyl (wherein amino is substituted with a substituent independently selected and the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _1-4) alkyl, (halo) _1-3 (C _1-4) alkoxy, hydroxy and hydroxy (C _{1- 4} ) alkyl; and where heterocyclyl is optionally substituted with oxo), - (O- (CH ₂ ) _1-6 ) _0-5 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _{1- 6} -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _0-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -NR ₆ -, - (O- (CH ₂ ) _1-6 ) _0-5 -S-, -O- (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O -, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -S-, -NR ₆ -, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 -NR ₈ -, -NR _{6 =} C (O) -, -C (O) -NR ₆ -, -C (O) - (CH ₂ ) _0-6 --NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O ) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 --NR ₇ -, -NR ₆ -C (O) -NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - ( CH ₂ ) _1-6 -O-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -NR ₆ - (CH ₂ ) _1-6 -S- ( CH ₂ ) _1-6 --NR ₇ - and –SO ₂ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _1-4 alkoxy (C _{1- 4} ) alkyl, carboxyl (C _1-4 ) alkyl, amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-4 ) alkyl, heterocyclyl (C _1-4) alkyl, aryl (C _1-4) alkyl and heteroaryl (C _1-4) alkyl (wherein the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4) alkyl, carboxyl, carboxyl _(C1-4) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-4 ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy and hydroxy (C _1-4 ) alkyl; where heterocyclyl is optionally substituted by oxo));

provided that if A and E are selected from a hydrogen substituted carbon atom, then R _{2 is} selected from the group consisting of -C _2-4 alkynyl-, -O- (C _1-4 ) alkyl-O-, -O- (C _2-4 ) alkenyl-O-, -O- (C _2-4 ) alkynyl-O-, -C (O) - (C _1-4 ) alkyl-C (O) - (where any of the above alkyl, alkenyl and alkynyl linking groups is a linear carbon chain optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl , carboxyl (C _1-4 ) alkyl, -C (O) O- (C _1-4 ) alkyl, -C _1-4 alkyl-C ( O) O- (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-4 ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy, hydroxy (C _{1- 4} ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroar sludge, heterocyclyl (C _1-4 ) alkyl, aryl (C _1-4 ) alkyl, heteroaryl (C _1-4 ) alkyl, spirocycloalkyl and spiroheterocyclyl (where any of the above cycloalkyl, heterocyclic, aryl and heteroaryl substituents is optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent, independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-4) alkyl (wherein amino is substituted Subst Telem independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _1-4) alkyl, (halo) _1-3 (C _1-4) alkoxy, hydroxy, and hydroxy (C _1-4 ) alkyl; and where any of the above heterocyclic substituents is optionally substituted with oxo)), cycloalkyl (where cycloalkyl is optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4 ) alkyl (where amino is substituted a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _{1 -4} ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy and hydroxy (C _1-4 ) alkyl, - (O- (CH ₂ ) _1-6 ) _1-5 -O-, - O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _1-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O -, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -NR ₆ -, - (O- (CH ₂ ) _1-6 ) _0-5 -S-, -O- ( CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -S-, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 -NR ₈ -, -NR _{9 =} C (O) -, -C (O) -NR ₉ -, -C (O) - (CH ₂ ) _0-6 --NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 --NR ₇ -, -NR ₆ -C (O) - NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S- and -NR ₆ - (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 --NR ₇ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen , C _1-4 alkyl, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl (C _1-4 ) alkyl, amino (C _1-4 ) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-4 ) alkyl, heterocyclyl (C _1-4 ) alkyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (where the above is heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-4 ) alkyl; (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy and hydroxy (C _1-4 ) alkyl; and where heterocyclyl is optionally substituted by oxo); and where R _{9 is} selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl (C _1-4 ) alkyl, amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-4 ) alkyl, heterocyclyl (C _1-4 ) alkyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (where the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy (C _1-4 ) alkyl, carboxyl car oxyl (C _1-4) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-4) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting from hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-4 ) alkyl, (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy and hydroxy (C _1-4 ) alkyl ; and where heterocyclyl is optionally substituted by oxo)).

6. The compound according to claim 1, where R ₂ selected from -C _1-8 alkyl- (optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy and oxo); aryl, heteroaryl, - (O- (CH ₂ ) _1-6 ) _0-5 -O-, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -O - (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O- and -NR ₆ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-4 alkyl and C _1-4 alkoxy (C _1-4 ) alkyl); provided that if A and E are selected from a hydrogen substituted carbon atom, then R _{2 is} selected from the group consisting of - (O- (CH ₂ ) _1-6 ) _1-5 -O-, - (O- (CH ₂ ) _1-6 ) _1-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, and -NR ₆ - (CH ₂ ) _1-6 - NR ₇ - (CH ₂ ) _1-6 -NR ₈ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-4 alkyl and hydroxy (C _1-4 ) alkyl).

7. The compound according to claim 1, where R _{2 is} selected from the group consisting of -C _1-8 alkyl- (optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy and oxo); phenyl, pyridinyl, - (O- (CH ₂ ) ₂ ) _1-4 -O-, -O- (CH ₂ ) ₂ -NR ₆ - (CH ₂ ) ₂ -O-, -O- (CH ₂ ) ₂ -S- (CH ₂ ) ₂ -O- and -NR ₆ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-3 alkyl and C _1-2 alkoxy (C _{1- 2} ) alkyl); provided that if A and E are selected from a hydrogen substituted carbon atom, then R _{2 is} selected from the group consisting of - (O- (CH ₂ ) ₂ ) _1-4 -O-, - (O- (CH ₂ ) ₂ ) ₂ -NR ₆ -, -O- (CH ₂ ) ₂ -NR ₆ - (CH ₂ ) ₂ -O-, and -NR ₆ - (CH ₂ ) ₂ -NR ₇ - (CH ₂ ) ₂ -NR ₈ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-3 alkyl and hydroxy (C _1-2 ) alkyl).

8. The compound according to claim 1, where R ₁ and R _{3 are} independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl (where alkyl, alkenyl and alkynyl are optionally substituted with a substituent selected from the group consisting of C _1-4 alkoxy, alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _{1- 4} alkyl), amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), (halogen) _1-3 , (halogen) _1-3 (C _{1 -4} ) alkyl , (halogen) _1-3 (C _1-4 ) alkoxy, hydroxy, hydroxy (C _1-4 ) alkyl and oxo), C _1-4 alkoxy, C _1-4 alkoxycarbonyl, (halogen) _1-3 (C _{1 -4} ) alkoxy, C _1-4 alkylthio, aryl, heteroaryl (where aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, alkoxy (C _1-4 ) alkyl, carboxyl, carboxyl (C _1-4 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-4 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 -alk la), halogen, (halo) _1-3 (C _1-4) alkyl, (halo) _1-3 (C _1-4) alkoxy, hydroxy and hydroxy _(C1-4) alkyl), amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), cyano, halogen, hydroxy and nitro.

9. The compound according to claim 1, where R ₁ and R _{3 are} independently selected from the group consisting of hydrogen, C _1-4 alkyl (optionally substituted with a substituent selected from the group consisting of C _1-4 alkoxy, amino (substituted with a substituent, independently selected from the group consisting of hydrogen and C _1-4 alkyl), (halogen) _1-3 , hydroxy and oxo), C _1-4 alkoxy, C _1-4 alkoxycarbonyl, (halogen) _1-3 (C _{1- 4} ) alkoxy, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, hydroxy and nitro.

10. The compound according to claim 1, where R ₁ and R ₃ represent hydrogen.

11. The compound according to claim 1, where the compound of formula (I) is selected from a compound of formula (Iaa):

Where

independently selected from the group consisting of 1H-indole, 1H-pyrrolo [2,3-b] pyridine and 1H-indazole;

R ₄ and R _{5 are} independently selected from C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, optionally substituted with oxo;

R _{2 is} selected from the group consisting of -C _1-8 alkyl-, -C _2-8 alkenyl-, -C _2-8 alkynyl, -O- (C _1-8 ) alkyl-O-, -O- ( C _2-8 ) alkenyl-O-, -O- (C _2-8 ) alkynyl-O-, -C (O) - (C _1-8 ) alkyl-C (O) - (where any of the above alkyl, alkenyl and alkynyl linking groups is a linear carbon chain optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, -C (O) O- (C _1-8 ) alkyl, -C _1-8 alkyl-C (O) O- (C _1-8 ) alkyl, amino (substituted Deputy, not The dependence selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halo ) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl binders groups optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl (C _1-8) alkyl, aryl (C _1-8) alkyl, Goethe oaril (C _1-8) alkyl, spirocycloalkyl and spirogeterotsiklila (wherein any of the foregoing cycloalkyl, heterocyclic, aryl and heteroaryl substituents optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, , C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _{1 -8} ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where any of the above heterocyclic substituents is optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected and the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _1-8) alkyl, (halo) _1-3 (C _1-8) alkoxy, hydroxy and hydroxy (C _{1- 8} ) alkyl; and where heterocyclyl is optionally substituted with oxo), - (O- (CH ₂ ) _1-6 ) _0-5 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _{1- 6} -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _0-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -NR ₆ -, - (O- (CH ₂ ) _1-6 ) _0-5 -S-, -O- (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O -, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -S-, -NR ₆ -, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 -NR ₈ -, -NR _{6 =} C (O) -, -C (O) -NR ₆ -, -C (O) - (CH ₂ ) _0-6 --NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O ) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 --NR ₇ -, -NR ₆ -C (O) -NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - ( CH ₂ ) _1-6 -O-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -NR ₆ - (CH ₂ ) _1-6 -S- ( CH ₂ ) _1-6 --NR ₇ - and –SO ₂ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen and C _1-8 alkyl, C _1-8 alkoxy (C _{1- 8} ) alkyl, carboxyl (C _1-8 ) alkyl, amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8) alkyl, aryl (C _1-8) alkyl and heteroaryl (C _1-8) alkyl (wherein the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected and from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8) alkyl, carboxyl, carboxyl _(C1-8) alkyl, amino (substituted with a substituent independently selected from a group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _{1- 3} (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where heterocyclyl is optionally substituted with oxo)), provided that if A and E are selected from a hydrogen substituted carbon atom, then R _{2 is} selected from the group consisting of -C _2-8 alkynyl-, -O- (C _1-8 ) alkyl -O-, -O- (C _2-8 ) alkenyl-O-, -O- (C _2-8 ) alkynyl-O-, -C (O) - (C _1-8 ) alkyl-C (O) - (where any of the above alkyl, alkenyl and alkynyl linking groups are linear carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8) alkyl, carboxyl, ct oxyl (C _1-8) alkyl, -C (O) O- (C _1-8) alkyl, -C _1-8 alkyl-C (O) O- (C _1-8) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen ) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl and oxo; and where any of the above alkyl, alkenyl and alkynyl binders groups optionally substituted with one to two substituents independently selected from ppy consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl (C _1-8) alkyl, aryl (C _1-8) alkyl, heteroaryl _(C1-8) alkyl, spirocycloalkyl and spirogeterotsiklila (wherein any of the foregoing cycloalkyl, heterocyclic, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 al yl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and _C1-4alkyl), halogen, (halo) _1-3 (C _1-8) alkyl, ( halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl, and where any of the above heterocyclic substituents is optionally substituted by oxo)), cycloalkyl (where cycloalkyl is optionally substituted by one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl, amino (substituted a group independently selected from the group consisting of hydrogen and C _1-4 alkyl), amino (C _1-8 ) alkyl (where the amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl, - (O- (CH ₂ ) _1-6 ) _1-5 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _{1 -6} -O- (CH ₂ ) _1-6 -O-, - (O- (CH ₂ ) _1-6 ) _1-5 -NR ₆ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 -NR ₆ -, - (O- (CH ₂ ) _1-6 ) _{0- 5} -S-, -O- (CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 -O-, -O- (CH ₂ ) _1-6 -O- (CH ₂ ) _1-6 - S-, -NR ₆ -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ -, -NR ₆ - (CH ₂ ) _1-6 -NR ₇ - (CH ₂ ) _1-6 - NR ₈ -, -NR _{9 =} C (O) -, -C (O) -NR ₉ -, -C (O) - (CH ₂ ) _0-6 --NR ₆ - (CH ₂ ) _0-6 -C (O) -, -NR ₆ - (CH ₂ ) _0-6 -C (O) - (CH ₂ ) _1-6 -C (O) - (CH ₂ ) _0-6 --NR ₇ -, -NR ₆ -C (O ) -NR ₇ -, -NR ₆ -C (NR ₇ ) -NR ₈ -, -O- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -O-, -S- (CH ₂ ) _1-6 -NR ₆ - (CH ₂ ) _1-6 -S- and -NR ₆ - ( CH ₂ ) _1-6 -S- (CH ₂ ) _1-6 --NR ₇ - (where R ₆ , R ₇ and R _{8 are} independently selected from the group consisting of hydrogen, C _1-8 alkyl, C _{1- 8} alkoxy (C _1-8 ) alkyl, carboxyl (C _1-8 ) alkyl, amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl and heteroaryl (C _1-8 ) alkyl (where the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl, carboxyl (C _1-8 ) alkyl amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl); amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl ), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl; and where heterocyclyl is optionally substituted by oxo)); and where R _{9 is} selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl (C _1-8 ) alkyl, amino (C _1-8 ) alkyl (where amino is substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl), hydroxy (C _1-8 ) alkyl, heterocyclyl (C _1-8 ) alkyl, aryl (C _1-8 ) alkyl and heteroaryl (C _1-8 ) alkyl (where the above heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy (C _1-8 ) alkyl, carboxyl car oxyl (C _1-8) alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C _1-4 alkyl) amino (C _1-8) alkyl (wherein amino is substituted with a substituent independently selected from the group consisting from hydrogen and C _1-4 alkyl), halogen, (halogen) _1-3 (C _1-8 ) alkyl, (halogen) _1-3 (C _1-8 ) alkoxy, hydroxy and hydroxy (C _1-8 ) alkyl ; and where heterocyclyl is optionally substituted by oxo)), and

and its pharmaceutically acceptable salts.

12. The compound according to claim 1, where the compound of formula (I) is selected from the group consisting of:

Where

R ₄ and R _{5 are} independently selected from C _1-8 alkyl, C _2-8 alkenyl, and C _2-8 alkynyl, optionally substituted with oxo,

and its pharmaceutically acceptable salts.

13. The compound of formula (Ia1)

where R ₄ , R ₂ and dependently selected from:

14. The compound of formula (Ib1)

where R ₄ , R ₂ and dependently selected from:

15. The compound of formula (If1)

where R ₄ , R ₂ and R _{5 are} dependently selected from:

16. The compound of formula (Ii1)

where R ₄ , R ₂ and R _{5 are} dependently selected from:

17. The compound of formula (Ij1)

where R ₄ , R ₂ and R _{5 are} dependently selected from:

18. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition obtained by mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

20. A method of obtaining a pharmaceutical composition, comprising mixing a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. A method of treating or improving a kinase-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.

22. The method according to item 21, where the violation is mediated by selective inhibition of a kinase selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

23. The method according to item 22, where the kinase is selected from the group consisting of protein kinase Cα, protein kinase Cβ-II, protein kinase Cγ and glycogen synthase kinase-3β.

24. The method according to item 21, where the violation is mediated by double inhibition of at least two kinases selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

25. The method according to paragraph 24, where at least two kinases are selected from the group consisting of protein kinase Cα, protein kinase Cβ-II, protein kinase Cγ and glycogen synthase kinase-3β.

26. The method according to item 21, where a therapeutically effective amount of a compound according to claim 1 is from about 0.001 mg / kg / day to about 300 mg / kg / day.

27. The method of claim 21, wherein the kinase-mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-related disorders, inflammatory diseases, immunological disorders, dermatological disorders, cancer and CNS disorders.

28. The method according to item 27, where the cardiovascular disease is selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy in premature birth and age-related macular degeneration.

29. The method according to item 27, where the diabetes is selected from the group consisting of insulin-dependent diabetes and non-insulin-dependent diabetes mellitus type II.

30. The method of claim 27, wherein the diabetes-related disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy, and neuropathy.

31. The method according to item 27, where the inflammatory disease is selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis and osteoarthritis.

32. The method according to item 27, where immunological disorders are selected from the group consisting of tissue transplant rejection, HIV-1 and PKC modulated immunological disorders.

33. The method according to item 27, where the dermatological disorders are selected from the group consisting of psoriasis, baldness and baldness.

34. The method according to item 27, where the cancer is selected from the group consisting of cancer, tumor growth, uncontrolled cell proliferation, proliferative angiopathy and angiogenesis.

35. The method of claim 27, wherein the central nervous system disorder is selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative condition, dementia, Alzheimer's disease, mood disorders, schizophrenia, manic depression and neurotraumatic injury, cognitive decline and ischemia-related diseases.

36. The method according to item 21, further comprising a method of using the compound according to claim 1 as an auxiliary agent in chemotherapy and radiation therapy.

37. The method of claim 21, further comprising administering to a subject in need of a therapeutically effective amount of the pharmaceutical composition of claim 18.

38. The method according to clause 37, where the therapeutically effective amount of the pharmaceutical composition according p, is from about 0.001 mg / kg / day to about 300 mg / kg / day.

39. The method according to clause 35, where the diseases associated with ischemia are diseases resulting from a head injury or transient ischemic stroke.

40. The use of compounds according to claims 1-17 in the treatment of kinase-mediated disorders.

41. The use of claim 40, wherein the kinase-mediated disorder is associated with the activity of protein kinase C and glycogen synthase kinase-3.

42. The application of paragraph 41, where the kinase is selected from the group consisting of protein kinase Cα, protein kinase C-II, protein kinase Cγ and glycogen synthase kinase-3β.

43. The application of claim 40, wherein the kinase-mediated disorder is a dual kinase-mediated disorder, and where at least one of the kinases is selected from the group consisting of protein kinase C and glycogen synthase kinase-3.

44. The use of claim 42, wherein at least one kinase is selected from the group consisting of protein kinase Cα, protein kinase Cβ-II, protein kinase Cγ and glycogen synthase kinase-3β.

45. The application of claim 40, wherein the kinase-mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-related disorders, inflammatory diseases, immunological disorders, dermatological disorders, cancer and CNS disorders.

46. The application of claim 45, wherein the cardiovascular disease is selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy in premature birth and age-related macular degeneration.

47. The application of claim 45, wherein the diabetes is selected from the group consisting of insulin-dependent diabetes and non-insulin-dependent diabetes mellitus type II.

48. The application of claim 45, wherein the diabetes-related disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.

49. The application of claim 45, wherein the inflammatory disease is selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis, and osteoarthritis.

50. The application of claim 45, wherein the immunological disorders are selected from the group consisting of tissue transplant rejection, HIV-1, and PKC modulated immunological disorders.

51. The application of claim 45, wherein the dermatological disorder is selected from the group consisting of psoriasis, baldness, and baldness.

52. The application of claim 45, wherein the oncological diseases are selected from the group consisting of cancer, tumor growth, uncontrolled cell proliferation, proliferative angiopathy, and angiogenesis.

53. The application of claim 45, wherein the central nervous system disorder is selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative condition, dementia, Alzheimer's disease, mood disorders, schizophrenia, manic depression and neurotraumatic injury, cognitive decline and ischemia-related diseases.

54. The use of the compounds according to claim 1-17 as an auxiliary agent in chemotherapy and radiation therapy.

55. The application of claim 40, wherein the subject in need thereof receives a therapeutically effective amount of a pharmaceutical composition containing said compound.

56. The use of claim 55, wherein the therapeutically effective amount of the pharmaceutical composition is from about 0.001 mg / kg / day to about 300 mg / kg / day.