RU2000110738A

RU2000110738A - BICYCLIC KINASE INHIBITORS

Info

Publication number: RU2000110738A
Application number: RU2000110738/04A
Authority: RU
Inventors: Суань ЧЭН; Дейвид Майкл ГОЛДСТЕЙН; Тереза Александро Трехо МАРТИН; Эрик Брайан ШУГРЕН
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1997-10-20
Filing date: 1998-10-13
Publication date: 2002-05-27

Claims

1. A compound selected from the group of compounds of formula (I)

in which R ¹ denotes heteroaryl;
--- denotes a bond between either B and CR ¹ , or Q and CR ¹ , as a result of which (I) when --- denotes a bond between Q and CR ¹ , then: B denotes nitrogen, R ² denotes aryl, and Q denotes - CR-, where R denotes hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano-, amino-, monosubstituted amino, disubstituted, acylamino, nitro, cyano-, amino-, monosubstituted amino, disubstituted amino-, acylamino, nitro, cyano-, amino, monosubstituted amino, disubstituted amino-, acylamino, nitro, cyano, amino, monosubstituted -OR ⁵ (wherein R ⁵ is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), -COOR ⁷ (wherein R ⁷ is hydrogen or alkyl) or -CONR'R "(where k each trunk R 'and R "are independently from each other hydrogen, alkyl or heteroalkyl), and
(Ii) when --- means a bond between B and CR ¹ , then: B is carbon, R ² is aryl or heteroaryl, and Q is -NR ⁴ -, -O- or -S-, where R ⁴ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, -OR ⁵ (wherein R ⁵ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -SO ₂ R "(wherein R "refers to alkyl, amino, monosubstituted amino or disubstituted amino group), -CONR'R" (where R 'and R "independently of one another denotes hydrogen , alkyl or heteroalkyl), - (alkylene) -Z or - (alkylene) -CO- (alkylene) -Z, where Z denotes cyano, -COOR ⁷ , where R ⁷ denotes hydrogen or alkyl, -CONR ⁸ R ⁹ , where R ⁸ is hydrogen or alkyl, R ⁹ is alkoxy or - (alkylene) -COOR ⁷ or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a heterocycle, -C (= NR ¹⁰ ) (NR ¹¹ R ¹² ), where R ¹⁰ , R ¹¹ and R ¹² independently of one another denote hydrogen or alkyl or R ¹⁰ and R ¹¹ together denote the group - (CH ₂ ) _n -, where n denotes 2 or 3, and R ¹² denotes hydrogen or alkyl, or -COR ¹³ , where R ¹³ denotes alkyl, heteroalkyl, heterocycle ilalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl,

denotes a group of formula (S), (T), (U), (V) or (W),

where R ⁶ denotes hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino group, -COOR ¹⁴ , - (alkylene) -COOR ¹⁴ (where R ¹⁴ denotes hydrogen or alkyl) , -CONR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ independently denote each other hydrogen or alkyl or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a heterocycle), -S (O) _n R ¹⁷ (where n represents an integer of 0-2, R ¹⁷ is a alkyl, amino, monosubstituted amino or disubstituted amino), -OR ¹⁸ (wherein R ¹⁸ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl l), -NRC (O) R "[where R denotes hydrogen, alkyl or hydroxyalkyl, and R" denotes hydrogen, alkyl, cycloalkyl or - (alkylene) -X, where X denotes hydroxyl, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or -S (O) _n R '(where n is 0-2, and R' denotes alkyl)], -NRSO ₂ R "[where R denotes hydrogen or alkyl, and R" denotes alkyl or - (alkylene ) -X, where X denotes hydroxyl, alkoxy, amino, alkylamino, dialkylamino or -S (O) _n R '(where n is 0-2, and R' denotes alkyl)], and
R ³ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino , sulfonylamino, -OR ¹⁹ (where R ¹⁹ denotes hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -COOR ²⁰ (where R ²⁰ denotes hydrogen or alkyl), -CONR ²¹ R ²² (where R ²¹ and R ²² independently of one another hydrogen, alkyl or heteroalkyl or R ²¹ and R ²² together with the nitrogen atom to which they are bonded heterocycle), -S (O) _n R ²³ (where n denotes an integer of 0-2, and R ²³ denotes alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino group), - (alkylene) -Z "or - (alkylene) -CO- (alkylene) -Z ", where
Z "represents cyano, -COOR ²⁴ , where R ²⁴ denotes hydrogen or alkyl, -CONR ²⁵ R ²⁶ , where R ²⁵ and R ²⁶ independently of one another denote hydrogen or alkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom, with to which they are linked, form a heterocycle, —C (= NR ²⁷ ) (NR ²⁸ R ²⁹ ), where each of R ²⁷ , R ²⁸ and R ²⁹ independently represents hydrogen or alkyl, or R ²⁷ and R ²⁸ together represent a group - (CH ₂ ) _n -, where n denotes 2 or 3, and R ²⁹ denotes hydrogen or alkyl, or -COR ³⁰ , where R ³⁰ denotes alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, and
its pharmaceutically acceptable salts, prodrugs, individual isomers and mixtures of isomers, provided that both R ³ and R ⁶ do not denote amino, monosubstituted amino or disubstituted amino groups.

2. Compounds according to claim 1, in which R ⁶ is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino group, -COOR ¹⁴ , - (alkylene) -COOR ¹⁴ (where R ¹⁴ is hydrogen or alkyl), —CONR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ independently of one another denote hydrogen or alkyl, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are bound form a heterocycle), -S (O) _n R ¹⁷ (where n denotes an integer of 0-2, and R ¹⁷ denotes alkyl, amino, monosubstituted amino or disubstituted amino group), -OR ¹⁸ (where R ¹⁸ denotes hydrogen, alkyl, hetero roalkyl or heterocyclylalkyl).

3. Compounds according to claim 1 or 2, selected from compounds of formula (Ia)

wherein Q represents -NR ⁴ -, -O- or -S-, where R ⁴ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl - OR ⁵ (where R ⁵ denotes hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), - (alkylene) -Z or - (alkylene) -CO- (alkylene) -Z, where
Z denotes cyano, -COOR ⁷ , where R ⁷ denotes hydrogen or alkyl, -CONR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another denote hydrogen, alkyl or alkoxy, or R ⁸ and R ⁹ together with the nitrogen atom, with to which they are linked, form a heterocycle, —C (= NR ¹⁰ ) (NR ¹¹ R ¹² ), where R ¹⁰ , R ¹¹ and R ¹² independently of one another denote hydrogen or alkyl or R ¹⁰ and R ¹¹ together denote the group - (CH ₂₎ _n -, wherein n is 2 or 3 and R ¹² is hydrogen or alkyl, or -COR ¹³ where R ¹³ is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, one of a and B convoy achaet nitrogen atom and the other represents -CR ⁶ -, where
R ⁶ is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halogen, cyano, nitro, amino, monosubstituted amino, disubstituted amino group, —COOR ¹⁴ , - (alkylene) -COOR ¹⁴ (where R ¹⁴ is hydrogen or alkyl), -CONR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ independently of one another denote hydrogen or alkyl or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a heterocycle), -S (O) _n R ¹⁷ (where n represents an integer of 0-2, and R ¹⁷ is alkyl, amino, monosubstituted amino or disubstituted amino), -OR ¹⁸ (wherein R ¹⁸ is hydrogen, alkyl, heteroalkyl or geterotsiklilal yl)
R ¹ denotes heteroaryl,
R ² denotes aryl or heteroaryl, and
R ³ denotes hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkyl-ethylacrylalkyl, cycloalkylthio, aralkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, cyano, nitro, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, cyano, nitro, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, mono-substituted, cyano, nitro, mono-substituted, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted , sulfonylamino, -OR ¹⁹ (where R ¹⁹ denotes hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -COOR ²⁰ (where R ²⁰ denotes hydrogen or alkyl), -CONR ²¹ R ²² (where R ²¹ and R ²² independently of one another hydrogen or alkyl or R ²¹ and R ²² together with the nitrogen atom to which they are attached form geterots Cl), -S (O) _n R ²³ (wherein n represents an integer of 0-2, and R ²³ is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), - (alkylene) -Z "or - ( alkylene) -CO- (alkylene) -Z ", where Z" denotes cyano, -COOR ²⁴ , where R ²⁴ denotes hydrogen or alkyl, -CONR ²⁵ R ²⁶ , where R ²⁵ and R ²⁶ independently of one another denote hydrogen or alkyl or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form a heterocycle, —C (= NR ²⁷ ) (NR ²⁸ R ²⁹ ), where R ²⁷ , R ²⁸ and R ²⁹ independently of one another denote hydrogen or alkyl or R ²⁷ and R ²⁸ together represent a group - (CH ₂ ) _n -, where n is 2 or 3, and R ²⁹ is hydrogen or alkyl, or -COR ³⁰ , where R ³⁰ is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl,
as well as their pharmaceutically acceptable salts, prodrugs, individual isomers and mixtures of isomers.

4. The compound according to claim 1 or 2, in which --- denotes a bond between B and -CR ¹ -,

is a group of formula (S), (V) or (W), and Q is -NR ⁴ -.

5. The compound according to claim 1, 2 or 4, in which R ¹ denotes a 4-pyridyl or 4-pyrimidinyl ring, optionally substituted by a substituent selected from heteroalkyls, —NRR ′ (where each of R and R ′ independently of each other denotes hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —NR ^a C (O) R ^b [where R ^a denotes hydrogen or alkyl, and R ^b denotes hydrogen, alkyl or - (alkylene) -X, where X denotes hydroxyl, alkoxy, amino -, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —S (O) _n R ′ (where n is 0-2, and R ′ is designated is alkyl)], -NRSO ₂ R "[where R denotes hydrogen or alkyl, and R" denotes alkyl or - (alkylene) -X, where X denotes hydroxyl, alkoxy, amino, alkylamino, dialkylamino or -S (O ) _n R '(where n represents 0-2, and R' denotes alkyl)], and -OR (where R denotes alkyl or heteroalkyl).

6. The compound according to claim 1, 2, 4 or 5, in which R ² denotes a phenyl ring, optionally substituted with one or two substituents selected from alkyl, halides and -OR, where R denotes alkyl.

7. The compound according to any one of paragraphs. 1, 2 and 4-6, in which R ⁶ denotes hydrogen, methyl, methoxy, fluorine or chlorine, and R ¹ denotes a 4-pyridyl ring, optionally substituted in the 2nd position by a substituent selected from amino, methylamino, dimethylamino -, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy and 2-dimethylaminoethoxy.

8. The compound according to any one of paragraphs. 1, 2 and 4-7, in which R ⁶ denotes hydrogen, R ² denotes a phenyl ring substituted by one or two substituents selected from methyl, fluorine, chlorine and methoxy, and R ³ denotes hydrogen, methyl, chlorine, fluorine, 2 -hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl.

9. The compound according to any one of paragraphs. 1, 2 and 4-8, in which R ⁴ denotes hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl , 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazine- 1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxyl, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2- (morpholine- 4-yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidi n-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1-yl) propoxy.

10. Compounds according to any one of paragraphs. 1 and 4-9 selected 3- (4-fluorophenyl) -2- [2- (2-hydroxyethylamino) pyridin-4-yl] -1H-pyrrolo [3,2-b] pyridine and 6- (2-acetylaminopyridine -4-yl) -7- (4-fluorophenyl) -5H-pyrrolo [2,3-b] pyrazine.

11. Compounds according to any one of paragraphs. 2 and 4-9 selected from 3- (4-fluorophenyl) -1-methyl-2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine and 7- (4-fluorophenyl) - 6- (pyridin-4-yl) -5H-pyrrolo [2,3-b] pyrazine.

12. Compounds according to any one of paragraphs. 3-9 selected from 3- (4-fluorophenyl) -2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine, 3- (4-fluorophenyl) -1-methoxy-2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine, 3- (4-fluorophenyl) -1- [2- (morpholin-4-yl) ethoxy] -2- (pyridin-4- yl) -1H-pyrrolo [3,2-b] pyridine, 3- (4-fluorophenyl) -1-hydroxy-2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine, 3 - (4-fluorophenyl) -1- [2- (piperidin-1-yl) ethoxy] -2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine, 3- (4-fluorophenyl ) -1- [2- (piperidin-1-yl) ethyl] -2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine and 3- (4-fluorophenyl) -1- [[ 2- (morpholin-4-yl) ethyl] -2- (pyridin-4-yl) -1H-pyrrolo [3,2-b] pyridine.

13. Compounds according to any one of p. 1-12, intended for use as pharmaceutically active substances, in particular for the treatment of inflammatory diseases.

14. Compounds of formulas

in which Y and Z denote groups that can be turned into a group

but

R ¹ , R ² , ---, B and Q have the meanings indicated in paragraph 1.

15. The method of producing compounds according to any one of paragraphs. 1-12, which includes
a) cyclization of a compound of the general formula

wherein

is a group indicated in paragraph 1, Y and Z denote groups that can be turned into a group

and R ¹ , R ² , ---, B and Q have the meanings indicated in paragraph 1, or
b) the introduction of the substituent R and / or R ⁴ in the compound of the formula

wherein

---, R ¹ , R ² and B have the meanings indicated in paragraph 1, a Q ¹ denotes -CH- or -NH-, or
C) the introduction of the substituent R ¹ in the compound of the formula

wherein

and R ² are as defined in paragraph 1, or
g) the conversion of compounds of formula

in which P ⁰ denotes a group of formula (S ⁰ ), (T ⁰ ), (V ⁰ ) or (W ⁰ ),

in which R ⁶⁰ is chlorine or bromine, and R ³ is as defined in claim 1, to a compound of formula (I) in which R ⁶ is alkoxy, monosubstituted or disubstituted amino, cyano or alkyl, or
d) upon receipt of a pharmaceutically acceptable salt of a compound of formula I bearing an acidic and / or basic substituent, the conversion of such a compound of formula I into such a salt.

16. Pharmaceutical composition comprising the compound obtained according to any one of paragraphs. 1-12, and a therapeutically inert carrier and intended primarily for the treatment and prevention of inflammatory diseases.

17. Compounds according to any one of paragraphs. 1-12, obtained in all cases by the method according to claim 15 or by the chemical equivalent apparent to it.

18. The use of compounds obtained according to any one of paragraphs. 1-12, in the treatment and prevention of inflammatory diseases or in the preparation of medicines for the treatment and prevention of inflammatory diseases.

19. New compounds, compositions, methods and their variants essentially as described in the present description.