6-(4-hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

1. A compound of formula I

wherein

R 1 is a) a residue of formula Ia

wherein

R 6 is H, F, Cl, (C 1 -C 3 )-alkyl or O—(C 1 -C 3 )-alkyl, wherein (C 1 -C 3 )-alkyl is unsubstituted or substituted by one to five F;

R 7 is H, F, Cl, (C 1 -C 3 )-alkyl or O—(C 1 -C 3 )-alkyl, wherein (C 1 -C 3 )-alkyl is unsubstituted or substituted by one to five F, or is CN, SO 2 (C 1 -C 3 )-alkyl, N((C 1 -C 4 )-alkyl) 2 1-piperidinyl, or 4-morpholinyl;

R 8 is H, F, Cl, (C 1 -C 5 )-alkyl or O—(C 1 -C 5 )-alkyl, wherein (C 1 -C 3 )-alkyl is unsubstituted or substituted by one to five F, or is OH, O-phenyl, SO 2 (C 1 -C 3 )-alkyl, CO—(C 1 -C 4 )-alkyl, or CO—N((C 1 -C 4 )-alkyl) 2 ; or

R 7 and R 8 form, together are

R 9 is H, F, CH 3 , or O—CH 3 ;and

R 10 is H; or

b) ethylene-phenyl, wherein phenyl is unsubstituted or substituted by one or two identical or different substituents selected from F, Cl, CH 3 , O—CH 3 , CF 3 , O—CF 3 , CN, SO 2 CH 3 , CO—CH 3 , and CO—N((CH 3 ) 2 ; and

R 2 is H, or CH 3 ;

R 3 is H, or O—CH 3 ; and

R 4 is piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl, which are unsubstituted or monosubstituted by (C 1 -C 3 )-alkyl, which is unsubstituted or substituted by one to five F, and

R 5 is H, or

R 4 and R 5 together with the nitrogen carrying them form

a) a residue of formula Ib

wherein

R 11 is H, CH 3 ,(C 3 -C 5 )-cycloalkyl, or (C 3 -C 4 )-alkyl, and

R 12 is H, or

R 11 and R 12 together with the C-atoms form 1′-spiro-cyclopentyl;

R 13 is H, (C 1 -C 4 )-alkyl, or (C 3 -C 5 )-cycloalkyl, and

R 14 is H, or CH 3 or

R 13 and R 14 together with the C-atom carrying them is 1′-spiro-cyclo-(C 3 -C 6 )-alkyl;

R 15 is H, CH 2 —CO—N((C 1 -C 4 )-alkyl) 2 , CO—(C 1 -C 6 )-alkyl, CO—(C 1 -C 4 )-alkylene-OH, CO—(C 1 -C 4 )-alkylene-O—CH 3 , CO—CH 2 -4-morpholinyl, CO—O—(C 1 -C 4 )-alkyl, CO—N((C 1 -C 4 )-alkyl) 2 , (C 3 -C 6 )-cycloalkyl, or pyridyl;

R 16 is H, or (C 1 -C 4 )-alkyl;

R 17 is H;

R 18 is H; and

R 19 is H; or

b) a 9 to 11 membered spiro-heterocycloalkyl containing 2 nitrogen atoms, which is attached via a nitrogen atom; or a pharmaceutically acceptable salt thereof.

2. A compound of formula I as claimed in claim 1 , wherein

R 1 is a) a residue of formula Ia

wherein

R 4 is 4 methyl-piperidin-4-yl and

R 5 is H, or

R 4 and R 5 together with the nitrogen carrying them form

a) a residue of formula Ib

wherein

R 11 is H, CH 3 ,(C 3 -C 4 )-alkyl, or (C 3 -C 4 )-cycloalkyl; and

R 12 is H;

or a pharmaceutically acceptable salt thereof.

3. A compound of formula I as claimed in claim 1 , wherein

R 1 is a) a residue of formula Ia

wherein

R 6 is H, F, Cl, CH 3 , CF 3 , or O—CH 3 ; and

R 7 is H, F, Cl, CH 3 , CF 3 , CN, O—CH 3 , SO 2 CH 3 , N(CH 3 ) 2 , 1-piperidinyl, or 4-morpholinyl;

R 8 is H, F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OH, O—CH 3 , O—C 2 H 5 , O—CHF 2 , O—CF 3 , O-phenyl, SO 2 CH 3 , CO—CH 3 , or CO—N(CH 3 ) 2 ; or

R 7 and R 8 together are

b) phenethyl; and

R 4 is 4-methyl-piperidin-4-yl, and

R 5 is H, or

R 4 and R 5 together with the nitrogen carrying them form

a) a residue of formula Ib

wherein

R 11 is H, CH 3 , or (CH 2 ) 3 —CH 3 , and

R 12 is H, or

R 11 and R 12 together with the C-atoms form 1′-spiro-cyclopentyl;

R 13 is H, CH 3 , or CH 2 —CH(CH 3 ) 2 , and

R 14 is H, or CH 3 , or

R 13 and R 14 together with the C-atom carrying them is 1′-spiro-cyclopentyl; and

R 15 is H, CH 2 —CO—N(CH 3 ) 2 , CO—CH(C 2 H 5 ) 2 , CO—C(CH 3 ) 2 —OH, CO—C(CH 3 ) 2 —CH 2 —OH, CO—(CH 2 ) 2 —O—CH 3 , CO—CH 2 —4-morpholinyl, CO—OCH 3 , CO—N(CH 3 ) 2 , cyclopropyl, or 3-pyridyl; and

R 16 is H, or CH 3 ; or

b) (2,7-Diaza-spiro[4.4]non-2-yl),

or a pharmaceutically acceptable salt thereof.

4. A compound of formula I as claimed in claim 1 , wherein

R 1 is a residue of formula Ia

wherein

R 6 is H, F, Cl, CH 3 , CF 3 , or O—CH 3 ;

R 7 is H, F, Cl, CH 3 , CF 3 , CN, O—CH 3 , SO 2 CH 3 , N(CH 3 ) 2 , 1-piperidinyl, or 4-morpholinyl;

R 8 is H, F, Cl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OH, O—CH 3 , O—C 2 H 5 , O—CHF 2 , O—CF 3 , O-phenyl, SO 2 CH 3 , CO—CH 3 , or CO—N(CH 3 ) 2 ; and

R 2 is H;

R 3 is H; and

R 4 and R 5 together with the nitrogen carrying them form a residue of formula Ib

wherein

R 11 is H, CH 3 , or (CH 2 ) 3 —CH 3 , and

R 12 is H, or

R 11 and R 12 together with the C-atoms carrying them are 1′-spiro-cyclopentyl;

R 13 is H, CH 3 , or CH 2 —CH(CH 3 ) 2 , and

R 14 is H, or CH 3 ,or

R 13 and R 14 together with the C-atom carrying them is 1′-spiro-cyclopentyl; and

R 15 is H; and

R 16 is H, or CH 3 ;

or a pharmaceutically acceptable salt thereof.

5. A compound selected from

[3-[(E)-2-(4-Chloro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

(3,3-Dimethyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-(S)-3-isobutyl-piperazin-1-yl)-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-((S)-2-methyl-piperazin-1-yl)-methanone,

[6-(4-Hydroxy-2-methyl-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

[6-(4-Hydroxy-3-methoxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[6-(4-Hydroxy-phenyl)-3-phenethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-2-p-tolyl-vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3-methanesulfonyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(3-Dimethylamino-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

3-{(E)-2-[6-(4-Hydroxy-phenyl)-4-(piperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-vinyl}-benzonitrile,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3-piperidin-1-yl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3-morpholin-4-yl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(4-Fluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-2-m-tolyl-vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(2,4-Dichloro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(3,5-Dimethyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(4-Difluoromethoxy-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(2,4-Dimethoxy-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-phenoxy-phenyl)vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(3,4-Dichloro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3-trifluoromethyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}piperazin-1-yl-methanone,

[3-[(E)-2-(4-Hydroxy-3-methyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(3-Chloro-phenyl)vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(2,4-Dimethyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(2,5-Dimethyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-isopropyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(2-Chloro-4-fluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(4-Ethyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone

[3-[(E)-2-(4-tert-Butyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(3-Fluoro-4-methyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3-methoxy-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

1-(4-{(E)-2-[6-(4-Hydroxy-phenyl)-4-(piperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]vinyl}-phenyl)-ethanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(3,4-Difluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(2-methoxy-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(4-Fluoro-2-methyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(3,4,5-trimethoxy-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[3-[(E)-2-(2-Fluoro-4-methyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(2,3-Dihydro-benzofuran-5-yl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-((E)-2-Benzo[1,3]dioxol-5-yl-vinyl)-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

4-{(E)-2[6-(4-Hydroxy-phenyl)-4-(piperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-vinyl}-N,N-dimethyl-benzamide,

[3-[(E)-2-(4-Ethoxy-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(2-trifluoromethyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

[6-(4-Hydroxy-phenyl)-3-((E)-2-o-tolyl-vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(3-Fluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

[3-[(E)-2-(2-Fluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone,

{6-(4-Hydroxy-phenyl)-3-[(E)-2-(4-methoxy-3-methyl-phenyl)-vinyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-piperazin-1-yl-methanone,

4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid dimethylamide,

6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-methyl-piperidin-4-yl)-amide,

((S)-2-Butyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

((R)-2-Butyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

(2,7-Diaza-spiro[4.4]non-2-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

(6,9-Diaza-spiro[4.5]dec-9-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

2-Ethyl-1-{4[-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazin-1-yl}-butan-1-one,

1-{4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazin-1-yl}-2-morpholin-4-yl-ethanone,

4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid methyl ester,

[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-[4-(pyridine-3-carbonyl)-piperazin-1-yl]-methanone,

2-{4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide,

(4-Cyclopropyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone,

2-Hydroxy-1-{4-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one,

3-Hydroxy-1-{4-[6-(4-hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]piperazin-1-yl}-2,2-dimethyl-propan-1-one, or

1-{4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazin-1-yl}-3-methoxy-propan-1-one,

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising at least one compound of formula I as claimed in claim 1 , or as claimed in claim 5 ; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The compound of formula I as claimed in claim 2 , wherein R 13 and R 14 together with the C-atom carrying them is 1′-spiro-cyclopentyl.