Substituted indolizine 1,2,3,6,7,8 derivatives, FGFs inhibitors, a method for the preparation thereof and pharmaceutical compositions containing said derivatives

1. A compound of formula I:

wherein:

R at 6-, 7- or 8-position of the indolizine ring is hydrogen, halogen, methyl, hydroxy, (C 1 -C 5 )-alkoxy, carboxy, (C 2 -C 6 )-alkoxycarbonyl, —NR 5 R 6 , —NH—SO 2 -Alk, —NH—CO-Alk, —NH—CO 2 -Alk, —O-Alk-COOR 7 , —O-Alk-NR 5 R 6 , —O—(CH 2 ) n —Ph, or —CO—NR 5 R 6 ;

R 1 is (C 1 -C 5 )-alkoxy, carboxy, (C 2 -C 6 )-alkoxycarbonyl, or Ph;

R 2 is (C 1 -C 5 )-alkyl, (C 3 -C 6 )-cycloalkyl, or phenyl, wherein the phenyl is optionally substituted with one or more halogen, or (C 1 -C 5 )-alkoxy;

R 3 and R 4 independently are hydroxy, (C 1 -C 5 )-alkoxy, amino, carboxy, (C 2 -C 6 )-alkoxycarbonyl, nitro, —NR 5 R 6 , —NH—CO-Alk, —NH—CO—CF 3 , —CO—NR 5 R 6 , or —CO—NHOH;

Alk is (C 1 -C 5 )-alkyl or (C 1 -C 5 )-alkylene;

n is an integer from 0 to 5;

R 5 and R 6 independently are hydrogen, (C 1 -C 5 )-alkyl, or benzyl;

R 7 is hydrogen or (C 1 -C 5 )-alkyl; and

Ph is phenyl optionally substituted with one or more halogen, (C 1 -C 5 )-alkoxy, carboxy, or (C 2 -C 6 )-alkoxycarbonyl;

provided that when R is hydrogen, and R 3 and R 4 independently are not —CO—NR 5 R 6 or —CO—NHOH, then R 1 is not (C 1 -C 5 )-alkoxy, carboxy, or (C 2 -C 6 )-alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein:

R at 6-, 7- or 8-position of the indolizine ring is hydrogen, halogen, hydroxy, (C 1 -C 5 )-alkoxy, carboxy, (C 2 -C 6 )-alkoxycarbonyl, —NR 5 R 6 , —NH—SO 2 -Alk, —NH—CO-Alk, —NH—CO 2 -Alk, —O-Alk-COOR 7 , —O-Alk-NR 5 R 6 , or —CO—NR 5 R 6 ;

R 1 is (C 1 -C 5 )-alkoxy, carboxy, (C 2 -C 6 )-alkoxycarbonyl, or Ph; and

R 3 and R 4 independently are hydroxy, (C 1 -C 5 )-alkoxy, amino, carboxy,

(C 2 -C 6 )-alkoxycarbonyl, nitro, —NR 5 R 6 , —NH—CO-Alk, —CO—NR 5 R 6 , or —CO—NHOH;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein:

R at 6-, 7- or 8-position of the indolizine ring is hydrogen, halogen, hydroxy, (C 1 -C 5 )-alkoxy, (C 2 -C 6 )-alkoxycarbonyl, —NR 5 R 6 , or —CO—NR 5 R 6 ;

R 1 is (C 1 -C 5 )-alkoxy, carboxy or Ph;

R 2 is (C 1 -C 5 )-alkyl; and

R 3 and R 4 independently are hydroxy, (C 1 -C 5 )-alkoxy, amino, carboxy, or —NR 5 R 6 ;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , which is [3-(4-amino-3-methoxybenzoyl)-6-methoxy-2-methylindolizin-1-yl]carboxylic acid, (4-amino-3-methoxyphenyl) [1-(4-methoxyphenyl)-2-methylindolizin-3-yl]methanone, 3-(4-amino-3-methoxybenzoyl)-(1-methoxy-N,2-dimethylindolizin-6-yl)carboxamide, [3-(4-amino-3-methoxybenzoyl)-2-methyl-7-(methylamino)indolizin-1-yl]carboxylic acid, [3-(4-amino-3-methoxybenzoyl)-7-(dimethylamino)-2-methylindolizin-1-yl]carboxylic acid, 2-amino-5-({1-methoxy-2-methyl-6-[(methylamino)carbonyl]indolizin-3-yl}-carbonyl)benzoic acid, 2-amino-5-[(1,6-dimethoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid, 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzamide, or [3-(4-amino-3-methoxybenzoyl)-1-(4-methoxyphenyl)-2-methylindolizin-6-yl]carboxamide,

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and an inert excipient.

6. A pharmaceutical composition comprising the compound according to claim 2 or a pharmaceutically acceptable salt thereof and an inert excipient.

7. A pharmaceutical composition comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof and an inert excipient.

8. A pharmaceutical composition comprising the compound according to claim 4 or a pharmaceutically acceptable salt thereof and an inert excipient.

9. A method for treating carcinoma having a high degree of vascularisation, in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the carcinoma having a high degree of vascularisation is carcinoma of lung, breast, prostate or oesophagus.

10. A method for treating cancer that induces metastasis, in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein the cancer that induces metastasis is colon cancer, stomach cancer, melanoma, glioma, lymphoma or leukaemia.