Fused pyrimidine piperidine cyclic derivative, preparation process and use thereof

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

X is CR 6 or N;

Y is CR 6 R 7 or C(═O);

Z is CR 6 or N;

R 1 is selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkylthio, —C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, —(CH 2 ) n —NR 6 R 7 and C 3 -C 6 cycloalkyl or 4-7 membered heterocycloalkyl, which can be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkylthio, and —NH 2 ;

R 2 is selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy or —C 3 -C 6 cycloalkyl;

R 3 , R 4 and R 5 are each independently selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C 1 -C 6 alkylthio, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, —C(═O)—NR 6 R 7 , —NR 6 R 7 , —OC(═O)R 6 , —COOR 6 , —NR 6 C(═O)R 7 , —NR 6 COOR 7 and —OSO 2 R 6 ;

R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 3 -C 6 cycloalkyl or —C 1 -C 6 alkylthio;

n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is a compound represented by formula (II), a compound represented by formula (III), a compound represented by formula (IV) or a compound represented by formula (V), wherein each of substituent variables has the same meaning as those in claim 1 ,

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein for the compound represented by formula (II) and the compound represented by formula (IV), the substituent R 6 of the benzene ring is selected from the group consisting of H, —C 1 -C 6 alkyl or —C 1 -C 6 alkoxy.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of H or —C 1 -C 6 alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkylthio, —C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, and —(CH 2 ) n —NR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl or —C 1 -C 6 alkoxy, n is 0, 1, 2 or 3.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, —(CH 2 ) n —NR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl or —C 1 -C 6 alkoxy, n is 0, 1 or 2.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —C 3 -C 6 cycloalkyl, haloC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, —(CH 2 ) n —NR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 4 alkyl or —C 1 -C 4 alkoxy, n is 0, 1 or 2.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, halogen, hydroxy or —C 1 -C 4 alkyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are each independently selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C 1 -C 6 alkylthio, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, and —C(═O)—NR 6 R 7 , and R 3 , R 4 and R 5 are not H at the same time, wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl or —C 1 -C 6 alkoxy.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are each independently selected from the group consisting of H, halogen, hydroxy, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C(═O)—NR 6 R 7 , and R 3 , R 4 and R 5 are not H at the same time, wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl or —C 1 -C 6 alkoxy.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are each independently selected from the group consisting of H, halogen, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, and —C(═O)—NR 6 R 7 , and R 3 , R 4 and R 5 are not H at the same time, wherein R 6 and R 7 are each independently selected from the group consisting of H, —C 1 -C 4 alkyl or —C 1 -C 4 alkoxy.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

2-(4-(4-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanol;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

1-(4-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl-4-ethylpiperazin-2-one;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(4-(4-ethylpiperazin-1-yl)-3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;

4-chloro-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)-7,8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methoxy-N-methylbenzamide;

4-chloro-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)-7,8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,5-dimethoxybenzamide;

4-chloro-3-(2-(4-(4-(dimethylamino)piperazin-1-yl)phenylamino)-7,8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methoxy-N-methylbenzamide;

2-(4-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)pyridin-2-yl)piperazin-1-yl)ethanol;

6-(2-fluoro-6-chloro-3,5-dimethoxyphenyl)-N-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine.

13. A process for preparing the compound represented by formula (I) according to claim 1 , which comprises the steps of:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z are defined as those in claim 1 ;

Compound Ia is used as starting material and reacted by diazotization to produce Compound Ib; Compound Ib and starting material A are reacted by coupling in a basic condition to produce Compound Ic; Compound Ic is hydrolyzed to produce Compound Id; Compound Id and DMF.DMA are reacted by formylation to produce Compound Ie;

starting materials B and C are reacted by substitution in a basic condition to produce Compound If; Compound If is catalytically hydrogenated to produce Compound Ig; Compound Ig and cyanoamine are reacted by nucleophilic addition to produce Compound Ih; Compound Ih and Compound Ie are finally reacted by ring closing in a basic condition to produce the compound represented by formula (I).

14. A process for preparing the compound represented by formula (I) according to claim 1 , which comprises the steps of:

wherein R 1 , R 2 , R 3 , Ra, R 5 , X, Y and Z are defined as those in claim 1 ;

Starting compound D and DMF.DMA are reacted by formylation to produce Compound Ij; Compound Ij and Compound Ih are reacted by ring closing in a basic condition to produce Compound Ik; Compound Ik is deprotected in an acidic condition to form a salt and produce Compound Im; Compound Im and Compound Ib are finally reacted by coupling in a basic condition to produce the compound represented by formula (I).

15. A pharmaceutical composition, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. A method of treating FGFR kinase mediated bladder cancer comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. A method of treating bladder cancer comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof.