Anthranilamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
View Patent ↗The invention relates to novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for preventing or treating diseases that are triggered by persistent angiogenesis.
1. A compound of formula (I)
wherein:
X is CH;
W is hydrogen or fluorine;
A, E and Q, are CH;
R 1 is 2-methyl-2H-indazol-6-yl;
R 2 and R 3 , independently of one another, are C 1 -C 12 alkyl optionally substituted with —OR 5 ; and
R 5 is hydrogen, C 1 -C 12 -alkyl, C 3 -C 8 -cycloalkyl or halo -C 1 -C 6 -alkyl;
or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof.
2. A compound as claimed in claim 1 , wherein W is fluorine.
3. A compound as claimed in claim 1 , wherein W is hydrogen.
4. A compound as claimed in claim 1 , wherein R 2 and R 3 independently of one another, are C 1 -C 12 alkyl substituted with —OR 5 .
5. A compound as claimed in claim 1 , wherein R 2 and R 3 independently of one another, are C 1 -C 2 alkyl optionally substituted with —OR 5 .
6. A compound as claimed in claim 1 , wherein R 2 and R 3 are both —CH 3 .
7. A compound as claimed in claim 1 , wherein R 5 is —CH 3 or hydrogen.
8. A compound as claimed in claim 1 , wherein R 5 is hydrogen.
9. A compound as claimed in claim 1 ,
wherein:
W is hydrogen, and
R 2 and R 3 , independently of one another, are C 1 -C 2 alkyl optionally substituted with —OR 5 .
10. A compound as claimed in claim 1 ,
wherein:
W is hydrogen, and
R 2 and R 3 , independently of one another, are C 1 -C 2 alkyl substituted with —OR 5 .
11. A compound as claimed in claim 1 , wherein:
R 2 and R 3 independently of one another are unsubstituted C 1 -C 2 alkyl.
12. A compound as claimed in claim 1 ,
wherein:
R 2 and R 3 are both unsubstituted C 1 -C 12 alkyl.
13. A compound, which is
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino }-N-(2-methyl-2H-indazol-6-yl) -benzamide
2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino }-N-(2-methyl-2H-indazol-6-yl)-benzamide
2-({2- [3- (2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl }-amino)-N-(2-methyl-2H -indazol-6-yl)-benzamide
2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl }-amino)-N-(2-methyl-2H -indazol-6-yl)-benzamide
2- {[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino }-N-(2-methyl-2H-indazol-6-yl) -benzamide or
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino }-6-fluoro-N-(2-methyl-2H-indazol-6-yl) -benzamide
or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof.
14. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.
16. A compound of formula (I) according to claim 1 ,
wherein:
X is CH;
W is hydrogen or fluorine;
A, E and Q, are CH;
R 1 is 2-methyl-2H-indazol-6-yl;
R 2 and R 3 , independently of one another, are C 1 -C 12 alkyl optionally substituted with —OR 5 ; and
R 5 is hydrogen, C 1 -C 12 -alkyl, C 3 -C 8 -cycloalkyl or halo -C 1 -C 6 -alkyl;
or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 13 , which is
2- {[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino }-N-(2-methyl-2H-indazol-6-yl) -benzamide
2- {[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide
2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl }-amino)-N-(2-methyl-2H -indazol-6-yl)-benzamide
2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl }-amino)-N-(2-methyl-2H -indazol-6-yl)-benzamide
2- {[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino }-N-(2-methyl-2H-indazol-6-yl) -benzamide
or
2- {[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino }-6-fluoro-N-(2-methyl-2H-indazol-6-yl) -benzamide
or a pharmaceutically acceptable salt thereof.