Substituted quinazoline and pyridopyrimidine derivatives useful as anticancer agents
Compounds of the general formula: processes for the preparation of these compounds, compositions containing these compounds, and administration of these compounds to patients to treat pancreatic, lung, colon and other cancers.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof; wherein:
A is —C(H)— or nitrogen;
B is oxygen or C(R 6 ) 2 ;
J is:
where W* represents the point of attachment to W, and where J is optionally substituted with 1 R 2 ;
K is:
or
K is:
where K is optionally substituted with 1 or 2 R 3 ;
W is selected from the group consisting of:
each R 1 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, cyano and N(R 6 ) 2 ;
R 2 is C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, halogen, and C 1 -C 6 halo-alkyl;
R 4 is —X—Y—Z where:
X is absent or is oxygen,
Y is absent or C 1 -C 6 alkylenyl, and
Z is selected from H, heterocycle having 3-12 ring atoms and C 3 -C 6 cycloalkyl, where R 4 is optionally substituted with R 7 ;
each R 6 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl, or two R 6 optionally join to form heterocycle having 3-12 ring atoms or C 3 -C 6 cycloalkyl;
each R 7 is independently R 7′ or C 1 -C 6 alkyl-R 7′ , where each R 7′ is independently selected from the group consisting of: C 1 -C 6 alkyl and —N(R 6 ) 2 ; and
m is 0, 1,2 or 3.
2. The compound or salt of claim 1 , wherein J is selected from the group consisting of:
3. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of:
4. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of:
5. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof; wherein:
A is —C(H)— or nitrogen;
J is:
where W* represents the point of attachment to W, and where J is optionally substituted with 1 or more R 2 ;
W is:
each R 1 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, cyano and N(R 6 ) 2 ;
R 2 is C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, halogen, and C 1 -C 6 halo-alkyl;
R 4 is —X—Y—Z where:
X is absent or is oxygen,
Y is absent or C 1 -C 6 alkylenyl, and
Z is selected from H, heterocycle having 3-12 ring atoms and C 3 -C 6 cycloalkyl,
where R 4 is optionally substituted with R 7 ;
each R 6 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl, or two R 6 optionally join to form heterocycle having 3-12 ring atoms or C 3 -C 6 cycloalkyl;
each R 7 is independently R 7′ or C 1 -C 6 alkyl-R 7′ , where each R 7′ is independently selected from the group consisting of: C 1 -C 6 alkyl and —N(R 6 ) 2 ; and
each m is independently 0, 1, 2 or 3.
6. The compound or salt of claim 5 , wherein
is selected from the group consisting of:
7. The compound or salt of claim 5 or 6 , wherein R 4 is selected from the group consisting of:
8. The compound or salt of claim 6 or 7 , wherein R 4 is selected from the group consisting of:
9. A compound of Formula (III):
or a pharmaceutically acceptable salt thereof; wherein:
J is:
where W* represents the point of attachment to W, and where J is optionally substituted with 1 or more R 2 ;
W is selected from the group consisting of:
each R 1 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, cyano and N(R 6 ) 2 ;
R 2 is C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, halogen, and C 1 -C 6 halo-alkyl;
R 4 is —X—Y—Z where:
X is absent or is oxygen,
Y is absent or C 1 -C 6 alkylenyl, and
Z is selected from H, heterocycle having 3-12 ring atoms and C 3 -C 6 cycloalkyl,
where R 4 is optionally substituted with R 7 ;
each R 6 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl, or two R 6 optionally join to form heterocycle having 3-12 ring atoms or C 3 -C 6 cycloalkyl;
each R 7 is independently R 7′ or C 1 -C 6 alkyl-R 7′ , where each R 7′ is independently selected from the group consisting of: C 1 -C 6 alkyl and —N(R 6 ) 2 ; and
each m is independently 0, 1, 2 or 3.
10. The compound or salt of claim 9 , wherein
is selected from the group consisting of:
11. The compound or salt of claim 9 , wherein R 4 is selected from the group consisting of:
12. The compound or salt of claim 9 , wherein R 4 is selected from the group consisting of:
13. A compound of Formula (IV):
or a pharmaceutically acceptable salt thereof; wherein:
J is:
where W* represents the point of attachment to W, and where J is optionally substituted with 1 or more R 2 ;
W is selected from the group consisting of:
each R 1 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, cyano and N(R 6 ) 2 ;
R 2 is C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, halogen, and C 1 -C 6 halo-alkyl;
R 4 is —X—Y—Z where:
X is absent or is oxygen,
Y is absent or C 1 -C 6 alkylenyl, and
Z is selected from H, heterocycle having 3-12 ring atoms and C 3 -C 6 cycloalkyl,
where R 4 is optionally substituted with R 7 ;
each R 6 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl, or two R 6 optionally join to form heterocycle having 3-12 ring atoms or C 3 -C 6 cycloalkyl;
each R 7 is independently R 7′ or C 1 -C 6 alkyl-R 7′ , where each R 7′ is independently selected from the group consisting of: C 1 -C 6 alkyl and —N(R 6 ) 2 ; and
each m is independently is 0, 1, 2 or 3.
14. The compound or salt of claim 13 , wherein
is selected from the group consisting of:
15. The compound or salt of claim 13 , wherein R 4 is selected from the group consisting of:
16. The compound or salt of claim 13 , wherein R 4 is selected from the group consisting of:
17. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A compound or pharmaceutically acceptable salt of according claim 1 , wherein one or more hydrogen atoms are replaced with deuterium atoms.
20. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
21. A method of treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 5 , 9 , 13 , 17 and 18 , or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, pancreatic cancer, or colon cancer.