Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
The present invention provides bicyclic azaheterocyclobenzylamines of Formula I: wherein the variables are defined herein, that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.
1. A compound of Formula IVb:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl;
R 4 is methyl, F or CN;
R 5 is Cl;
R 6 is H;
R 3b is H, Cy, —(C 1-3 alkylene)-Cy, C 1-6 alkyl, C 1-6 haloalkyl, C(═O)R b , C(═O)NR c R d , C(═O)OR a , or S(═O) 2 R b , wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 13b groups;
each R a , R b , R c , and R d is independently selected from C 1-6 alkyl and Cy; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 13b groups;
each Cy is independently selected from monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl, wherein said monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 13b groups;
each R 13b is independently selected from CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , NR c1 C(═O)R b1 , S(═O) 2 R b1 , and S(═O) 2 NR c1 R d1 , wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R 11 groups;
each R 11 is independently selected from OH and carbamyl;
each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and
each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
2. The compound of claim 1 , wherein R 3b is H.
3. The compound of claim 1 , wherein R 4 is methyl.
4. The compound of claim 1 , wherein the compound is 9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one, or a pharmaceutically acceptable salt thereof.
5. A compound of Formula XXIV:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl;
R 3a is methyl;
R 4 is methyl, F or CN;
R 5 is Cl;
R 6 is H;
R 3b is H, Cy, —(C 1-3 alkylene)-Cy, C 1-6 alkyl, C 1-6 haloalkyl, C(═O)R b , C(═O)NR c R d , C(═O)OR a , or S(═O) 2 R b , wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 13b groups;
each R a , R b , R c , and R d is independently selected from C 1-6 alkyl and Cy; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 13b groups;
each Cy is independently selected from monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl, wherein said monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 13b groups;
each R 13b is independently selected from CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , NR c1 C(═O)R b1 , S(═O) 2 R b1 , and S(═O) 2 NR c1 R d1 , wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R 11 groups;
each R 11 is independently selected from OH and carbamyl;
each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and
each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
6. The compound of claim 5 , wherein R 3b is Cy.
7. The compound of claim 5 , wherein R 4 is methyl.
8. The compound of claim 5 , wherein the compound is 4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
11. A method of treating B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
12. A method of treating diffuse large B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13. A method of treating chronic lymphocytic leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. A method of treating follicular B-cell Non-Hodgkin lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method of treating small lymphocytic lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16. A method of treating Non-Hodgkin lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A method of treating B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
18. A method of treating diffuse large B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
19. A method of treating chronic lymphocytic leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
20. A method of treating follicular B-cell Non-Hodgkin lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
21. A method of treating small lymphocytic lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
22. A method of treating Non-Hodgkin lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.