N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
The present invention provides N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines derivatives 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 IIa:
or a pharmaceutically acceptable salt thereof; wherein:
R 1 is methyl or ethyl;
R 2 is selected from C 1-6 alkyl, —O—(C 1-6 alkyl), —O—(C 1-4 alkylene) n -(4-7 membered heterocycloalkyl), and phenyl; wherein said phenyl is optionally substituted by 1, 2, 3, or 4 independently selected halo groups;
Cy 3 is a pyridine ring which is optionally substituted with 1, 2, 3, or 4 independently selected R 3a groups;
R 4 is selected from H, halo, C 1-3 alkyl, CN, cyano-C 1-6 alkyl, and C 1-6 haloalkyl;
R 5 is selected from C 1-3 alkyl, halo, and CN;
each R 3a is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, (4-7 membered heterocycloalkyl)-C 1-3 alkyl, (5-6 membered heteroaryl)-C 1-3 alkyl, OR a , C(O)R b , C(O)OR a , C(O)NR c R d , NR c R d , NR c C(O)R b , and S(O) 2 R b ; wherein said C 1-6 alkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C 3-7 cycloalkyl;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and amino;
each R b is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and amino; and
n is 0 or 1.
2. The compound of claim 1 , which is 6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.
3. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
4. A composition comprising a compound according to claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
5. A method of inhibiting an activity of a PI3K kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
6. A method of treating rheumatoid arthritis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.
7. A method of treating acute myeloblastic 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, wherein said treating refers to inhibiting or ameliorating.
8. 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, wherein said treating refers to inhibiting or ameliorating.
9. A method of treating chronic myeloid 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, wherein said treating refers to inhibiting or ameliorating.
10. 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, wherein said treating refers to inhibiting or ameliorating.
11. A method of inhibiting an activity of a PI3K kinase, comprising contacting the kinase with a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
12. A method of treating rheumatoid arthritis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.
13. A method of treating acute myeloblastic leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.
14. A method of treating B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.
15. A method of treating chronic myeloid leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.
16. 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 2 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.