Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors

1. A method of treating a disease selected from Mantle cell lymphoma, follicular lymphoma, extranodal marginal zone lymphoma, and splenic marginal zone lymphoma in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ar is:

R 1 is methyl;

R 2 is C 1-6 alkoxy, C 1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3 is Cy or C(═O)NR c R d ;

provided that either (i) R 2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or (ii) R 3 is Cy;

R 4 is halo, C 1-4 alkyl, or C 1-4 haloalkyl;

R 5 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl;

R 6 is H;

each Cy is independently selected from 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1 or 2 independently selected R 3b groups;

each R c and R d is independently selected from H and C 1-6 alkyl; and

each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 16 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl.

2. The method of claim 1 , wherein R 2 is C 1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

3. The method of claim 1 , wherein R 3 is C(═O)NR c R d .

4. The method of claim 1 , wherein R 3 is Cy.

5. The method of claim 1 , wherein R 4 is C 1-4 alkyl or halo.

6. The method of claim 1 , wherein R 5 is halo, CN, or methyl.

7. The method of claim 1 , wherein:

Ar is:

R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;

R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;

each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl;

R 4 is C 1-4 alkyl or halo;

R 5 is halo; and

R 6 is H.

8. The method of claim 1 , wherein:

Ar is:

R 2 is C 1-6 alkoxy;

R 3 is 4-6 membered heterocycloalkyl;

R 4 and R 5 are each independently halo; and

R 6 is H.

9. The method of claim 1 , wherein:

Ar is:

R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;

R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;

each R 3b is di(C 1-6 alkyl)carbamyl;

R 4 is halo or C 1-4 alkyl;

R 5 is halo; and

R 6 is H.

10. The method of claim 1 , wherein the compound is selected from:

4-{3-chloro-6-ethoxy-2-fluoro-5-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]phenyl}pyrrolidin-2-one;

4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one;

5-{3-chloro-6-methoxy-2-methyl-5-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;

4-chloro-N-ethyl-3′,5′-difluoro-3-methyl-6-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]biphenyl-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is selected from:

(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;

(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;

(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one; and

(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the disease is Mantle cell lymphoma.

13. The method of claim 1 , wherein the disease is follicular lymphoma.

14. The method of claim 1 , wherein the disease is extranodal marginal zone lymphoma.

15. The method of claim 1 , wherein the disease is splenic marginal zone lymphoma.

16. The method of claim 1 , wherein the compound is 4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

17. The method of claim 12 , wherein the compound is 4-{3-chloro-6-ethoxy-2-fluoro-5[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

18. The method of claim 13 , wherein the compound is 4-{3-chloro-6-ethoxy-2-fluoro-5[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

19. The method of claim 14 , wherein the compound is 4-{3-chloro-6-ethoxy-2-fluoro-5[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

20. The method of claim 15 , wherein the compound is 4-{3-chloro-6-ethoxy-2-fluoro-5[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.