Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
View Patent ↗This application relates to derivatives of Formula I: and pharmaceutically acceptable salts thereof, which are inhibitors of PI3K, and compositions and methods of treatment related thereto.
1. 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 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy or ethoxy.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cy, C(═O)NR c R d .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cy.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl or halo.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl or fluoro.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo, CN, or methyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, 3, or 4 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.
15. The compound of claim 12 , having Formula (II):
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 12 , having Formula (III):
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 12 , having Formula (Ha):
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 12 , having Formula (Ma):
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is selected from:
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-([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-[(1 S)-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.
20. The compound of claim 1 , 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.
21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, and benzazapene.
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrrolidin-2-one.
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 1,3-isoxazolidin-2-one.