IP Library Granted Patent US 9,290,514
Granted Patent B2
US 9,290,514 · App. 14/324,560 · Granted Mar 22, 2016

Tricyclic heterocycles as BET protein inhibitors

Inventors: Andrew P. Combs (Kennett Square, PA); Eddy W. Yue (Landenberg, PA); Richard B. Sparks (Wilmington, DE); Thomas P. Maduskuie, Jr. (Wilmington, DE)
Assignees: Incyte Holdings Corporation; Incyte Corporation
C07D498/06
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Quick Facts
Patent No.
US 9,290,514
App. No.
14/324,560
Granted
Mar 22, 2016
Kind
B2
Abstract

The present invention relates to tricyclic heterocycles of Formula (I), which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

Claims (109)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond;

L is O;

X is N or NR 5 ;

Y is N, CR 6 , C(═O), or C(═S);

provided X is not NR 5 when Y is N;

Cy 1 is selected from phenyl and a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl and 5-6 membered heteroaryl of Cy 1 are optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 ;

R 1 and R 2 are independently selected from H, halo, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a1 , SR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , OC(═O)R b1 , OC(═O)NR c1 R d1 , NR c1 R d1 , NR c1 C(═O)R b1 , NR c1 C(═O)NR c1 R d1 , NR c1 C(═O)OR a1 , S(═O)R b1 , S(═O)NR c1 R d1 , S(═O) 2 R b1 , NR c1 S(═O) 2 R b1 and S(═O) 2 NR c1 R d1 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 1 and R 2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR a1 , SR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , OC(═O)R b1 , OC(═O)NR c1 R d1 , NR c1 R d1 , NR c1 C(═O)R b1 , NR c1 C(═O)NR c1 R d1 , NR c1 C(═O)OR a1 , S(═O)R b1 , S(═O)NR c1 R d1 , S(═O) 2 R b1 , NR c1 S(═O) 2 R b1 and S(═O) 2 NR c1 R d1 ;

provided R 1 and R 2 are other than Cl, Br, I, CN, and OH when L is O;

alternatively, R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 20 ;

Cy 3 is selected from phenyl, C 3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy 3 are optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 , wherein a ring-forming nitrogen atom of said 5-10 membered heteroaryl group or a ring-forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;

R 4 is H or C 1-6 alkyl;

R 5 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 5 are optionally substituted by 1, 2, 3, or 4 groups independently selected from R 15 ;

R 6 is selected from H, halo, CN, OH, OR a6 , SR a6 , C(═O)R b6 , C(═O)NR c6 R d6 , C(═O)OR a6 , OC(═O)R b6 , OC(═O)NR c6 R d6 , NR c6 R d6 , NR c6 C(═O)R b6 , NR c6 R d6 , NR c6 C(═O)OR a6 , S(═O)R b6 , S(═O)NR c6 R d6 , S(═O) 2 R b6 , NR c6 S(═O) 2 R b6 , S(═O) 2 NR c6 R d6 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl of R 6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected from R 16 ;

alternatively, R 6 is selected from C 6-10 aryl, C 3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected from R 20 ;

R 7 is selected from H, halo, CN, OR a , NR c R d , SR b , CONR c R d , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group of R 7 are optionally substituted with 1, 2, or 3 groups independently selected from R 17 ;

R 8 is selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, halo, CN, OR a , NR c R d , SR b , and CONR c R d , wherein said C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl of R 8 are optionally substituted with 1, 2, or 3 groups independently selected from R 18 ;

R 11 is independently at each occurrence selected from H, C 1-3 alkyl, C 1-3 haloalkyl, halo, CN, OR a , NR c R d , SR b , and CONR c R d ;

R 13 is independently at each occurrence selected from H, halo, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a3 , SR a3 , C(═O)R b3 , C(═O)NR c3 R d3 , C(═O)OR a3 , OC(═O)R b3 , OC(═O)NR c3 R d3 , NR c3 R d3 , NR c3 C(═O)R b3 , NR c3 C(═O)NR c3 R d3 , NR c3 C(═O)OR a3 , S(═O)R b3 , S(═O)NR c3 R d3 , S(═O) 2 R b3 , NR c3 S(═O) 2 R b3 and S(═O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 13 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR a3 , SR a3 , C(═O)R b3 , C(═O)NR c3 R d3 , C(═O)OR a3 , OC(═O)R b3 , OC(═O)NR c3 R d3 , NR c3 R d3 , NR c3 C(═O)R b3 , NR c3 C(═O)NR c3 R d3 , NR c3 C(═O)OR a3 , S(═O)R b3 , S(═O)NR c3 R d3 , S(═O) 2 R b3 , NR c3 S(═O) 2 R b3 and S(═O) 2 NR 3 R d3 ;

R 15 is independently at each occurrence selected from H, halo, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a5 , SR a5 , C(═O)R b5 , C(═O)NR c5 R c5 , C(═O)OR a5 , OC(═O)R b5 , OC(═O)NR c5 R c5 , NR c5 R c5 , NR c5 C(═O)R b5 , NR c5 C(═O)NR c5 R c5 , NR c5 C(═O)OR a5 , S(═O)R b5 , S(═O)NR c5 R c5 , S(═O) 2 R b5 , NR c5 S(═O) 2 R b5 and S(═O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 15 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR a5 , SR a5 , C(═O)R b5 , C(═O)NR c5 R c5 , C(═O)OR a5 , OC(═O)R b5 , OC(═O)NR c5 R c5 , NR c5 R c5 , NR c5 C(═O)R b5 , NR c5 C(═O)NR c5 R c5 , NR c5 C(═O)OR a5 , S(═O)R b5 , S(═O)NR c5 R c5 , S(═O) 2 R b5 , NR c5 S(═O) 2 R b5 and S(═O) 2 NR c5 R d5 ;

R 16 is independently at each occurrence selected from halo, CN, OH, OR a6 , SR a6 , C(═O)R b6 , C(═O)NR c6 R d6 , C(═O)OR a6 , OC(═O)R b6 , OC(═O)NR c6 R d6 , NR c6 R d6 , NR c6 C(═O)R b6 , NR c6 C(═O)NR c6 R d6 , NR c6 C(═O)OR a6 , S(═O)R b6 , S(═O)NR c6 R d6 , S(═O) 2 R b6 , NR c6 S(═O) 2 R b6 , S(═O) 2 NR c6 R d6 , C 6-10 aryl, C 3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R 20 ;

R 17 and R 18 are independently at each occurrence selected from halo, CN, OR a , NR c R d , SR b , and CONR c R d ;

R a , R c , and R d are independently at each occurrence selected from H and C 1-6 alkyl;

R b is at each occurrence C 1-6 alkyl;

R a1 , R b1 , R c1 and a R d1 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl forming R a1 , R b1 , R c1 and R d1 are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;

R a3 , R b3 , R a1 and R d3 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl forming R a3 , R b3 , R a1 and R d3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, OR′, SR′, C(═O)R b4 , C(═O)NR 11 R 11 , C(═O)OR a4 , OC(═O)R b4 , OC(═O)NR 11 R 11 , NR 11 R 11 , NR 11 C(═O)R b4 , NR 11 C(═O)NR 11 R 11 , NR 11 C(═O)OR a4 , S(═O)R b4 , S(═O)NR c4 R d4 , S(═O) 2 R b4 , NR c4 S(═O) 2 R b4 and S(═O) 2 NR c4 R d4 ;

R a4 , R b4 , R c4 and R d4 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl forming R a4 , R b4 , R c4 and R d4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;

R a5 , R b5 , R c5 and R d5 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl forming R a5 , R b5 , R c5 and R d5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;

R a6 , R c6 and R d6 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl group, and 4-7 membered heterocycloalkyl group forming R a6 , R c6 and R d6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;

alternatively, R c6 and R d6 together with the nitrogen atom to which they are attached may be combined to form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;

R b6 is independently at each occurrence selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ; and

R 20 is at each occurrence independently selected from H, halo, OH, CN, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 halo alkyl, C 1-4 haloalkoxy, C 1-4 alkyl-C(═O)—, C 1-4 alkyl-C(═O)O—, C 1-4 alkyl-OC(═O)—, HOC(═O)—, H2NC(═O)—, C 1-4 alkyl-NHC(═O)—, di(C 1-4 alkyl)NC(═O)—, C 1-4 alkyl-C(═O)NH—, C 1-4 alkyl-S(═O)—, H 2 NS(═O)—, C 1-4 alkyl-NHS(═O)—, di(C 1-4 alkyl)NS(═O)—, C 1-4 alkyl-S(═O) 2 —, C 1-4 alkyl-S(═O) 2 NH—, H 2 NS(═O) 2 —, C 1-4 alkyl-NHS(═O) 2 —, and di(C 1-4 alkyl)NS(═O) 2 —.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is NR 5 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 6 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is C(═O).

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X Y is N═N.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is isoxazolyl substituted with 1 or 2 groups independently selected from R 11 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is pyrazolyl substituted with 1 or 2 groups independently selected from R 11 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, methyl, —C(═O)OCH 2 CH 3 , —C(═O)N(H)CH 2 CH 3 , —C(═O)N(H)CH 2 CH 2 OH, and —C(═O)N(CH 3 ) 2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is pyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is oxidopyridinyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is thiazolyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is cyclohexyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is dihydrobenzofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 3 is tetrahydrofuranyl optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 .

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methoxy.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, halo, C 1-4 alkyl, and CN.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, Br, F, methyl, and CN.

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is Br.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is F.

31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.

32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CN.

33. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halo, C 1-4 alkyl, and CN.

34. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

35. The compound of claim 1 having Formula (IIa), (IIb), or (IIc):

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , having Formula (IIIa), (IIIb), or (IIIc):

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

L is O;

Y is N, CR 6 , or C(═O);

Cy 1 is a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl of Cy 1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 ;

R 1 is selected from H, F, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 1 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , NR c1 R d1 , and NR c1 C(═O)R b1 ; provided R 1 is not OH;

R 7 is selected from H, halo, CN, OR a , C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered heterocycloalkyl group of R 7 are optionally substituted with 1, 2, or 3 groups independently selected from R 17 ;

R 8 is selected from H and C 1-3 alkyl; and

R a1 , R b1 , R c1 and R d1 are independently at each occurrence selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

38. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

L is O;

Y is N, CR 6 , or C(═O);

Cy 1 is a 5-membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said 5-membered heteroaryl of Cy 1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 11 ;

R 1 and R 2 are both H;

Cy 3 is selected from phenyl and a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl and 5-6 membered heteroaryl of Cy 3 are optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 , wherein a ring-forming nitrogen atom of said 5-6 membered heteroaryl group;

R 4 is H;

R 5 is selected from H and C 1-6 alkyl;

R 6 is selected from H, OR a6 ;

R 7 is selected from H and halo; and

R 8 is H.

39. The compound of claim 1 selected from:

9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;

9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;

9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;

9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;

7-bromo-9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;

9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;

9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole; and

7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydro[1,2,3]triazolo[1,5,4-de][1,4]benzoxazine;

or a pharmaceutically acceptable salt of any of the aforementioned.

40. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

41. A method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , wherein the cancer is adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.

42. A method of treating an autoimmune or inflammatory disease comprising administering to a patient in need of such treatment a therapeutically effective amount of claim 1 , wherein the autoimmune or inflammatory disease is selected from allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septic shock, systemic lupus erythematosus, tissue graft rejection, type I diabetes.

43. A method of treating a viral infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

44. The method of claim 43 , wherein the viral infection is infection with adenovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, a herpes virus, human immunodeficiency virus, human papilloma virus or a pox virus.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY INFORMATION PREVIOUSLY RECORDED ON REEL 035920 FRAME 0576. ASSIGNOR(S) HEREBY CONFIRMS THE RECEIVING PARTY NAME SHOULD BE RECORDED AS TWO PARTIES. Recorded Jul 2, 2015
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 036054/0740 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2015
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION AND INCYTE CORPORATION
Reel/Frame 035920/0576 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 21, 2014
From: COMBS, ANDREW P.; YUE, EDDY W.; SPARKS, RICHARD B.; MADUSKUIE, THOMAS P., JR.
To: INCYTE CORPORATION
Reel/Frame 033349/0894 →
Continuity (2)
Provisional Application 61843638 · Jul 8, 2013
Related Publication 20150011540A1 · Jan 8, 2015