Tricyclic heterocycles as BET protein inhibitors
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.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond;
L is O;
Cy 1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 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 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 neither R 1 nor R 2 are Cl, Br, I, CN, or OH;
alternatively, R 1 and R 2 together with the carbon atom to which they are attached are combined to 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 is 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, C(═O)NR 14a R 14b , C(═O)R 14a , C(═O)OR 14a , or C 1-6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR 14a R 14b , OR 14 a, SR 14a , CN, C(═O)R 14a , C(═O)NR 14a R 14b , C(═O)OR 14a , OC(═O)R 14b , OC(═O)NR 14a R 14b , NR 14a C(═O)R 14b , NR 14a C(═O)NR 14a R 14b , NR 14a C(═O)OR 14b , S(═O)R 14a , S(═O)NR 14a R 14b , S(═O) 2 R 14a , NR 14a S(═O) 2 R 14b , and S(═O) 2 NR 14a R 14b ;
R 5 is ═O
R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, and C 1-6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R 6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R 16 ;
alternatively, R 6 is selected from 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 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 R 20 ;
R 7 is selected from H, halo, CN, OR a , NR c R d , SR b , C(═O)NR 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 alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 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 C(═O)NR c R d , wherein said C 1-3 alkyl of R 8 is 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 C(═O)NR c R d , wherein said C 1-3 alkyl is optionally substituted by OH;
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 is 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 c3 R d3 ;
R 14a and R 14b are independently at each occurrence selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl of R 14a and R 14b is optionally substituted with 1, 2, or 3 substituents selected from R 20 ;
or R 14a and R 14b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R 20 ;
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 and S(═O) 2 NR c6 R d6 , 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 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, C 1-4 alkyl, CN, OR a , NR c R d , SR b , C(═O)NR c R d , C(═O)OR a , and NR c C(═O)R a ;
R a , R c , and R d are independently at each occurrence selected from H, C 1-6 alkyl, C(O)R e , S(═O) 2 R f , C(═O)NR g R h , and phenyl optionally substituted by C 1-4 alkoxy;
R b is at each occurrence C 1-6 alkyl;
R e is at each occurrence C 1-4 alkyl optionally substituted by a group selected from phenyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, and C 2-8 dialkylamino;
R f is C 1-4 alkyl;
R g and R h are independently at each occurrence selected from H and C 1-4 alkyl;
R a1 , R b1 , R c1 and 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 c3 and R d3 are independently at each occurrence selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 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 c3 and R d3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, OR a4 , SR a4 , C(═O)R b4 , C(═O)NR c4 R d4 , C(═O)OR a4 , OC(═O)R b4 , OC(═O)NR c4 R d4 , NR c4 R d4 , NR c4 C(═O)R b4 , NR c4 C(═O)NR c4 R d4 , NR c4 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 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, and C 1-6 haloalkyl wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl 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 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, 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 alkyl, alkenyl, alkynyl, phenyl, 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 haloalkyl, 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)—, H 2 NC(═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-O—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:
Cy 1 is a five membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said five membered heteroaryl of Cy 1 is optionally substituted with 1, 2, or 3 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, OR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , and C(═O)OR a1 ;
R 2 is selected from H, F, and C 1-6 alkyl;
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 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 ; additionally, 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 6 is selected from H and C 1-6 alkyl, wherein said alkyl of R 6 is optionally substituted by 1, 2, or 3 groups independently selected R 16 ;
R 7 is selected from H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, phenyl, and 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, or 5-6 membered heteroaryl group, of R 7 are optionally substituted with 1, 2, or 3 groups independently selected from R 17 ;
R 8 is selected from H, halo, CN, OH, and C 1-6 alkyl;
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 C(═O)NR 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 is 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 c3 R d3 ;
R 16 is independently at each occurrence selected from halo, CN, OH, OR a6 , C(═O)R b6 , C(═O)NR c6 R d6 , C(═O)OR a6 , OC(═O)R b6 , NR c6 R d6 , NR c6 C(═O)R b6 , and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl of R 16 is optionally substituted by 1, 2, 3, or 4 groups independently selected R 20 ;
R 17 is independently at each occurrence selected from halo, CN, OR a , NR c R d , SR b , and C(═O)NR 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 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 c3 and R d3 are independently at each occurrence selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl forming R a3 , R b3 , R c3 and R d3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, OR a4 , SR a4 , C(═O)R b4 , C(═O)NR c4 R d4 , C(═O)OR a4 , OC(═O)R b4 , OC(═O)NR c4 R d4 , NR c4 R d4 , NR c4 C(═O)R b4 , NR c4 C(═O)NR c4 R d4 , NR c4 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 and C 1-6 alkyl, wherein said C 1-6 alkyl forming R a4 , R b4 , R c4 and R d4 is 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 and C 1-6 alkyl;
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; 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 haloalkyl, 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)—, H 2 NC(═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 —.
3. The compound of claim 1 having Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
represents a single bond;
Cy 1 is selected from isoxazolyl and pyrazolyl, wherein said isoxazolyl and pyrazolyl of Cy 1 is optionally substituted with 1 or 2 groups independently selected from R 11 ;
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 ;
Cy 3 is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy 3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 13 ;
R 5 is ═O,
R 6 is selected from H, methyl, ethyl, and propyl wherein said methyl, ethyl, and propyl of R 6 are each optionally substituted by 1, 2, or 3 groups independently selected R 16 ;
R 7 is selected from H, F, Cl, Br, methyl, methoxy, ethoxy, CN, phenyl, and pyridinyl;
R 11 is independently at each occurrence selected from H, methyl, ethyl, chloro, and methoxy;
R 13 is independently at each occurrence selected from H, F, CN, methoxy, —CF 3 , —OCH 2 C(═O)OH, —OCH 2 C(═O)N(H)CH 2 CH 3 , —OCH 2 C(═O)N(H)CH 2 CH 2 OH, and —OCH 2 C(═O)N(CH 3 ) 2 ; and
R 16 is independently at each occurrence selected from H, morpholinyl, and piperidinyl.
4. 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 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
7. 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 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.
11. The compound of claim 1 selected from:
7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4R)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
4-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]benzonitrile;
7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3-methyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4R)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(1-oxidopyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
4-cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate;
7-(3,5-dimethylisoxazol-4-yl)-4-(1,3-thiazol-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
2-{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-ethylacetamide;
ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate;
7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;
7-(1-Methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-Bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-Methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbonitrile;
7-(3,5-Dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(1,4-dimethyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;
7-(3,5-Dimethylisoxazol-4-yl)-4-(4-fluorophenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
2-{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-(2-hydroxyethyl)acetamide;
2-{2-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N,N-dimethylacetamide; and
7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-9-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 , selected from:
7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
4-(1-Acetylpiperidin-2-yl)-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl acetate;
7-(3,5-Dimethylisoxazol-4-yl)-4-(hydroxymethyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide;
N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide;
4-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;
7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-[1-(methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-isopropylpiperidine-1-carboxamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-N,N-dimethylpyridine-2-carboxamide;
tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-3,6-dihydropyridine-1(2H)-carboxylate;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-pyrimidin-5-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-methyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
ethyl (2E)-3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]acrylate;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N,N-dimethylpyridine-2-carboxamide;
4-[2-(Aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
N-({3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridin-2-yl}methyl)acetamide;
Methyl 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylate;
3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide;
N-Cyclopropyl-3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxamide;
3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-(2-hydroxyethyl)pyridine-2-carboxamide;
3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide;
(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}acetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2-phenylacetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2-methoxyacetamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}methanesulfonamide;
N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-N′-isopropylurea;
2-(Dimethylamino)-N-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}acetamide;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxyethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(3-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(3,5-dimethyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(6-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-(anilinomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-{[(4-methoxybenzyl)amino]methyl}-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxy-2-methylpropyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;
7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one; and
7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbonitrile;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
14. A method of inhibiting a BET protein in vitro comprising contacting a compound of claim 1 , or a pharmaceutically acceptable salt thereof, with said BET protein.