发明名称 TRICYCLIC HETEROCYCLES AS BET PROTEIN INHIBITORS
摘要 The present invention relates to tricyclic heterocycles 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.
申请公布号 US2016046650(A1) 申请公布日期 2016.02.18
申请号 US201514923105 申请日期 2015.10.26
申请人 INCYTE CORPORATION ;INCYTE HOLDINGS CORPORATION 发明人 Combs Andrew P.;Sparks Richard B.;Maduskuie, JR. Thomas P.;Rodgers James D.
分类号 C07D498/06;C07D519/00 主分类号 C07D498/06
代理机构 代理人
主权项 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: represents a single bond or a double bond; L is CR9R9a, O, S, SO, or SO2; Cy1 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 Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11; R1 and R2 are independently selected from H, halo, CN, OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, ORa1, SRa1, C(═O)Rb1, C(═O)NRc1Rd1, C(═O)ORa1, OC(═O)Rb1, OC(═O)NRc1Rd1, NRc1Rd1, NRc1C(═O)Rb1, NRc1C(═O)NRc1Rd1, NRc1C(═O)ORa1, S(═O)Rb1, S(═O)NRc1Rd1, S(═O)2Rb1, NRc1S(═O)2Rb1 and S(═O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORa1, SRa1, C(═O)Rb1, C(═O)NRc1Rd1, C(═O)ORa1, OC(═O)Rb1, OC(═O)NRc1Rd1, NRc1Rd1, NRc1C(═O)Rb1, NRc1C(═O)NRc1Rd1, NRc1C(═O)ORa1, S(═O)Rb1, S(═O)NRc1Rd1, S(═O)2Rb1, NRc1S(═O)2Rb1 and S(═O)2NRc1Rd1; provided neither R1 nor R2 are Cl, Br, I, CN, or OH when L is O or S; alternatively, R1 and R2 together with the carbon atom to which they are attached are combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20; Cy3 is selected from phenyl, C3-7 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, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R13, 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; R4 is H, C(═O)NR14aR14b, C(═O)R14a, C(═O)OR14a, or C1-6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR14aR14b, OR14a, SR14a, CN, C(═O)R14a, C(═O)NR14aR14b, C(═O)OR14a, OC(═O)R14b, OC(═O)NR14aR14b, NR14aC(═O)R14b, NR14aC(═O)NR14aR14b, NR14aC(═O)OR14b, S(═O)R14a, S(═O)NR14aR14b, S(═O)2R14a, NR14aS(═O)2R14b, and S(═O)2NR14aR14b; R5 is selected from ═O and ═S when  is a single bond, alternatively, when  is a double bond the R5 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NR15aR15b, —C(═O)NR15aR15b, —C(═O)OR15a, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-10 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15; R6 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, and C1-6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16; alternatively, R6 is selected from C6-10 aryl, C3-7 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 C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20; R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(═O)NRcRd, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, phenyl, C3-7 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 R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17; R8 is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(═O)NRcRd, wherein said C1-3 alkyl of R8 is optionally substituted with 1, 2, or 3 groups independently selected from R18; R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(═O)NRcRd; R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(═O)NRcRd, wherein said C1-3 alkyl is optionally substituted by OH; R13 is independently at each occurrence selected from H, halo, CN, OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, ORa3, SRa3, C(═O)Rb3, C(═O)NRc3Rd3, C(═O)ORa3, OC(═O)Rb3, OC(═O)NRc3Rd3, NRc3Rd3, NRc3C(═O)Rb3, NRc3C(═O)NRc3Rd3, NRc3C(═O)ORa3, S(═O)Rb3, S(═O)NRc3Rd3, S(═O)2Rb3, NRc3S(═O)2Rb3 and S(═O)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R13 is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORa3, SRa3, C(═O)Rb3, C(═O)NRc3Rd3, C(═O)ORa3, OC(═O)Rb3, OC(═O)NRc3Rd3, NRc3Rd3, NRc3C(═O)Rb3, NRc3C(═O)NRc3Rd3, NRc3C(═O)ORa3, S(═O)Rb3, S(═O)NRc3Rd3, S(═O)2Rb3, NRc3S(═O)2Rb3 and S(═O)2NRc3Rd3; R15 is independently at each occurrence selected from H, C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, ORa5, SRa5, C(═O)Rb5, C(═O)NRc5Rd5, C(═O)ORa5, OC(═O)Rb5, OC(═O)NRc5Rd5, NRc5Rd5, NRc5C(═O)Rb5, NRc5C(═O)NRc5Rd5, NRc5C(═O)ORa5, S(═O)Rb5, S(═O)NRc5Rd5, S(═O)2Rb5, NRc5S(═O)2Rb5, and S(═O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(═O)Rb5, C(═O)NRc5Rd5, C(═O)ORa5, OC(═O)Rb5, OC(═O)NRc5Rd5, NRc5Rd5, NRc5C(═O)Rb5, NRc5C(═O)NRc5Rd5, NRc5C(═O)ORa5, S(═O)Rb5, S(═O)NRc5Rd5, S(═O)2Rb5, NRc5S(═O)2Rb5, S(═O)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl; R14a and R14b are independently at each occurrence selected from H and C1-6 alkyl, wherein said C1-6 alkyl of R14a and R14b is optionally substituted with 1, 2, or 3 substituents selected from R20; or R14a and R14b 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 R20; R15a and R15b are independently at each occurrence selected from H and C1-6 alkyl, wherein said C1-6 alkyl of R15a and R15b is optionally substituted with 1, 2, or 3 substituents selected from R20; or R15a and R15b 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 R20; R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(═O)Rb6, C(═O)NRc6Rd6, C(═O)ORa6, OC(═O)Rb6, OC(═O)NRc6Rd6, NRc6Rd6, NRc6C(═O)Rb6, NRc6C(═O)NRc6Rd6, NRc6C(═O)ORa6, S(═O)Rb6, S(═O)NRc6Rd6, S(═O)2Rb6, NRc6S(═O)2Rb6 and S(═O)2NRc6Rd6, C6-10 aryl, C3-7 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 C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20; R17 and R18 are independently at each occurrence selected from halo, C1-4 alkyl, CN, ORa, NRcRd, SRb, C(═O)NRcRd, C(═O)ORa, and NRcC(═O)Ra; Ra, Rc, and Rd are independently at each occurrence selected from H, C1-6 alkyl, C(O)Re, S(═O)2Rf, C(═O)NRgRh, and phenyl optionally substituted by C1-4 alkoxy; Rb is at each occurrence C1-6 alkyl; Re is at each occurrence C1-4 alkyl optionally substituted by a group selected from phenyl, C1-4 alkoxy, amino, C1-4 alkylamino, and C2-8 dialkylamino; Rf is C1-4 alkyl; Rg and Rh are independently at each occurrence selected from H and C1-4 alkyl; Ra1, Rb1, Rc1 and Rd1 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra1, Rb1, Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(═O)Rb4, C(═O)NRc4Rd4, C(═O)ORa4, OC(═O)Rb4, OC(═O)NRc4Rd4, NRc4Rd4, NRc4C(═O)Rb4, NRc4C(═O)NRc4Rd4, NRc4C(═O)ORa4, S(═O)Rb4, S(═O)NRc4Rd4, S(═O)2Rb4, NRc4S(═O)2Rb4 and S(═O)2NRc4Rd4; Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, and C1-6 haloalkyl wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; or Rc5 and Rd5 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 independently selected from R20; Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; alternatively, Rc6 and Rd6 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 R20; Rb6 is independently at each occurrence selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 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 R20; and R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl-C(═O)—, C1-4 alkyl-C(═O)O—, C1-4 alkyl-OC(═O)—, HOC(═O)—, H2NC(═O)—, C1-4 alkyl-NHC(═O)—, di(C1-4 alkyl)NC(═O)—, C1-4 alkyl-C(═O)NH—, C1-4 alkyl-O—C(═O)NH—, C1-4 alkyl-S(═O)—, H2NS(═O)—, C1-4 alkyl-NHS(═O)—, di(C1-4 alkyl)NS(═O)—, C1-4 alkyl-S(═O)2—, C1-4 alkyl-S(═O)2NH—, H2NS(═O)2—, C1-4 alkyl-NHS(═O)2—, and di(C1-4 alkyl)NS(═O)2—.
地址 Wilmington DE US