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1. A method of treating or inhibiting a cancer associated with the activity of one or more BET-family bromodomains in a patient comprising administering to said patient in need thereof a therapeutically effective amount of the compound of Formulae (I), (II), (III) or (IV): wherein: W is O, S, C(O), or CHR3; X is N or CR4; Y is N or CR6; Z is N or CR7; R1 is C1-C6 alkyl, or C1-C6 haloalkyl; R2 is hydrogen or NRaRb; R3 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, or C1-C6 haloalkyl; R4 is hydrogen, —(CH2)nRd, —O(CH2)nRd, —N(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd; R5 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and RC; R6 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C1-C6)-alkylene-aryl, —(C1-C6)-alkylene-heteroaryl, —(C1-C6)-alkylene-heterocycloalkyl, —(CRaRb)nOR, —(CRaRb)nRc, —O(CRaRb)nNRaRb, —NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, or Rc, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc; R7 is hydrogen or halogen; R8 is Ra, —ORa, —NRa, or heterocycloalkyl; Ra and Rb are each independently hydrogen, halogen, C1-C6 alkyl, cycloalkyl, or heterocycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; Rc is —NH2, OH, —NH(C1-C6 alkyl), —O(CH2)nNRaRb, —NH(C1-C6 alkoxy), —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, —NRa—S(O)2Rb, —NHC(O)Ra, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Re; or two adjacent Rc can combine with the carbons to which they are attached to form a carbocycle or heterocycle; Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc; Re is hydrogen, halogen, OH, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, or S(O)2(C1-C6 alkyl); andn is 0, 1, or 2; wherein: W is O, C(O), or CHR3; Ar is aryl or heteroaryl; R2 is hydrogen or NRaRb; R3 is hydrogen, hydroxy, or halo; R4 hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd; R7 is hydrogen or halo; R8 is Ra, —ORa, or heterocycloalkyl; Ra and Rb are independently hydrogen, C1-C6 alkyl, heterocycloalkyl, or cycloalkyl; Rc is Ra, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, halo, or oxo; and n is 0, 1, or 2; wherein: Ar is pyrazolyl or phenyl; R4 is hydrogen, —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd; R8 is methyl, methoxy, or cyclopropyl; Ra and Rb are independently hydrogen or C1-C6 alkyl; Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —(CH2)nS(O)2CH3, —S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo; Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc; and n is 0, 1, or 2; wherein: R4 is —O(CH2)nRd, —O(CH2)nC(O)Rd, or —O(CH2)nS(O)2Rd; R8 is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl Ra and Rb are independently hydrogen or C1-C6 alkyl; Rc is —(CH2)nRa, —(CH2)nORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb—S(O)2Ra, —S(O)2NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo; Rd is hydrogen, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from Ra, Rb, and Rc; andn is 0, 1, or 2;
or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer, or tautomer of the compound of Formulae (I), (II), (III) or (IV); wherein the cancer is selected from the group consisting of prostate, ovary, pancreas, esophagus, thyroid, bladder, bone, bile duct, testicle, uterus, head, neck, salivary gland, small cell ling cancer, non-small cell lung cancer, castration-resistant prostate cancer, glioblastoma, astrocytoma, mebulloblastoma, neuroblastoma, neurofibromatosis, merkel cell carcinoma, soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, cholangiocarcinoma, PD-L1 positive tumors, and DNA mismatch repair deficient tumors. |
