9H-PYRIMIDO[4,5-B]INDOLES AND RELATED ANALOGS AS BET BROMODOMAIN INHIBITORS

摘要

The present disclosure provides substituted 9H-pyrimido[4,5-b]indoles and 5H-pyrido[4,3-b]indoles and related analogs represented by Formula I:;;and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1a, A, B1, B2, G, X1, Y1, Y2, and Y3 are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a condition or disorder responsive to inhibition of BET bromodomains. Compounds of the present disclosure are especially useful for treating cancer.

主权项

1. A compound having Formula I:or a pharmaceutically acceptable salt, hydrate, or solvate thereof,wherein:
B1 is —N═ or —C(R1b)—; B2 is —N═ or —C(R1c)—; Y1 is selected from the group consisting of —C(R2a)═ and —N═; Y2 is selected from the group consisting of —C(R2b)═ and —N═; Y3 is selected from the group consisting of —C(R2c)═ and —N═; G is selected from the group consisting of halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, —OS(═O)2CF3, and —Z—R3 R1a and R1b are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino, and halo; R1c is selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino, and fluoro; R2a and R2c are independently selected from the group consisting of hydrogen, halo, alkyl, and carboxamido; R2b is selected from the group consisting of hydrogen, amino, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, heteroalkyl, (heterocyclo)alkyl, (amino)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, and carboxamido; R3 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclo; A is optionally substituted 5-membered heteroaryl; X1 is selected from the group consisting of —O—, —S—, and —N(R5a1)—; Z is selected from the group consisting of —C(═O)—, —O—, —S—, —SO2—, and —N(R5b1)—; R5a1 is selected from the group consisting of hydrogen and alkyl; and R5b1 is selected from the group consisting of hydrogen and alkyl,with the provisos that:
a) when G is halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, or —OS(═O)2CF3 then either B1 or B2, or both, is —N═; or b) when G is halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, or —OS(═O)2CF3, then either R1b or R1c, or both, is hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino, carboxamido, or fluoro; and c) A is not 1,3-dimethyl-1H-pyrazol-4-yl, or: wherein: R4a and R4b are each independently selected from the group consisting of hydrogen, halo, haloalkyl, and alkyl; and X5 is selected from the group consisting of —O— and —S—.