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US 2013/0281399 A1Published application
Treatment of diseases by epigenetic regulation
AssigneeRVX Therapeutics Inc.
InventorsKevin G. McLure, Peter R. Young
Life of this patent
Estimating the term…
Abstract
The present disclosure provides non-naturally occurring polyphenol compounds that inhibit the bromodomain and extra terminal domain (BET) proteins. The disclosed compositions and methods can be used for treatment and prevention of diseases or disorders that are susceptible to administration of a BET inhibitor.
Claims26
A method for inhibiting BET proteins comprising administering a therapeutically effective amount of at least one compound of Formula I:
- or stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
- Q and V are independently selected from CH and nitrogen;
- Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C3-C6 cycloalkyl;
- Rb2 and Rb6 are independently selected from hydrogen;
- Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino;
- or wherein Rb2 and Rb3 and/or Rb5 and Rb6 are optionally connected to form a cycloalkyl or a heterocycle;
- represents a 3-8 membered ring system wherein:
- W is selected from carbon and nitrogen;
- Z is selected from CR6R7, NR8, oxygen, sulfur, —S(O)—, and —SO2—;
- said ring system being optionally fused to another ring selected from cycloalkyl, heterocycle, and phenyl, and wherein said ring system is optionally selected from rings having the structures:
- R3, R4, and R5 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryl, aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide;
- R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, halogen, hydroxyl, —CN, amino, and amido;
- and
- R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl;
- and
- R9, R10, R11, and R12 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, aryl, heterocycle, hydroxyl, sulfonyl, and acyl;
- provided that:
- if Q is CH, then at least one of Ra1 and Ra3 is not hydrogen;
- if Z is NAc, then Ra1 and Ra3 are not hydrogen, and Ra1 is not —OCH2CH2OMe;
- and
- if Ra1 and Ra3 are both OMe, then R8 is not —C(O)CH2OH.
18 more elements
A method of inhibiting BET proteins comprising administering a therapeutically effective amount of at least one compound of Formula II:
- or stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
- Q and V are independently selected from CH and nitrogen;
- Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, hydroxyl, cycloalkyl, and heterocycle;
- Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino;
- Rn1 is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
- Rn2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, alkenyl, sulfonyl and acyl;
- or wherein Rn1 and/or Rn2 are optionally connected with Rb3 and/or Rb5 to form a 5- or 6-membered heterocyclic ring;
- provided that:
- at least one of Ra1 and Ra3 are not hydrogen;
- and
- Rn1 and Rn2 are not both methyl or ethyl.
8 more elements
A method of inhibiting BET proteins in a subject, comprising administering a therapeutically effective amount of at least one compound of Formula III:
- or stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
- Q is selected from CH and nitrogen;
- V is selected from CH and nitrogen;
- X is selected from oxygen, sulfur, SR1, nitrogen, NR6R7, and CR6R7;
- Z is selected from unsubstituted C1-C6 alkyl and C1-C6 alkyl substituted with one or more groups selected from C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, hydroxyl, amino, and halogen;
- n is selected from 0, 1, 2, or 3;
- G is selected from heterocycle, cycloalkyl, and aryl;
- R1 is selected from hydrogen, and C1-C6 alkyl;
- R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, C1-C6 alkoxy, and halogen;
- Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle;
- and
- Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and amino;
- provided that:
- if Ra1 and Ra3 are OMe, and Q is CH, then
- at least one of Ra1 and Ra3 is not hydrogen;
- and
- if Ra3 is chloro, then Ra1 is not hydrogen.
14 more elements
A method of inhibiting BET proteins comprising administering a therapeutically effective amount of at least one compound of Formula IV:
- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
- Q1 is selected from nitrogen and C—Ra1;
- Q3 is selected from nitrogen and C—Ra3;
- V is selected from CH and nitrogen;
- Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and heterocycle;
- or wherein Ra1 and Ra2 and/or Ra2 and Ra3 are connected to form a cycloalkyl or a heterocycle;
- and
- Rb3 and Rb5 are independently selected from hydrogen, methyl, ethyl, C3-C6 cycloalkyl, O1—O3 alkoxy, and amino;
- provided that:
- if Ra3 is alkoxy, then Ra1 is not hydrogen;
- and
- if Rb5 is hydrogen, then Rb3 is not —CH2OH.
9 more elements
A method of inhibiting BET proteins comprising administering a therapeutically effective amount of at least one compound of Formula V:
- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
- Q is selected from CH and nitrogen;
- Y is selected from oxygen, nitrogen, sulfur, NR6, CR6R7;
- A is C1-C4 alkyl, wherein the alkyl chain may be connected to Y, D, and/or Rb3 to form a cycloalkyl or heterocycle;
- D, if present, is selected from —OR1, —NR1R2;
- R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, sulfonamide, carboxamide, acyl, and nitrile, wherein R1 and R2 may be connected to form a cycloalkyl or a heterocycle;
- R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and halogen;
- Ra1 and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle;
- and
- Rb3 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, and amino;
- provided that at least one of Ra1 and Ra3 is not hydrogen.
8 more elements
Dependencies are inferred from the claim text.