Compounds and uses thereof for the modulation of hemoglobin

摘要

Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

主权项

1. In certain aspects of the invention, a compound of formula (I) is provided: or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is an optionally substituted 4-10 membered cycloalkyl or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; ring B is a C6-C10 aryl or 5-10 membered heteroaryl having 1-3 nitrogen atoms, preferably 1-2 nitrogen atoms and more preferably 1 nitrogen atom, or oxidized versions thereof, wherein the aryl or heteroaryl is optionally substituted; is a single or a double bond; each Y and Z is independently CR10R11, O, S, SO, SO2, or NR12; each R10 and R11 independently is hydrogen or C1-C3 alkyl optionally substituted with halo, OH, or C1-C6 alkoxy, or CR10R11 is C═O; R12 is hydrogen or C1-C6 alkyl; provided that if one of Y and Z is O, S, SO, SO2, then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof; ring C is C6-C10 aryl; V1 and V2 independently are C1-C6 alkoxy; or V1 and V2 together with the carbon atom they are attached to form a ring of formula: wherein each V3 and V4 are independently O, S, or NH, provided that when one of V3 and V4 is S, the other is NH, and provided that V3 and V4 are both not NH; q is 1 or 2; each V5 is independently C1-C6 alkyl or CO2R60, where each R60 independently is C1-C6 alkyl or hydrogen; t is 0, 1, 2, or 4; or CV1V2 is C═V, wherein V is O, NOR80, or NNR81R82; R5 is hydrogen, C1-C6 alkyl or a prodrug moiety R, wherein the C1-C6 alkyl is optionally substituted with 1-5 halo; R6 is halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6S(O)—, C1-C6S(O)2—, wherein the C1-C6 alkyl is optionally substituted with 1-5 halo; or R6 is 4-10 membered cycloalkyl or heterocycle substituted with an R′R′N— moiety wherein each R′ is independently C1-C6 alkyl or hydrogen; R80 is optionally substituted C1-C6 alkyl; R81 and R82 independently are selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, COR83, or CO2R84; R83 is hydrogen or optionally substituted C1-C6 alkyl; R84 is optionally substituted C1-C6 alkyl; k is 0 or 1; and p is 0, 1, 2 or 3.