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. A compound of formula (I): or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is phenyl optionally substituted with 1-3 halo and/or C1-C6 alkoxy, or is a 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, optionally substituted, or is  wherein R7 is C1-C6 alkyl, optionally substituted with 3-5 fluoro groups, or is C3-C6 cycloalkyl; ring B is selected from the group consisting of  wherein R8 is C1-C6 alkyl, —CO—C1-C6 alkyl or a prodrug moiety; X is 0, S, SO, or SO2; is a single or a double bond; ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, —OR1, C1-C6 alkyl and/or C1-C6 alkoxy, wherein the C1-C6 alkyl is optionally substituted with 1-5 halo, C1-C6 alkoxy and/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; and each R1 is hydrogen or a prodrug moiety; 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 1, 2, or 4; or CV1V2 is C═V, wherein V is O, NOR80, or NNR81R82; wherein 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; provided that when ring C is C6-C10 aryl; and ring B is optionally substituted 4-10 membered heterocyclyl; then ring A excludes optionally substituted 5-10 membered heteroaryl.