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US 11,713,335 B2Granted
Aminocoumarin compounds and methods of their use
AssigneePresident and Fellows of Harvard College
InventorsDaniel Kahne, Michael D. Mandler
Life of this patent
Estimating the term…
Abstract
Disclosed are aminocoumarin compounds, pharmaceutical compositions containing aminocoumarin compounds, and methods of their use, e.g., in the treatment of a Gram-negative bacterial infection.
Claims14
A compound of formula (XX):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O or S;
- L is —CO— or —SO2—;
- R1 is unsubstituted phenyl, substituted phenyl, optionally substituted C6-10 aryl C1-4 alkyl, optionally substituted C6-10 aryl C2-4 alkenyl, o-phenylphenyl, optionally substituted C3-10 cycloalkyl, optionally substituted C1-9 heteroaryl comprising at least one nitrogen heteroatom within the heteroaryl ring system, benzofuryl, optionally substituted furyl, or —NHR8,
- wherein the substituted phenyl is substituted:
- (i) at one and only one of its meta position relative to L, with optionally substituted C6-10 aryl, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl comprising an allylic carbon-carbon double bond, optionally substituted C6-10 aryl C1-4 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryloxy, optionally substituted (C6-10 aryl)-C1-6 alkoxy, optionally substituted C3-10 cycloalkyl, optionally substituted C1-9 heteroaryl comprising at least one nitrogen heteroatom within the heteroaryl ring system, optionally substituted C3-9 heterocyclyl, or —SF5;
- or
- (ii) at its para position relative to L with hydroxyl, optionally substituted C6-10 aryl C1-4 alkyl, optionally substituted C6-10 aryl C2-4 alkynyl, optionally substituted C6-10 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryloxy, or optionally substituted (C6-10 aryl)-C1-6 alkoxy;
- and, valency permitting, the substituted phenyl is further optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, hydroxyl, —N(R9)2, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryloxy, or optionally substituted C6-10 aryl;
- each of R2 and R3 is independently hydroxyl, —O—CO—NH—R10, or —O—CO—R11;
- each of R4, R6, and R7 is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C6-10 aryl;
- R5 is halogen, hydroxyl, or optionally substituted C1-6 alkoxy;
- R8 is optionally substituted C6-10 aryl;
- each R9 is independently H or optionally substituted C1-6 alkyl;
- R10, when present, is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-10 cycloalkyl, or optionally substituted C6-10 aryl;
- and
- R11, when present, is optionally substituted C1-9 heteroaryl or optionally substituted C6-10 aryl;
- and
- wherein, when R5 is hydroxyl, then R1 is substituted phenyl or benzofuryl,
- wherein the substituted phenyl is substituted:
- (i) at one and only one of its meta position relative to L, with:
- C1-6 alkyl substituted with aryloxy, arylalkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heteroaryl, heterocyclyloxy, heteroaryloxy, nitro, thiol, ═S, or —NRy2, where each Ry is independently aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl;
- C3-6 alkenyl comprising an allylic carbon-carbon double bond and substituted with aryloxy, arylalkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heteroaryl, heterocyclyloxy, heteroaryloxy, nitro, thiol, ═S, or —NRy2, where each Ry is independently aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl;
- optionally substituted C6-10 aryloxy;
- optionally substituted (C6-10 aryl)-C1-6 alkoxy;
- optionally substituted C3-10 cycloalkyl;
- optionally substituted C1-9 heteroaryl comprising at least one nitrogen heteroatom within the heteroaryl ring system;
- optionally substituted C3-9 heterocyclyl;
- or
- —SF5;
- or
- (ii) at its para position relative to L, with optionally substituted C6-10 aryl C1-4 alkyl, optionally substituted C6-10 aryl C2-4 alkynyl, optionally substituted C3-10 cycloalkyl, or optionally substituted (C6-10 aryl)-C1-6 alkoxy;
- and, valency permitting, the substituted phenyl is further optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, hydroxyl, —N(R9)2, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryloxy, optionally substituted (C6-10 aryl)-C1-6 alkoxy, or optionally substituted C6-10 aryl.
31 more elements
A compound of formula (XX-II):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O or S;
- L is —CO— or —SO2—;
- R1 is substituted phenyl or benzofuryl,
- wherein the substituted phenyl is substituted:
- (i) at one and only one of its meta position relative to L, with:
- C1-6 alkyl substituted with aryloxy, arylalkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heteroaryl, heterocyclyloxy, heteroaryloxy, nitro, thiol, ═S, or —NRy2, where each Ry is independently aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl;
- C3-6 alkenyl comprising an allylic carbon-carbon double bond and substituted with aryloxy, arylalkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heteroaryl, heterocyclyloxy, heteroaryloxy, nitro, thiol, ═S, or —NRy2, where each Ry is independently aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl;
- optionally substituted C6-10 aryloxy;
- optionally substituted (C6-10 aryl)-C1-6 alkoxy;
- optionally substituted C3-10 cycloalkyl;
- optionally substituted C1-9 heteroaryl comprising at least one nitrogen heteroatom within the heteroaryl ring system;
- optionally substituted C3-9 heterocyclyl;
- or
- —SF5;
- or
- (ii) at its para position relative to L, with optionally substituted C6-10 aryl C1-4 alkyl, optionally substituted C6-10 aryl C2-4 alkynyl, optionally substituted C3-10 cycloalkyl, or optionally substituted (C6-10 aryl)-C1-6 alkoxy;
- and, valency permitting, the substituted phenyl is further optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, hydroxyl, —N(R9)2, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryloxy, optionally substituted (C6-10 aryl)-C1-6 alkoxy, or optionally substituted C6-10 aryl;
- each of R2 and R3 is independently hydroxyl, —O—CO—NH—R10, or —O—CO—R11, provided that at least one of R2 and R3 is —O—CO—NH—R10 or —O—CO—R11;
- R4 is hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C6-10 aryl;
- R5 is halogen, hydroxyl, or optionally substituted C1-6 alkoxy;
- R8 is optionally substituted C6-10 aryl;
- each R9 is independently H or optionally substituted C1-6 alkyl;
- R10, when present, is hydrogen, optionally substituted C2-6 alkyl, optionally substituted C3-10 cycloalkyl;
- or optionally substituted C6-10 aryl;
- and
- R11, when present, is optionally substituted C1-9 heteroaryl.
25 more elements
A compound, or a pharmaceutically acceptable salt thereof, selected from the following table:
A compound of formula (XY):
- or a pharmaceutically acceptable salt thereof,
- wherein
- X is O or S;
- L is —CO— or —SO2—;
- each of R2 and R3 is independently hydroxyl, —O—CO—NH—R10, or —O—CO—R11;
- each of R4, R6, and R7 is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C6-10 aryl;
- R5 is halogen, hydroxyl, or optionally substituted C1-6 alkoxy;
- R10, when present, is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-10 cycloalkyl, or optionally substituted C6-10 aryl;
- and
- R11, when present, is optionally substituted C1-9 heteroaryl or optionally substituted C6-10 aryl;
- and
- R1 is selected from the group consisting of
9 more elements
Dependencies are inferred from the claim text.