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US 2021/0206715 A1Published application
Benzoylglycine Derivatives and Methods of Making and Using Same
AssigneesDuke University, The University of North Carolina at Chapel Hill
InventorsPei Zhou, Eric J. Toone, Robert A. Nicholas, Ramesh Gopalaswamy, Xiaofei Liang, Frank Navas, III
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Abstract
Disclosed are compounds of formulae: and pharmaceutically acceptable salts thereof, wherein the variables, R1, R2, R3, R4, R5, R6, R7, R11, R12, R13, R14, R15, R16, R17, n, and m are defined herein. These compounds are useful for treating Gram-negative bacteria infections. Also disclosed are methods of making these compounds.
Claims20
A method for preparing a compound for treating Gram-negative bacterial infections, the method comprising coupling a compound of formula:
- with a compound of formula:
- wherein
- Y represents aryl optionally substituted with R8, heteroaryl optionally substituted with R8, or heterocyclyl optionally substituted with R8;
- m is an integer 0, 1, 2, 3, or 4;
- n is an integer 0, 1, 2, 3, or 4;
- R1 is hydrogen, C1-C6 alkyl optionally substituted with R9, aryl optionally substituted with R8, heteroaryl optionally substituted with R9, or heterocyclyl optionally substituted with R8;
- each R7 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- each R8 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
- or two R8 groups when attached to the same carbon atom form ═O;
- each R9 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- or two R9 groups when attached to the same carbon atom form ═O;
- wherein R10 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R19, (C3-C8 cycloalkyl)C1-C6 alkyl- optionally substituted with R19, or heterocyclyl optionally substituted with R19;
- R11 is —C≡C—R10, C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R18, (C3-C8 cycloalkyl)C1-C6 alkyl- optionally substituted with R18, or heterocyclyl optionally substituted with R18;
- each R17 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- each R18 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-(C1-C6 alkoxy), —C1-C6 alkyl-NH2, —C1-C6 alkyl-NH—C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, —C1-C6 alkyl-NH(SO2C1-C6 alkyl), —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —NH(SO2C1-C6 alkyl), —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C1-C6 alkyl-CONH2, —C1-C6 alkyl-CON(C1-C6 alkyl), —C1-C6 alkyl-CON(C1-C6 alkyl)2, —C1-C6 alkyl-CONH—OH, —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, and —C1-C6 alkyl-CO2(C1-C6 alkyl);
- or
- two R18 groups when attached to the same carbon atom form ═O;
- and
- each R19 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-(C1-C6 alkoxy), —C1-C6 alkyl-NH2, —C1-C6 alkyl-NH—C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, —C1-C6 alkyl-NH(SO2C1-C6 alkyl), —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —NH(SO2C1-C6 alkyl), —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C1-C6 alkyl-CONH2, —C1-C6 alkyl-CON(C1-C6 alkyl), —C1-C6 alkyl-CON(C1-C6 alkyl)2, —C1-C6 alkyl-CONH—OH, —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, and —C1-C6 alkyl-CO2(C1-C6 alkyl);
- or
- two R19 groups when attached to the same carbon atom form ═O.
18 more elements
A method for preparing a compound according to the following formula and/or a pharmaceutically acceptable salt thereof:
- wherein
- q is an integer 0, 1, 2, 3, or 4;
- R21 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R28, (C3-C8 cycloalkyl)C1-C6 alkyl- optionally substituted with R28, aryl optionally substituted with R28, (aryl)C1-C6 alkyl- optionally substituted with R28, heteroaryl optionally substituted with R28, (heteroaryl)C1-C6 alkyl- optionally substituted with R28, heterocyclyl optionally substituted with R28, or (heterocycloalkyl)C1-C6 alkyl- optionally substituted with R28,
- R22 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
- R23 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
- R24 is C1-C6 alkyl or C1-C6 haloalkyl;
- R25 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
- R26 is hydrogen or C1-C6 alkyl;
- each R27 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- and
- each R28 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-(C1-C6 alkoxy), —C1-C6 alkyl-NH2, —C1-C6 alkyl-NH—C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, —C1-C6 alkyl-NH(SO2C1-C6 alkyl), —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —NH(SO2C1-C6 alkyl), —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C1-C6 alkyl-CONH2, —C1-C6 alkyl-CON(C1-C6 alkyl), —C1-C6 alkyl-CON(C1-C6 alkyl)2, —C1-C6 alkyl-CONH—OH, —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, and —C1-C6 alkyl-CO2(C1-C6 alkyl);
- or
- two R28 groups when attached to the same carbon atom form ═O;
- the method comprising reacting haloethynyl compound of formula:
- wherein X is halogen with
- in the presence of transition metal catalyst and base.
13 more elements
A method for inhibiting deacetylase enzyme in Gram-negative bacteria and/or treating Gram-negative bacterial infection, the method comprising:
- administering to a subject a composition comprising one or more compounds of formula (I):
- wherein
- Y represents aryl optionally substituted with R8, alkyne optionally substituted with R8, heteroaryl optionally substituted with R8, or heterocyclyl optionally substituted with R8;
- n is an integer 0, 1, 2, 3, or 4;
- R1 is hydrogen, C1-C6 alkyl optionally substituted with R9, aryl optionally substituted with R9, heteroaryl optionally substituted with R9, or heterocyclyl optionally substituted with R9;
- R2 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
- R3 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
- R4 is C1-C6 haloalkyl;
- R5 is independently selected from the group consisting of halogen, —NO2, —ON, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
- R6 is hydrogen or C1-C6 alkyl;
- each R7 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- each R8 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
- or two R8 groups when attached to the same carbon atom form ═O;
- and
- each R9 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- or two R9 groups when attached to the same carbon atom form ═O.
13 more elements
Dependencies are inferred from the claim text.