# US 10,118,934 B2 · Inhibitors of UDP-galactopyranose mutase

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,118,934 B2
- Document ID: US10118934B2
- Status: Granted
- Kind: B2
- Application number: 15/622,972
- Filed: 2017-06-14
- Published: 2017-10-05
- Granted: 2018-11-06
- Earliest claimed: 2014-06-03
- Assignees: Wisconsin Alumni Research Foundation
- Applicants: Wisconsin Alumni Research Foundation; The Regents of the University of California
- Inventors: Laura L. Kiessling; Virginia A. Kincaid; Nir London; Brian K. Shoichet
- Web page: https://patentgrep.com/patent/US10118934B2

## CPC

- C07D 513/04: Ortho-condensed systems
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds and salts thereof which inhibit microbial growth or attenuate the virulence of pathogenic microorganisms and which inhibit UDP-galactopyranose mutase (UGM). Compounds of the invention include triazolothiadiazines, particularly 3, 6, 7-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, and 4-(1H-pyrrol-3-yl) thiazoles, particularly 4-(1,2,5-substituted-1H-pyrrol-3-yl)-2-substituted thiazoles, and salts thereof. Methods for inhibiting growth or attenuating virulence of microbial pathogens including mycobacterium, for example, M. tuberculosis and M. smegmatis and Klebsiella, for example, Klebsiella pneumoniae. Methods for inhibiting eukaryotic human and animal pathogens, and fungi and nematodes in particular. Methods for treatment of infections by prokaryotic and eukaryotic pathogens employing compounds of the invention.

## Claims

### Claim 1

A method for inhibiting uridine 5′-diphosphate-galactopyranose mutase (UGM) which comprises contacting UGM with an amount of one or more compounds of formula II or salts thereof effective for inhibiting the enzyme wherein
formula II is
and salts thereof,
where:
Y is —OR4, or —NH2;
p is 1, 2 or 3;
R4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R10 is an —NR6R7 group or hydrogen, where:
R6 and R7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, sulfonamide (—SO2—N(RF)2), azide, sulfonyl (—SO2—RF), —COORF, —CORF, —CON(RF)2, —N(RF)2, and C1-C6 haloalkyl groups, where RF is hydrogen or a C1-C6 alkyl group.

### Claim 2 (depends on 1)

The method of claim 1, wherein the UGM is that of a mycobacterium or a nematode.

### Claim 3 (depends on 1)

The method of claim 1, wherein contacting comprises contacting a microorganism having UGM or contacting the environment of the microorganism with the one or more compounds of formula II, or salts thereof.

### Claim 4

A method for inhibiting the growth of a microorganism which comprises contacting the microorganism or an environment containing the microorganism with an effective amount of one or more compounds formula II or salts thereof as defined herein, wherein
formula II is
and salts thereof,
where:
Y is —OR4, or —NH2;
p is 1, 2 or 3;
R4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R10 is an —NR6R7 group or hydrogen,
where:
R6 and R7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, sulfonamide (—SO2—N(RF)2), azide, sulfonyl (—SO2—RF), —COORF, —CORF, —CON(RF)2, —N(RF)2, and C1-C6 haloalkyl groups, where RF is hydrogen or a C1-C6 alkyl group,
wherein the microorganism is a bacterium, a fungus, an algae or a nematode.

### Claim 5 (depends on 4)

The method of claim 4, wherein the microorganism is a mycobacterium or a nematode.

### Claim 6 (depends on 4)

The method of claim 4, where, in the compound of formula II, Y is OH, both R5 are methyl, R10 is —NR6R7, R6 is hydrogen and R7 is 1-phenylethyl.

### Claim 7

A method of treating an infection by a microorganism having UGM in an individual in need of such treatment by administering to the individual an effective amount of one or more compounds of formula II or salts thereof, wherein:
formula II is
and salts thereof,
where:
Y is —OR4, or —NH2;
p is 1, 2 or 3;
R4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R10 is an —NR6R7 group or hydrogen,
where:
R6 and R7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, sulfonamide (—SO2—N(RF)2), azide, sulfonyl (—SO2—RF), —COORF,
—CORF, —CON(RF)2, —N(RF)2, and C1-C6 haloalkyl groups, where RF is hydrogen or a C1-C6 alkyl group, wherein the microorganism is a bacterium, a fungus, an algae or a nematode.

### Claim 8 (depends on 7)

The method of claim 7, wherein the infection is tuberculosis.

### Claim 9 (depends on 7)

The method of claim 7, where in the compound of formula II Y is OH, both R5 are methyl, R10 is —NR6R7, R6 is hydrogen and R7 is 1-phenylethyl.

### Claim 10

A pharmaceutically acceptable composition which comprises one or more compounds of formula II or salts thereof and a pharmaceutically acceptable carrier wherein formula II is
and salts thereof,
where:
Y is —OR4, or —NH2;
p is 1, 2 or 3;
R4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R10 is an —NR6R7 group or hydrogen,
where:
R6 and R7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, sulfonamide (—SO2—N(RF)2), azide, sulfonyl (—SO2—RF), —COORF, —CORF,
CON(RF)2, —N(RF)2, and C1-C6 haloalkyl groups, where RF is hydrogen or a C1-C6 alkyl group, and wherein when R4 is an alkyl group, the alkyl has 6-12 carbon atoms, and with the exception that the compound is not compound 10 of formula:
or
compound 14 of formula:

### Claim 11

A compound of formula II or a salt thereof, wherein formula II is
and salts thereof,
where:
Y is —OR4, or —NH2;
p is 1, 2 or 3;
R4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R10 is an —NR6R7 group or hydrogen,
where:
R6 and R7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, sulfonamide (—SO2—N(RF)2), azide, sulfonyl (—SO2—RF), —COORF, —CORF, —CON(RF)2, —N(RF)2, and C1-C6 haloalkyl groups, where RF is hydrogen or a C1-C6 alkyl group,
and wherein when R4 is an alkyl group, the alkyl has 6-12 carbon atoms, and with the exception that the compound is not compound 10 of formula:
or
compound 14 of formula:

### Claim 12 (depends on 11)

A compound or salt thereof of claim 11, where R10 is —NR6R7, R6 is hydrogen or methyl and R7 is a substituted phenyl, benzyl or phenethyl group.

### Claim 13 (depends on 12)

A compound or salt thereof of claim 12, where the phenyl, benzyl or phenethyl group is substituted with one or more halogen, one or more alkoxy, one or more alkyl, or one or more nitro groups.

### Claim 14 (depends on 12)

A compound or salt thereof of claim 12, where the phenyl, benzyl or phenethyl group is substituted with one or more halogen.

### Claim 15 (depends on 4)

The method of claim 4, where in the compound of formula II, Y is OH and R10 is —NR6R7.

### Claim 16 (depends on 10)

The composition of claim 10, where, in the compound of formula II, Y is OH, and R10 is —NR6R7.

### Claim 17 (depends on 11)

The compound or salt of claim 11, wherein Y is OH and R10 is —NR6R7.

### Claim 18

A compound of formula II:
and salts thereof,
wherein Y is OH, both R5 are methyl, R10 is —NR6R7, R6 is hydrogen and R7 is 1-phenylethyl.

### Claim 19 (depends on 18)

A pharmaceutically acceptable composition which comprises a compound of claim 18 or salts thereof and a pharmaceutically acceptable carrier.