# US 10,945,999 B2 · Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of tuberculosis

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- Number: US 10,945,999 B2
- Document ID: US10945999B2
- Status: Granted
- Kind: B2
- Application number: 16/091,774
- Filed: 2017-04-07
- Published: 2019-03-28
- Granted: 2021-03-16
- Earliest claimed: 2016-04-08
- Assignees: Quretech Bio AB; The Washington University In Saint Louis
- Applicants: Quretech Bio AB; Washington University in Saint Louis
- Inventors: Christina L. Stallings; Fredrik Almqvist; Kelly Flentie; James Arthur Dudley Good; Fritiof Ponten
- Web page: https://patentgrep.com/patent/US10945999B2

## CPC

- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/69: Boron compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/06: for tuberculosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure provides a combination comprising: (i) a drug against tuberculosis, or a pharmaceutically acceptable salt thereof, and (ii) a compound of Formula II, or a pharmaceutically acceptable combination thereof. The combination may be used in the treatment and/or prevention of tuberculosis.

## Claims

### Claim 1

A method for treatment of tuberculosis comprising administering to a mammal in need of treatment thereof an effective amount of a drug against tuberculosis,
or a pharmaceutically acceptable salt thereof; and an effective amount of a compound of Formula H
or a pharmaceutically acceptable salt thereof,
wherein
R1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) CH2OH,
d) C(O)NR6aR6b,
e) C(O)NHSO2R7,
f) C(O)OR8,
g) NH2,
h) H,
i)
j)
and
k)
R2 is selected from the group consisting of:
a) H
b) Cl, F, Br or I,
c) CH2OH,
d) C1-C4alkyl, and
e) NY1Y2,
R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano, and methoxy,
b) phenyl substituted with 0,1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano, and trifluoromethyl,
c) aminophenyl substituted with 0,1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, and trifluoromethyl,
d) 2-(3-methyl)phenylmethylene,
e) benzothiophen-2-yl,
f) H or C1-C4-alkyl,
g) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
h) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
R4 is selected from the group consisting of:
a) C1-C4alkyl substituted by 0, 1, 2, 3 or 4 fluoro;
b) C3-C6cycloalkyl,
c) C1-C4alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,
d) C3-C6cycloalkoxy,
e) a 3-, 4-, 5-or 6-membered heterocycle,
f) N-methyl 3-indolyl, and
g) NR9R10,
R5 is selected from the group consisting of:
a) H
b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),
c) benzyl,
d) thienyl,
e) C1-C4alkoxy, and
f) 3-, 4-, 5-or 6-membered heterocycle, and in the above definitions:
R6a is selected from the group consisting of H and C1-C4alkyl,
R6b is selected from the group consisting of H, C1-C4alkoxy, and isonicotinoylamino;
R7 is C1-C4alkyl or phenyl,
R8 represents 2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl),
R9a represents C1-C4 alkyl,
R9b represents C1-C4alkyl,
R10 represents C1-C4alkyl, or
R9 and R10 together form CH2(CH2)m CH2,
Y1 and Y2 each independently represents hydrogen, methyl, CH3S(O)2 or C(O)CH3, or
Y1 and Y2 together form CH2CH2CH2CH2 or CH2CH2CH2CH2CH2,
m is 1, 2 or 3, and
X is S, SO or SO2, thereby treating tuberculosis.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound of Formula II is a compound of Formula IIa or Formula IIb:
wherein R1, R2, R3, R4, R5 and X are as defined in claim 1,
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound of Formula II is a compound of Formula IIa51:
wherein
R1, R2, R3, R4 and X are as defined in claim 1,
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method according to claim 1, wherein X is S or SO.

### Claim 5 (depends on 1)

The method according to claim 1, wherein R1 is C(O)OH, tetrazolyl, or C(O)NHSO2R7.

### Claim 6 (depends on 1)

The method according to claim 1, wherein R2 is H.

### Claim 7 (depends on 1)

The method according to claim 1, wherein R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, cyano, and methoxy, and
b) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano, and trifluoromethyl.

### Claim 8 (depends on 1)

The method according to claim 1, wherein R4 is cyclopropyl.

### Claim 9 (depends on 1)

The method according to claim 1, wherein R5 is H or phenyl substituted with 0, 1, 2 or 3 methyl group(s).

### Claim 10 (depends on 1)

The method according to claim 1, wherein the compound of Formula II is selected from the group consisting of:
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
(3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (N-Methylmethoxyamino) {(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde,
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
(3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,
(3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
(3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide,
{(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde,
(3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
{(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde,
(3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic acid,
7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,
(3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone,
(2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic acid,
(2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic acid,
2-{2-[1-(Hydroxymethyl)propylamino]ethylamino}butyl 7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate,
{7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde,
7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid
(3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
(3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-1H-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound of Formula II is selected from the group consisting of:
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid,
7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic acid, and
(3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic,
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the effective amount of the drug against tuberculosis or the pharmaceutically acceptable salt thereof and the effective amount of a compound of Formula II or the pharmaceutically acceptable salt thereof are provided in separate compositions.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the effective amount of the drug against tuberculosis or the pharmaceutically acceptable salt thereof and the effective amount of a compound of Formula II or the pharmaceutically acceptable salt thereof are provided in a single composition.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the drug against tuberculosis is at least one of the following: isonicotinylhydrazide, bedaquiline, ethionamide, pretomanid, 4-aminosalisalicylic acid, rifampicin, pyrazinamide, or ethambutol.

### Claim 15 (depends on 1)

A method for sensitizing tuberculosis bacteria to treatment with a drug against tuberculosis comprising administering to a mammal in need thereof an effective amount of a compound of Formula II of claim 1, thereby sensitizing tuberculosis bacteria to treatment with a drug against tuberculosis.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the method further comprises, after the step of sensitizing tuberculosis bacteria to treatment with a drug against tuberculosis, administering to the mammal in need thereof an effective amount of a drug against tuberculosis, thereby treating tuberculosis.

### Claim 17 (depends on 1)

The method according to Claim 1, wherein the adminstration of the effective amount of the drug against tuberculosis or the pharmaceutically acceptable salt thereof; and the effective amount of a compound of Formula II or the pharmaceutically acceptable salt thereof comprises administering the effective amount of a compound of Formula II or the pharmaceutically acceptable salt thereof is performed in one step, and administering the effective amount of the drug against tuberculosis or the pharmaceutically acceptable salt thereof is performed in a step separate from the step of administering the effective amount of a compound of Formula II or the pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A method for sensitizing tuberculosis bacteria to treatment with a drug against tuberculosis comprising administering to a mammal in need thereof an effective amount of a compound of Formula II of claim 1, thereby sensitizing tuberculosis bacteria to treatment with a drug against tuberculosis.

### Claim 19 (depends on 15)

The method according to claim 15, wherein the method further comprises contacting the tuberculosis bacteria with an effective amount of the drug against tuberculosis, thereby eradicating the tuberculosis bacteria.

### Claim 20 (depends on 1)

The method according to claim 1, wherein R2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, I,
c) CH2OH, and
d) C1-C4 alkyl.