# US 10,479,792 B2 · Compounds

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- Number: US 10,479,792 B2
- Document ID: US10479792B2
- Status: Granted
- Kind: B2
- Application number: 15/750,896
- Filed: 2016-08-03
- Published: 2018-08-09
- Granted: 2019-11-19
- Earliest claimed: 2015-08-07
- Assignees: GiaxoSmithKline Intellectual Property Development Limited; University of Dundee
- Applicants: GlaxoSmithKline Intellectual Property Development Limited; University of Dundee
- Inventors: Stephen Brand; Peter George Dodd; Eun Jung Ko; Maria Marco Martin; Timothy James Miles; Lars Henrik Sandberg; Michael George Thomas; Stephen Thompson
- Web page: https://patentgrep.com/patent/US10479792B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61P 33/14: Ectoparasiticides, e.g. scabicides
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

A compound of Formula (I), or a salt thereof, compositions comprising the compound, processes for its preparation and its use in therapy, for example in the treatment of parasitic diseases such as Chagas disease, Human African Trypanosomiasis (HAT), Animal African trypanosomiasis (AAT) and leishmaniasis, particularly visceral leishmaniasis (VL).

## Claims

### Claim 1

A compound of Formula (I), or a salt thereof,
wherein
A1 is CH;
A2 is selected from CR13 and N;
R1 is selected from C1-C6alkyl, C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl, C5-C6heteroaryl, C1-C6alkoxy, —OC3-C7cycloalkyl and NR10aR10b; wherein C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl, C5-C6heteroaryl and —OC3-C7cycloalkyl are optionally substituted with one to three groups independently selected from hydroxy, methoxy, C1-C3alkyl and halo;
L1 is a linker group selected from —C(O)— and —S(O)n—, wherein n represents 1 to 2;
R3 is selected from hydrogen, halo, methyl, methoxy and cyano;
R4 is selected from hydrogen, halo, methyl, methoxy and cyano;
R2 is selected from hydrogen, halo, Ar, Cy, X, NR5aR5b and —C(O)—R15;
Ar is selected from phenyl and C5-C6heteroaryl, each of which is optionally substituted with one to three groups independently selected from halo and -L2-R7;
L2 is a linker group selected from a bond, —(CH2)m—, —O(CH2)m—, —C2-C4alkenyl-, —OC2-C4alkenyl-, —(CH2)p—NH—(CH2)q—, and —(CH2)pC(O)—(CH2)q—; wherein m represents 1 to 4 and p and q independently represent 0 to 4;
R7 is selected from hydrogen; hydroxy; NR8aR8b; C4-C7heterocycloalkyl optionally substituted with one or two C1-C3alkyl groups; C3-C7cycloalkyl; C1-C6alkoxy optionally substituted with one NR14aR14b group; and phenyl optionally substituted with one to three groups independently selected from halo, methoxy and methyl;
Cy is selected from C3-C7cycloalkyl, C4-C7heterocycloalkyl, C5-C7cycloalkenyl and C5-C7heterocycloalkenyl, each of which is optionally substituted with one to three groups independently selected from C1-C3alkyl, C1-C3alkoxy, C4-C7heterocycloalkyl, NR11aR11b, ═O, —C(O)—R15 and —C(O)O—R15;
X is selected from C1-C6alkyl, C2-C6alkenyl and C1-C6alkoxy, each of which is optionally substituted with one to three groups independently selected from hydroxy, methoxy, halo, NR13aR13b and C4-C7heterocycloalkyl, wherein C4-C7heterocycloalkyl is optionally substituted with one to three C1-C3alkyl groups;
R5a is selected from hydrogen; C1-C6alkyl optionally substituted with one group selected from Ar and Cy; —C(O)—R9; —C(O)—OR9; and —SO2—R9;
R5b is selected from hydrogen and C1-C3alkyl;
R8a and R8b are independently selected from hydrogen and C1-C3alkyl;
R9 is selected from C1-C6alkyl, C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl and C5-C6heteroaryl;
R10a and R10b are independently selected from hydrogen and C1-C3alkyl;
R11a and R11b are independently selected from hydrogen and C1-C3alkyl;
R12 is selected from hydrogen, halo and methyl;
R13 is selected from hydrogen, C1-C3alkyl, —C(O)—C4-C7heterocycloalkyl, —C(O)—C1-C3alkyl and —C(O)—C3-C7cycloalkyl;
R13a and R13b are independently selected from hydrogen and C1-C3alkyl;
R14a and R14b are independently selected from hydrogen and C1-C3alkyl; and
R15 is selected from C1-C6alkyl, Ar, C3-C7cycloalkyl and C4-C7heterocycloalkyl.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is C4-C7heterocycloalkyl optionally substituted with one C1-C3alkyl or with one or two halo.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein L1 is —C(O)—.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R2 is selected from hydrogen, halo, Ar, Cy, and X.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R2 is Cy and Cy is optionally substituted C4-C7heterocycloalkyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R3 is hydrogen or halo and R4 is hydrogen, halo, or methyl.

### Claim 7 (depends on 1)

A compound of Formula (I) according to claim 1, which is

### Claim 8

A compound of Formula (IA), or a salt thereof,
wherein
A1 is CH;
A2 is selected from CR13 and N;
R1 is selected from C1-C6alkyl, C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl, C5-C6heteroaryl, C1-C6alkoxy, —OC3-C7cycloalkyl and NR10aR10b; wherein C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl, C5-C6heteroaryl and —OC3-C7cycloalkyl are optionally substituted with one to three groups selected from hydroxy, methoxy, C1-C3alkyl and halo;
L1 is a linker group selected from —C(O)— and —S(O)n—; wherein n represents 1 to 2;
R3 is selected from hydrogen, halo, methyl, methoxy and cyano;
R4 is selected from hydrogen, halo, methyl, methoxy and cyano;
R2 is selected from hydrogen, halo, Ar, Cy, X and NR5aR5b;
Ar is selected from phenyl and C5-C6heteroaryl, each of which is optionally substituted with one to three groups independently selected from NR6aR6b and -L2-R7;
L2 is a linker group selected from a bond, —(CH2)m—, —O(CH2)m—, —C2-C4alkenyl- and —OC2-C4alkenyl-; wherein m represents 1 to 4;
R7 is selected from hydrogen, C4-C7heterocycloalkyl, C3-C7cycloalkyl, C1-C6alkoxy, hydroxy and NR8aR8b;
Cy is selected from C3-C7cycloalkyl, C4-C7heterocycloalkyl, C5-C7cycloalkenyl and C5-C7heterocycloalkenyl, each of which is optionally substituted with one to three groups independently selected from C1-C3alkyl, C4-C7heterocycloalkyl and NR11aR11b;
X is selected from C1-C6alkyl, C2-C6alkenyl and C1-C6alkoxy, each of which is optionally substituted with one to three groups independently selected from hydroxy, methoxy, halo and C4-C7heterocycloalkyl, wherein C4-C7heterocycloalkyl is optionally substituted with one to three C1-C3alkyl groups;
R5a is selected from hydrogen, C1-C6alkyl, —C(O)—R9, —C(O)—OR9 and —SO2—R9;
R5b is selected from hydrogen and C1-C3alkyl;
R6a and R6b are independently selected from hydrogen and C1-C3alkyl;
R8a and R8b are independently selected from hydrogen and C1-C6alkyl;
R9 is selected from C1-C6alkyl, C3-C7cycloalkyl, C4-C7heterocycloalkyl, phenyl and C5-C6heteroaryl;
R10a and R10b are independently selected from hydrogen and C1-C3alkyl;
R11a and R11b are independently selected from hydrogen and C1-C3alkyl;
R12 is selected from hydrogen, halo and methyl; and
R13 is selected from hydrogen and C1-C3alkyl.

### Claim 9 (depends on 1)

A compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising (a) a compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A combination comprising (a) a compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.

### Claim 12 (depends on 1)

A method of treatment of a parasitic disease selected from Chagas disease, Human African Trypanosomiasis, Animal African trypanosomiasis and leishmaniasis, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The method of treatment according to claim 12, wherein the mammal is a human.

### Claim 14 (depends on 12)

The method of treatment according to claim 12, wherein the leishmaniasis is visceral leishmaniasis.

### Claim 15 (depends on 8)

A compound of Formula (IA) according to claim 8, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 8)

A pharmaceutical composition comprising (a) a compound of Formula (IA) according to claim 8, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

### Claim 17 (depends on 8)

A combination comprising (a) a compound of Formula (IA) according to claim 8, or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.

### Claim 18 (depends on 8)

A method of treatment of a parasitic disease selected from Chagas disease, Human African Trypanosomiasis, Animal African trypanosomiasis and leishmaniasis, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (IA) according to claim 8, or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The method of treatment according to claim 18, wherein the mammal is a human.

### Claim 20 (depends on 18)

The method of treatment according to claim 18, wherein the leishmaniasis is visceral leishmaniasis.

### Claim 21 (depends on 11)

The combination of claim 11, wherein the at least one additional therapeutic agent is selected from the group consisting of an anti-leishmaniasis agent, an anti-parasitic agent, an anti-AIDS agent, an anti-HIV agent, and an anti-TB agent.

### Claim 22 (depends on 17)

The combination of claim 17, wherein the at least one additional therapeutic agent is selected from the group consisting of an anti-leishmaniasis agent, an anti-parasitic agent, an anti-AIDS agent, an anti-HIV agent, and an anti-TB agent.

### Claim 23 (depends on 11)

The combination of claim 11, wherein the at least one additional therapeutic agent is an anti-leishmaniasis agent selected from the group consisting miltefosine, paromomycin, sodium stibugluconate, meglumine antimoniate, amphotericin B deoxycholate, and liposomal amphotericin B.

### Claim 24 (depends on 17)

The combination of claim 17, wherein the at least one additional therapeutic agent is an anti-leishmaniasis agent selected from the group consisting miltefosine, paromomycin, sodium stibugluconate, meglumine antimoniate, amphotericin B deoxycholate, and liposomal amphotericin B.