IP Library › Granted Patent US 10,053,457

Granted Patent B2

US 10,053,457 · App. 15/543,457 · Granted Aug 21, 2018

Hydroxyalkyl-piperazine derivatives as CXCR3 receptor modulators

Inventors: Eva Caroff (Allschwil, CH); Emmanuel Meyer (Allschwil, CH)

Assignee: IDORSIA PHARMACEUTICALS LTD.

C07D417/14

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Quick Facts

Patent No.: US 10,053,457
App. No.: 15/543,457
Granted: Aug 21, 2018
Kind: B2

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Abstract

The invention relates to compounds of Formula (I) wherein n, X, R 1 and R 2 are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.

Claims (108)

1. A compound of Formula (I)

wherein

n represents the integer 1 or 2;

X represents N or CH;

R 1 represents heteroaryl, wherein the heteroaryl is a 5- to 10-membered monocyclic or bicyclic aromatic ring comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen or sulphur, and wherein the heteroaryl is independently unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 3-6 )cycloalkyl; (C 1-4 )alkoxy; (C 1-2 )alkoxy-(C 1-2 )alkyl; (C 1-2 )alkyl-carbonyl; hydroxy-(C 1-4 )alkyl; halogen; (C 1-2 )fluoroalkyl; phenyl; or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic aromatic ring comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen or sulphur, and wherein the heteroaryl is independently unsubstituted or mono-substituted with (C1-4)alkyl; and

R 2 represents (C 3-6 )cycloalkyl, (C 1-4 )alkoxy or (C 1-2 )fluoroalkyl;

or a salt thereof.

2. The compound according to claim 1 , wherein

n represents the integer 1 or 2;

X represents N;

R 1 represents a 5-membered monocyclic heteroaryl group comprising 2 or 3 nitrogen atoms which is independently mono- or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C 1-2 )alkoxy-(C 1-2 )alkyl, hydroxy-(C 1-4 )alkyl or (C 1-2 )fluoroalkyl; or a 9-membered bicyclic aromatic ring comprising 1, 2 or 3 nitrogen atoms which is unsubstituted or mono-substituted with (C1-4)alkoxy or halogen; and

R 2 represents (C 3-6 )cycloalkyl, (C 1-4 )alkoxy or trifluoromethyl;

or a salt thereof.

3. The compound according to claim 1 , wherein

or a salt thereof.

4. The compound according to claim 1 , wherein

R 2 represents trifluoromethyl;

or a salt thereof.

5. The compound according to claim 1 , which is also a compound of Formula (I TA )

wherein

n represents the integer 1 or 2;

R 1A represents hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C 1-2 )alkoxy-(C 1-2 )alkyl, (C 1-2 )alkyl-carbonyl, hydroxy-(C 1-4 )alkyl, (C 1-2 )fluoroalkyl, phenyl or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic aromatic ring comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen or sulphur, and wherein the heteroaryl is independently unsubstituted or mono-substituted with (C 1-4 )alkyl;

R 1B represents hydrogen or (C 1-4 )alkyl; and

R 2 represents (C 3-6 )cycloalkyl, (C 1-4 )alkoxy or (C 1-2 )fluoroalkyl;

or a salt thereof.

6. The compound according to claim 5 , wherein

R 1A represents (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C 1-2 )alkoxy-(C 1-2 )alkyl, hydroxy-(C 1-4 )alkyl or (C 1-2 )fluoroalkyl;

or a salt thereof.

7. The compound according to claim 5 , wherein

R 1A represents (C 1-4 )alkyl or (C 3-6 )cycloalkyl;

or a salt thereof.

8. The compound according to claim 5 , wherein

R 1B represents hydrogen;

or a salt thereof.

9. The compound according to claim 5 , wherein

R 1B represents methyl;

or a salt thereof.

10. The compound according to claim 5 , wherein

R 2 represents trifluoromethyl;

or a salt thereof.

11. The compound according to claim 1 , wherein the compound is:

2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3-Cyclopropyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(S)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(S)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(S)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-piperazin-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone;

2-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-piperazin-1-yl}-ethanone;

1-{(S)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-piperazin-1-yl}-2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(S)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-piperazin-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone;

2-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-Benzoimidazol-1-yl-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(5-Fluoro-indol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(5-methoxy-indol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-phenyl-[1,2,4]triazol-1-yl)-ethanone;

2-(3-Acetyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-pyridin-2-yl-[1,2,4]triazol-1-yl)-ethanone;

2-(3-Ethyl-5-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(5-Ethyl-3-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-imidazo[4,5-b]pyridin-3-yl-ethanone;

2-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone;

2-(3-Cyclobutyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3-tert-Butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3-Cyclopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3-Ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(5-Ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(5-methyl-[1,2,4]triazol-1-yl)-ethanone;

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; or

2-(3-Difluoromethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

or a salt thereof.

12. The compound according to claim 1 , wherein the compound is:

1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone;

2-(3-Ethyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

2-(3-Cyclopropyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

1-{(S)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone;

2-(3-Ethyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone; or

2-(3-Cyclopropyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-ethanone;

or a salt thereof.

13. A pharmaceutical composition comprising, as active principle, the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, formulated as a medicament.

15. A method of treating a disease comprising administering to a subject in need thereof, an effective amount of the compound according to claim 1 , wherein the disease is an autoimmune disorder, inflammatory disease, infectious disease, transplant rejection, fibrosis, neurodegenerative disorder, or cancer.

16. A method of treating a disease comprising administering to a subject in need thereof, an effective amount of the pharmaceutical composition according to claim 13 , wherein the disease is an autoimmune disorder, inflammatory disease, infectious disease, transplant rejection, fibrosis, neurodegenerative disorder, or cancer.

17. The compound according to claim 1 , wherein the compound is:

1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone;