Piperidine CXCR7 receptor modulators
The present invention relates to piperidine derivatives of formula (I) wherein Ar 1 , Ar 2 , R Ar1 , R 1 , R 2 , and R 3 are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.
1. A compound of formula (I)
wherein
the two substituents of the piperidine ring: R 1 —CO— and —NH—CO—Ar 1 —Ar 2 , are in relative trans-configuration;
Ar 1 represents an unsubstituted 5-membered heteroarylene group containing one sulfur ring atom and one or two nitrogen ring atoms, wherein the —NH—CO— group and Ar 2 are attached in meta arrangement to ring atoms of Ar 1 ;
Ar 2 represents phenyl, or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from fluoro, chloro, methyl, cyano, methoxy, or (C 1 )fluoroalkyl;
R 1 represents R N1 R N2 N—, wherein
R N1 represents
hydrogen;
(C 1-6 )alkyl;
(C 1-6 )alkyl which is mono-substituted with
hydroxy;
(C 1-3 )alkoxy;
2-hydroxy-ethoxy;
—CO—NH 2 ;
—SO 2 —(C 1-3 )alkyl;
cyano;
(C 1-3 )fluoroalkoxy;
—NR N3 R N4 , wherein R N3 and R N4 independently represent hydrogen or (C 1-4 )alkyl;
(C 2-6 )alkynyl;
(C 2-5 )fluoroalkyl;
(C 1-4 )alkoxy;
2-(2-oxo-pyrrolidin-1-yl)-ethyl;
a group -L 1 -Cy 1 ; wherein
L 1 represents a direct bond, —(C 1-3 )alkylene-, or —(C 3-5 )cycloalkylene-; and
Cy 1 represents (C 3-6 )cycloalkyl, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl independently is unsubstituted; or mono-substituted with fluoro, methyl, or hydroxy, —CO—(C 1-4 )alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;
a group -L 2 -Ar 3 , wherein
L 2 represents a direct bond, —(C 1-4 )alkylene-; *—(C 3-5 )cycloalkylene-(C 0-2 )alkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; *—(C 1-2 )alkylene-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached;
or —(C 1-3 )alkylene- which is mono-substituted with hydroxy, trifluoromethyl, or —CO—(C 1-4 )alkoxy; and
Ar 3 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, hydroxy, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
and R N2 independently represents hydrogen, (C 1-4 alkyl, or (C 2-3 )fluoroalkyl;
or R N1 and R N2 together with the nitrogen atom to which they are attached to form a 4- to 6-membered ring selected from
azetidinyl, pyrrolidinyl or piperidinyl; each independently
unsubstituted;
or mono-substituted with fluoro, methyl, or hydroxy;
or di-substituted with fluoro;
or mono-substituted with Ar 4 , wherein Ar 4 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; or
morpholinyl;
R 2 represents
hydrogen;
(C 1-6 )alkyl;
(C 2-6 )alkyl which is mono-substituted with (C 1-3 )alkoxy, or hydroxy;
(C 3-5 )alkenyl;
cyano-methyl;
(C 2-3 )fluoroalkyl;
(C 3-8 )cycloalkyl-(C 0-3 )alkyl; wherein the (C 3-8 )cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C 1-3 )alkyl, fluoro, hydroxy, hydroxy-(C 1-3 )alkyl, (C 1-3 )alkoxy, or (C 1-3 )fluoroalkyl;
thietan-3-yl;
(C 3-8 )cycloalkenyl-(C 1-3 )alkyl; or
Ar 5 —CH 2 — wherein Ar 5 represents phenyl, or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; and
R 3 represents hydrogen, or methyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of formula (I) as defined for claim 1 which are also compounds of Formula (I S ), wherein the two substituents of the piperidine ring: R 1 —CO— and —NH—CO—Ar 1 —Ar 2 , are in relative trans-configuration, wherein the absolute configuration of the two chiral carbon atoms in position 3 and 4 of the piperidine ring is (3S,4S):
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 ; wherein R 3 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 ; wherein Ar 1 represents [1,3,4]thiadiazol-2,5-diyl or isothiazol-3,5-diyl;
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 ; wherein Ar 2 represents phenyl which is mono-, di- or tri-substituted; wherein one or two of said substituents is/are independently selected from fluoro, chloro, and methyl, and the remaining, if present, is/are fluoro;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 ; wherein R 1 represents R N1 R N2 N—, wherein
R N1 represents
(C 1-6 )alkyl;
(C 1-6 )alkyl which is mono-substituted with
hydroxy;
(C 1-3 )alkoxy;
2-hydroxy-ethoxy;
—CO—NH 2 ;
—SO 2 —(C 1-3 )alkyl;
cyano;
(C 1-3 )fluoroalkoxy;
—NR N3 R N4 , wherein R N3 and R N4 independently represent hydrogen or (C 1-4 )alkyl;
(C 2-6 )alkynyl;
(C 2 -s)fluoroalkyl;
2-(2-oxo-pyrrolidin-1-yl)-ethyl;
a group -L 1 -Cy 1 ; wherein
L 1 represents a direct bond, —(C 1-3 )alkylene-, or —(C 3-5 )cycloalkylene-; and
Cy 1 represents (C 3-6 )cycloalkyl, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl independently is unsubstituted: or mono-substituted with fluoro, methyl, hydroxy, CO—(C 1-4 )alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;
a group -L 2 -Ar 3 , wherein
L 2 represents a —(C 1-4 )alkylene-; —(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom; *—(C 3-5 )cycloalkylene-(C 1-2 )alkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; *—(C 1-2 )alkylene-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached;
or —(C 1-3 )alkylene- which is mono-substituted with hydroxy or trifluoromethyl; and
Ar 3 represents phenyl, or 5-membered heteroaryl containing one oxygen atom and one or two nitrogen atoms, or 6-membered heteroaryl containing one or two nitrogen atoms; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
and R N2 independently represents hydrogen, or (C 1-4 )alkyl;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 ; wherein
R 1 represents R N1 R N2 N—, wherein
R N1 represents
(C 3-6 )cycloalkyl, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl independently is unsubstituted, or mono-substituted with fluoro, methyl, or hydroxy, or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;
(C 3-6 )cycloalkyl-(C 1-3 )alkylene-, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom;
(C 3-6 )cycloalkyl-(C 3-5 )cycloalkylene-;
phenyl-(C 1-4 )alkylene- wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy;
phenyl-(C 1-3 )alkylene- wherein said —(C 1-3 )alkylene- is mono-substituted with hydroxy;
phenyl-(C 3-5 )cycloalkylene-; wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, hydroxy, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy;
phenyl-(C 3-5 )cycloalkylene-(C 1-2 )alkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-substituted with halogen;
phenyl-(C 1-2 )alkylene-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom;
5-membered heteroaryl-(C 1-3 )alkylene-, wherein said 5-membered heteroaryl contains one oxygen atom and one or two nitrogen atoms; and wherein said 5-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy;
6-membered heteroaryl-(C 1-4 )alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
6-membered heteroaryl-(C 1-3 )alkylene-, wherein said —(C 1-3 )alkylene- is mono-substituted with hydroxy or trifluoromethyl; wherein said 6-membered heteroaryl contains one or two nitrogen atoms; or
6-membered heteroaryl-(C 3-5 )cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
6-membered heteroaryl-(C 3-5 )cycloalkylene-(C 1-2 )alkylene- wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted;
and R N2 independently represents hydrogen, or (C 1-4 )alkyl;
or R N1 represents (C 1-3 )alkyl; and R N2 represents hydrogen, or methyl;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 5 ; wherein R 1 represents R N1 R N2 N—, wherein
R N1 represents
(C 3-6 )cycloalkyl-(C 1-3 )alkylene-, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom;
phenyl-(C 1-4 )alkylene- wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy;
phenyl-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, hydroxy, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy;
6-membered heteroaryl-(C 1-4 )alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
6-membered heteroaryl-(C 3-5 )cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
and R N2 independently represents hydrogen, or (C 1-4 )alkyl;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 5 ; wherein R 1 represents R N1 R N2 N—, wherein
R N1 represents
6-membered heteroaryl-(C 1-4 )alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
6-membered heteroaryl-(C 3-5 )cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;
and R N2 independently represents hydrogen or methyl;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 7 ; wherein R 2 represents
(C 3-8 )cycloalkyl-(C 1-3 )alkyl, wherein the (C 3-8 )cycloalkyl is unsubstituted; or mono-substituted wherein the substituent is (C 1-3 )alkyl, fluoro, or (C 1-3 )fluoroalkyl; or di-substituted with fluoro; or
(C 3-8 )cycloalkyl, wherein the (C 3-8 )cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C 1-3 )alkyl, or fluoro;
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 8 ; wherein R 2 represents
unsubstituted (C 3-8 )cycloalkyl-(C 1-3 )alkyl; or
unsubstituted (C 3-6 )cycloalkyl; or
(C 3-8 )cycloalkyl, wherein the (C 3-8 )cycloalkyl is di-substituted with fluoro; or
(C 3-8 )cycloalkyl-(C 1-3 )alkyl; wherein the (C 3-8 )cycloalkyl is mono-substituted with methyl, fluoro, or (C 1 )fluoroalkyl; or di-substituted with fluoro;
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 which is:
(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide;
(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or
(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; wherein said compound is in free form.
15. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; wherein said compound is in pharmaceutically acceptable salt form.
16. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
17. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 11 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
18. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 12 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
19. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 13 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
20. A method for the treatment of cancer; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11 , or a pharmaceutically acceptable salt thereof.
21. A method of treating tumors comprising administering an effective amount of the compound of formula (Ia) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating the CXCL11/CXCL12 receptor pathway.
22. A method for the treatment of fibrosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11 , or a pharmaceutically acceptable salt thereof.
23. A method for the treatment of autoimmune disorders which have an inflammatory component selected from inflammatory demyelinating diseases, multiple sclerosis (MS), Guillain Barré syndrome, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), lupus nephritis, and auto-immune encephalomyelitis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11 , or a pharmaceutically acceptable salt thereof.
24. A method for the treatment of inflammatory diseases selected from
lung inflammatory diseases selected from asthma, chronic obstructive pulmonary disorder (COPD), and acute lung injury; and
atherosclerosis;
comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11 , or a pharmaceutically acceptable salt thereof.
25. A method for the treatment of cancer; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13 , or a pharmaceutically acceptable salt thereof.
26. A method of treating tumors comprising administering an effective amount of the compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating the CXCL11/CXCL12 receptor pathway.
27. A method for the treatment of fibrosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13 , or a pharmaceutically acceptable salt thereof.
28. A method for the treatment of autoimmune disorders which have an inflammatory component selected from inflammatory demyelinating diseases, multiple sclerosis (MS), Guillain Barré syndrome, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), lupus nephritis, and auto-immune encephalomyelitis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13 , or a pharmaceutically acceptable salt thereof.
29. A method for the treatment of inflammatory diseases selected from
lung inflammatory diseases selected from asthma, chronic obstructive pulmonary disorder (COPD), and acute lung injury; and
atherosclerosis;
comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13 , or a pharmaceutically acceptable salt thereof.