CCR6 RECEPTOR MODULATORS
The present invention relates to compounds of Formula (I), their synthesis and use as CCR6 receptor modulators for the prevention or treatment of e.g. inflammatory/autoimmune diseases/disorders and cancer.
1 . A compound of Formula (I)
wherein
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl;
L- represents
*—C≡C—C 0-2 -alkylene-**, optionally mono-substituted with hydroxy; wherein the asterisk (*) denotes the attachment point to the pyridinyl ring and two asterisks (**) denote the attachment point to R 4 ; or
oxadiazol-diyl; and
R 4 represents
C 3-7 -cycloalkyl;
saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system, wherein one ring carbon atom is optionally replaced with a nitrogen atom; or
6-membered heteroaryl containing one or two ring nitrogen atoms;
wherein R 4 independently is unsubstituted or mono-substituted with hydroxy, hydroxy-C 1-3 -alkyl, carbamoyl, C 1-3 -alkyl-carbonyl-amino, or C 1-3 -alkyl-carbonyl; or
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents isopropyl; and
L-R 4 represents 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl; and
L-R 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl;
or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 , wherein
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl;
-L- represents
*—C≡C—C 0-2 -alkylene-**, optionally mono-substituted with hydroxy; wherein the asterisk (*) denotes the attachment point to the pyridinyl ring and two asterisks (**) denote the attachment point to R 4 ; or
oxadiazol-diyl; and
R 4 represents
mono-substituted C 3-7 -cycloalkyl, wherein the substituent is selected from hydroxy, carbamoyl, or C 1-3 -alkyl-carbonyl-amino;
saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system, wherein one ring carbon atom is optionally replaced with a nitrogen atom, wherein said 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system independently is mono-substituted with hydroxy, hydroxy-C 1-3 -alkyl, carbamoyl, C 1-3 -alkyl-carbonyl-amino, or C 1-3 -alkyl-carbonyl; or
unsubstituted 6-membered heteroaryl containing one or two ring nitrogen atoms;
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents isopropyl; and
-L-R 4 represents 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl; and
-L-R 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl;
or a pharmaceutically acceptable salt thereof.
3 . A compound according to claim 1 , wherein
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl;
L- represents
*—C≡C—C 0-2 -alkylene-**, optionally mono-substituted with hydroxy; wherein the asterisk (*) denotes the attachment point to the pyridinyl ring and two asterisks (**) denote the attachment point to R 4 ;_and
R 4 represents
mono-substituted C 3-7 -cycloalkyl, wherein the substituent is hydroxy; or
unsubstituted 6-membered heteroaryl containing one or two ring nitrogen atoms;
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl;
-L- represents
oxadiazol-diyl; and
R 4 represents
mono-substituted C 3-7 -cycloalkyl, wherein the substituent is selected from hydroxy, carbamoyl, or C 1-3 -alkyl-carbonyl-amino; or
saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system, wherein one ring carbon atom is optionally replaced with a nitrogen atom, wherein said 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system independently is mono-substituted with hydroxy, hydroxy-C 1-3 -alkyl, carbamoyl, C 1-3 -alkyl-carbonyl-amino, or C 1-3 -alkyl-carbonyl;
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents isopropyl; and
-L-R 4 represents 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or
R 1 represents C 1-3 -alkyl;
R 2 represents C 1-4 -alkyl;
R 3 represents 2,2,2-trifluoro-ethyl; and
-L-R 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl;
or a pharmaceutically acceptable salt thereof.
4 . A compound according to claim 1 , wherein R 1 represents methyl; or a pharmaceutically acceptable salt thereof.
5 . A compound according to claim 1 , wherein R 2 represents methyl; or a pharmaceutically acceptable salt thereof.
6 . A compound according to claim 1 , wherein
R 1 represents methyl;
R 2 represents methyl;
R 3 represents 2,2,2-trifluoro-ethyl; and
-L-R 4 represents 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-5-yl, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl;
R 1 represents methyl;
R 2 represents methyl;
R 3 represents isopropyl; and
-L-R 4 represents 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or
R 1 represents methyl;
R 2 represents methyl;
R 3 represents 2,2,2-trifluoro-ethyl; and
-L-R 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl;
or a pharmaceutically acceptable salt thereof.
7 . A compound according to claim 1 , wherein the asymmetric carbon atom bearing the hydroxy group has the absolute configuration depicted in Formula (II)
or a pharmaceutically acceptable salt thereof.
8 . A compound according to claim 1 , which is
trans-4-[3-(5-{(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol;
cis-4-[3-(5-{(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol;
(R)-(1,3-Dimethyl-azetidin-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-3-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol;
N-[3-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[1.1.1]pent-1-yl]-acetamide;
4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octan-1-ol;
2-[5-(5-{(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-methyl-propan-1-ol;
1-[6-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-2-aza-spiro[3.3]hept-2-yl]-ethanone;
trans-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide;
cis-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide;
cis-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide;
trans-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide;
(R)-(1,3-Dimethyl-azetidin-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol;
(R)-4-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol;
(S)-4-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol;
trans-4-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol;
cis-4-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol;
4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide;
cis-4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide; or
trans-4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide;
or a pharmaceutically acceptable salt thereof.
9 . A compound according to claim 1 , which is
4-[3-(5-{(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-bicyclo[2.2.2]octane-1-carboxylic acid amide; or
N-{4-[3-(5-{(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-trans-cyclohexyl}-acetamide;
or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and further comprising at least one pharmaceutically acceptable carrier.
11 - 13 . (canceled)
14 . A method for the prevention or treatment of cancer; or inflammatory/autoimmune diseases, conditions, or disorders; said method comprising administering to a subject in need of said prevention or treatment a pharmaceutically active amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
15 . (canceled)
16 . A compound according to claim 1 , wherein
R 1 represents methyl;
R 2 represents methyl;
R 3 represents isopropyl; and
-L-R 4 represents 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl;
or a pharmaceutically acceptable salt thereof.
17 . A compound according to claim 1 , wherein
R 1 represents methyl;
R 2 represents methyl;
R 3 represents isopropyl; and
-L-R 4 represents 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazole-3-yl;
or a pharmaceutically acceptable salt thereof.
18 . A compound, which is
cis-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide;
or a pharmaceutically acceptable salt thereof.
19 . A compound, which is
trans-N-[4-(3-{5-[(R)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide;
or a pharmaceutically acceptable salt thereof.
20 . A pharmaceutical composition comprising a compound according to claim 8 or a pharmaceutically acceptable salt thereof and further comprising at least one pharmaceutically acceptable carrier.
21 . A pharmaceutical composition comprising a compound according to claim 18 or a pharmaceutically acceptable salt thereof and further comprising at least one pharmaceutically acceptable carrier.
22 . A pharmaceutical composition comprising a compound according to claim 19 or a pharmaceutically acceptable salt thereof and further comprising at least one pharmaceutically acceptable carrier.
23 . A method for the prevention or treatment of cancer; or inflammatory/autoimmune diseases, conditions, or disorders; said method comprising administering to a subject in need of said prevention or treatment a pharmaceutically active amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof.
24 . A method for the prevention or treatment of cancer; or inflammatory/autoimmune diseases, conditions, or disorders; said method comprising administering to a subject in need of said prevention or treatment a pharmaceutically active amount of a compound according to claim 18 or a pharmaceutically acceptable salt thereof.
25 . A method for the prevention or treatment of cancer; or inflammatory/autoimmune diseases, conditions, or disorders; said method comprising administering to a subject in need of said prevention or treatment a pharmaceutically active amount of a compound according to claim 19 or a pharmaceutically acceptable salt thereof.