Cyclic amidine compounds for the treatment of autoimmune disease
The present invention relates to compounds of formula (I), wherein R 1 , R 2 and R 3 are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds as antagonist of TLR7 and/or TLR8 and/or TLR9 in the treatment of autoimmune diseases as well as auto-inflammation diseases.
1. A compound of formula (I),
wherein:
R 1 is
wherein R 8 is cyano, C 1-6 alkyl, halogen, haloC 1-6 alkyl or nitro;
R 2 is C 1-6 alkyl, C 3-7 cycloalkyl or haloC 1-6 alkyl; and
R 3 is
wherein:
R 4 and R 5 are independently selected from H and C 1-6 alkyl;
R 6 is H, halogen, C 1-6 alkyl or heterocyclyl;
R 7 is H or C 1-6 alkyl;
m is 0, 1, 2 or 3; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein:
R 1 is
wherein R 8 is cyano;
R 2 is C 1-6 alkyl; and
R 3 is
wherein:
R 4 is H;
R 5 is H;
R 6 is H, halogen, tetrahydropyridinyl, diazaspiro[4.4]nonanyl,
hydroxypiperidinyl, C 1-6 alkylpiperazinyl, morpholinyl, piperazinyl or piperidinyl;
R 7 is H; and
m is 1 or 2;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein:
R 1 is
wherein R 8 is cyano;
R 2 is methyl;
R 3 is
wherein:
R 4 is H;
R 5 is H;
R 6 is H, bromo, tetrahydropyridinyl, 2,7-diazaspiro[4.4]nonan-2-yl, hydroxypiperidinyl, methylpiperazinyl, morpholinyl, piperazinyl or piperidinyl;
R 7 is H; and
m is 1 or 2;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 2 , or pharmaceutically acceptable salt thereof, wherein R 6 is C 1-6 alkylpiperazinyl or piperazinyl.
5. A compound according to claim 4 , or pharmaceutically acceptable salt thereof, wherein R 6 is methylpiperazinyl or piperazinyl.
6. A compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein n is 1.
7. A compound according to claim 2 , selected from:
5-[(2R,6R)-2-(5-bromo-3,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-(6-bromo-3,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-(1,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-(7-bromo-3,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-(8-bromo-3,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(5-piperazin-1-yl-3,4-dihydroquinazolin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(6-piperazin-1-yl-3,4-dihydroquinazolin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(7-piperazin-1-yl-3,4-dihydroquinazolin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(8-piperazin-1-yl-3,4-dihydroquinazolin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-[5-(4-hydroxy-1-piperidyl)-3,4-dihydroquinazolin-2-yl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(5-morpholino-3,4-dihydroquinazolin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-[5-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-2-yl]morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-[5-(2,7-diazaspiro[4.4]nonan-2-yl)-3,4-dihydroquinazolin-2-yl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-(6-bromo-4,5-dihydro-3H-1,3-benzodiazepin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-[6-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydro-3H-1,3-benzodiazepin-2-yl]morpholin-4-yl]quinoline-8-carbonitrile;
5-[(2R,6R)-2-methyl-6-(7-piperazin-1-yl-4,5-dihydro-3H-1,3-benzodiazepin-2-yl)morpholin-4-yl]quinoline-8-carbonitrile; and
5-[(2R,6R)-2-methyl-6-[5-(4-piperidyl)-3,4-dihydroquinazolin-2-yl]morpholin-4-yl]quinoline-8-carbonitrile;
or a pharmaceutically acceptable salt thereof.
8. A process for preparing a compound according to claim 1 , the process comprising:
a) cyclizing a compound of formula (VII)
in the presence of an acid;
wherein the acid is HCl in t-BuOH.
9. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.
10. A method for the treatment of systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
11. A method for the treatment of systemic lupus erythematosus or lupus nephritis, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 7 , or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound in accordance with claim 7 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.