Benzothiazole compounds for the treatment of autoimmune diseases

1. A compound of formula (I),

wherein:

R 1 is

wherein R 4 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 —C 1-6 alkyl-R 5 or —CONR 6 R 7 , wherein:

R 5 is aminoazabicyclo[3.2.1]octanyl, aminopiperidinyl, C 1-6 alkyldiazaspiro[5.5]undecanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.5]decanyl, diazaspiro[5.5]undecanyl, piperidinylpiperidinyl, or 3-amino-8-azabicyclo[3.2.1]octan-8-yl;

R 6 is H; and

R 7 is C 1-6 alkylpiperidinyl or C 1-6 alkylmorpholinylC 1-6 alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

2. A compound according to claim 1 , wherein:

R 4 is cyano; and

R 2 is C 1-6 alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

3. A compound according to claim 2 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R 3 is —CH 2 —R 5 or —CONR 6 R 7 .

4. A compound according to claim 3 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R 2 is methyl.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R 5 is selected from: 2,8-diazaspiro[3.5]nonan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl, 2,9-diazaspiro[4.5]decan-2-yl, 2,9-diazaspiro[5.5]undecan-9-yl, 2-methyl-2,9-diazaspiro[5.5]undecan-9-yl, 3,9-diazaspiro[5.5]undecan-3-yl, 3-amino-8-azabicyclo[3.2.1]octan-8-yl, 4-(1-piperidinyl)-1-piperidinyl, and 4-amino-1-piperidinyl.

6. A compound according to claim 5 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R 7 is 1-methyl-4-piperidinyl or 4-methylmorpholin-2-ylmethyl.

7. A compound according to claim 2 , selected from:

7-[(2S,6R)-2-(2,9-diazaspiro[4.5]decan-2-ylmethyl)-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2S,6R)-2-[(4-amino-1-piperidyl)methyl]-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2S,6R)-2-(2,9-diazaspiro[5.5]undecan-9-ylmethyl)-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2S,6R)-2-(2,8-diazaspiro[3.5]nonan-2-ylmethyl)-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2S,6R)-2-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2S,6R)-2-(2,8-diazaspiro[4.5]decan-8-ylmethyl)-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2R,6S)-2-methyl-6-[[4-(1-piperidyl)-1-piperidyl]methyl]morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

Endo-7-[(2S,6R)-2-[[(1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl]methyl]-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

Exo-7-[(2S,6R)-2-[[(1S,5R)-3-amino-8-azabicyclo[3.2.1]octan-8-yl]methyl]-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

7-[(2R,6S)-2-methyl-6-[(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)methyl]morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

(2R,6R)-4-(4-cyano-1,3-benzothiazol-7-yl)-6-methyl-N-(1-methyl-4-piperidyl)morpholin-2-carboxamide;

(2R,6R)-4-(4-cyano-1,3-benzothiazol-7-yl)-6-methyl-N-[(4-methylmorpholin-2-yl)methyl]morpholine-2-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

8. A process for preparing a compound according to claim 1 comprising any one of the following:

substituting a compound of formula (VII),

with an amine in the presence of a base; or

reacting a compound of formula (VIII),

with amine (IX) in the presence of a coupling reagent;

wherein:

Tf is trifluoromethansulfonyl;

the base is Cs 2 CO 3 ; and

the coupling reagent is HATU.

9. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and a therapeutically inert carrier.

10. A method for inhibiting TLR7, TLR8, or TLR9, or any combination thereof, in a patient in need thereof, which method comprises:

administering a therapeutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, to the patient in need thereof.

11. A pharmaceutical composition comprising a compound in accordance with claim 7 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and a therapeutically inert carrier.

12. A method for inhibiting TLR7, TLR8, or TLR9, or any combination thereof, in a patient in need thereof, which method comprises administering a therapeutically effective amount of a compound of claim 7 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, to the patient in need thereof.