Thiophene derivatives as Sphingosine-1-phosphate-1 receptor agonists

A compound of the Formula (I),

• R1 represents hydrogen, lower alkyl, lower alkoxy, or halogen;
• R2 represents hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or halogen;
• R3 represents hydrogen, hydroxy-lower alkyl, 2,3-dihydroxypropyl, di-(hydroxy-lower alkyl)-lower alkyl, —CH2—(CH2)k—NR31R32, (azetidine-3-carboxylic acid)-1-yl-methyl, (azetidine-3-carboxylic acid lower alkylester)-1-yl-methyl, 2-[(azetidine-3-carboxylic acid)-1-yl]-ethyl, 2-[(azetidine-3-carboxylic acid lower alkylester)-1-yl]-ethyl, 3-[(azetidine-3-carboxylic acid)-1-yl]-propyl, 3-[(azetidine-3-carboxylic acid lower alkylester)-1-yl]-propyl, (pyrrolidine-3-carboxylic acid)-1-yl-methyl, (pyrrolidine-3-carboxylic acid lower alkylester)-1-yl-methyl, (pyrrolidine-2-carboxylic acid)-1-yl-methyl, (pyrrolidine-2-carboxylic acid lower alkylester)-1-yl-methyl, 2-[(pyrrolidine-3-carboxylic acid)-1-yl]-ethyl, 2-[(pyrrolidine-3-carboxylic acid lower alkylester)-1-yl]-ethyl, 2-[(pyrrolidine-2-carboxylic acid)-1-yl]-ethyl, 2-[(pyrrolidine-2-carboxylic acid lower alkylester)-1-yl]-ethyl, 3-[(pyrrolidine-3-carboxylic acid)-1-yl]-propyl, 3-[(pyrrolidine-3-carboxylic acid lower alkylester)-1-yl]-propyl, 3-[(pyrrolidine-2-carboxylic acid)-1-yl]-propyl, 3-[(pyrrolidine-2-carboxylic acid lower alkylester)-1-yl]-propyl, —CH2—(CH2)n—CONR31R32, —CO—NHR31, —(CH2)nCH(OH)—CH2—NR31R32, hydroxy, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, —OCH2—(CH2)m—NR31R32, 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2-[4-(lower alkyl)-piperazin-1-yl]- ethoxy, 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethoxy, 3-piperazin-1-yl-propoxy, 3-[4-(lower alkyl)-piperazin-1-yl]-propoxy, 3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[(azetidine-3-carboxylic acid)-1-yl]-ethoxy, 2-[(azetidine-3-carboxylic acid lower alkylester)-1-yl]-ethoxy, 2-[(pyrrolidine-3-carboxylic acid)-1-yl]-ethoxy, 2-[(pyrrolidine-3-carboxylic acid lower alkylester)-1-yl]-ethoxy, 2-[(pyrrolidine-2-carboxylic acid)-1-yl]-ethoxy, 2-[(pyrrolidine-2-carboxylic acid lower alkylester)-1-yl]-ethoxy, 2-[(2-hydroxy-pyrrolidine)-1-yl]-ethoxy, 2-[(3-hydroxy-pyrrolidine)-1-yl]-ethoxy, 3-[(azetidine-3-carboxylic acid)-1-yl]-propoxy, 3-[(azetidine-3-carboxylic acid lower alkylester)-1-yl]-propoxy, 3-[(pyrrolidine-3-carboxylic acid)-1-yl]-propoxy, 3-[(pyrrolidine-3-carboxylic acid lower alkylester)-1-yl]-propoxy, 3-[(pyrrolidine-2-carboxylic acid)-1-yl]-propoxy, 3-[(pyrrolidine-2-carboxylic acid lower alkylester)-1-yl]-propoxy, 3-[(2-hydroxy-pyrrolidine)-1-yl]-propoxy, 3-[(3-hydroxy-pyrrolidine)-1-yl]-propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, —O—CH2—CONR31R32, 3-carbamoyl-propoxy, 3-(lower alkylcarbamoyl)propoxy, 3-(2-hydroxyethylcarbamoyl)propoxy, —OCH2—CH(OH)—CH2—NR31R32, 3-[(azetidine-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 3-[(azetidine-3-carboxylic acid lower alkylester)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]-propoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid lower alkylester)-1-yl]-propoxy, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid)-1-yl]-propoxy, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid lower alkylester)-1-yl]-propoxy, 2-hydroxy-3-[(2-hydroxy-pyrrolidine)-1-yl]-propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidine)-1-yl]-propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3-[4-(lower alkyl)-piperazin-1-yl]-propoxy, 2-hydroxy-3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, —NR31R32, —NHCO—R31, —CH2—(CH2)k—NHSO2R33, —(CH2)nCH(OH)—CH2—NHSO2R33, —OCH2—(CH2)m—NHSO2R33, —OCH2—CH(OH)—CH2—NHSO2R33, —CH2—(CH2)k—NHCOR34, —(CH2)nCH(OH)—CH2—NHCOR34, —OCH2—(CH2)m—NHCOR34, or —OCH2—CH(OH)—CH2—NHCOR34;
• R31 represents hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethyl-ethyl, 2-lower alkoxyethyl, 3-hydroxypropyl, 3-lower alkoxypropyl, 2-aminoethyl, 2-(lower alkylamino)ethyl, 2-(di-(lower alkyl)amino)ethyl, carboxymethyl, lower alkylcarboxymethyl, 2-carboxyethyl, or 2-(lower alkylcarboxy)ethyl;
• R32 represents hydrogen, methyl, or ethyl;
• R33 represents methyl, ethyl, propyl, isopropyl, butyl, 2-hydroxyethyl, 2-methoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, or dimethylamino;
• R34 represents hydroxymethyl, hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, 2-methylamino-ethyl, or 2-dimethylamino-ethyl;
• k represents the integer 1, 2, or 3;
• m represents the integer 1 or 2;
• n represents 0, 1, or 2;
• and
• R4 represents hydrogen, lower alkyl, or halogen,
• in free form or an optically pure enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a diastereomeric racemate, or a mixture of diastereomeric racemates, or a salt, form of said compound.