Fused thiophene derivatives and their uses

A method for treating a disease selected from the group consisting of an infection, a viral infection, a bacterial infection, a cancer, a metabolic disease, a cardiovascular disease, an inflammatory disorder, and iron storage disease or disorder in a subject in need thereof, comprising administering a compound having the formula (I):

• wherein:
• X represents:
• a —CR1bR1b′ unit,
• a —N—R1b″ unit, or
• an oxygen atom;
• n is 0, 1, or 2;
• when X is a —CR1bR1b′ unit, then at most one of R1a, R1a′, R1b, R1b′, R1c, R1c′, R1d, and R1d′ represents:
• a halogen,
• a (C1-C6)alkyl, optionally substituted by at least one halogen,
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen,
• a cyano, or
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy, and
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen, and the others represent a hydrogen;
• when X is a —N—R1b″ unit or an oxygen atom, then R1a, R1a′, R1c, R1c′, R1d, and R1d′ represent independently:
• a hydrogen,
• a halogen,
• a (C1-C6)alkyl, optionally substituted by at least one halogen,
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen,
• a cyano, or
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy, or
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen;
• and R1b″ represents:
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy, and
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen, or
• a —CO2—R8 with R8 being a (C1-C6)alkyl;
• R2 represents —COOH;
• R3 represents:
• a 5-10 membered ring, saturated or unsaturated selected from the group consisting of:
• an aryl optionally fused to a dioxole,
• a heteroaryl,
• a cycloalkyl,
• a heterocycloalkyl, and
• a 5-10 membered bridged carbocyclyl or heterocyclyl,
• said 5-10 membered ring is optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen, or a (C1-C6)alkyloxy,
• a —NH—(C1-C6)alkyl or a —N—((C1-C6)alkyl)2, optionally substituted by a heterocycloalkyl or a (C1-C6)alkyloxy,
• a —NH-heterocycloalkyl, a —NH-cycloalkyl, a —N((C1-C6)alkyl)-heterocycloalkyl or a —N((C1-C6)alkyl)-cycloalkyl, optionally substituted by a (C1-C6)alkyloxy or a —CO—R4 with R4 being a hydrogen or a (C1-C6)alkyl,
• a hydroxy, a —CO—R4 or a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl,
• a (C1-C6)alkyloxy optionally substituted by at least one radical selected from the group consisting of a halogen, a hydroxy, a (C1-C6)alkyloxy, a —NR5R6 with R5 and R6 are independently a hydrogen or a (C1-C6)alkyl, a —NHCOR7, a —NHCO2R7, with R7 being a (C1-C6)alkyl, a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl, and a heterocycle,
• a —NHCOR7 or —NHCO2R7 with R7 being a (C1-C6)alkyl, and
• a heterocycloalkyl, a heterocycloalkyloxy or a spiroheterocycloalkyl, optionally substituted by a (C1-C6)alkyloxy, a hydroxy, a halogen or a (C1-C6)alkyl optionally substituted by a (C1-C6)alkyloxy, or
• a (C1-C6)alkyl or a (C2-C6)alkenyl, optionally substituted by a 5-10 membered ring as defined above or a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl;
• and with the proviso that R3 is not a 5-membered heteroaryl;
• and the stereoisomers, and the pharmaceutical salts thereof.

A compound of formula (I):

• wherein:
• X represents:
• a —CR1bR1b′ unit,
• a N—R1b″ unit, or
• an oxygen atom;
• n is 0, 1, or 2;
• when X is a —CR1bR1b′ unit, and n is 0 or 2, then one of R1a, R1a′, R1b, R1b′, R1c, R1c′, R1d and R1d′ represents:
• a halogen,
• a (C1-C6)alkyl, optionally substituted by at least one halogen,
• a (C1-C6)alkyloxy, optionally substituted by at least one halogen,
• a cyano, or
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy,
• a (C1-C6)alkyloxy optionally substituted by at least one halogen, and the others represent a hydrogen;
• when X is a N—R1b″ unit, then R1a, R1a′, R1c, R1c′, R1d, and R1d′ represent independently:
• a hydrogen,
• a halogen,
• a (C1-C6)alkyl, optionally substituted by at least one halogen,
• a (C1-C6)alkyloxy optionally substituted by at least one halogen,
• a cyano,
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy, or
• a (C1-C6)alkyloxy optionally substituted by at least one halogen;
• and R1b represents:
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy, and
• a (C1-C6)alkyloxy optionally substituted by at least one halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen, or
• a —CO2—R8 with R8 being a (C1-C6)alkyl;
• and
• when X is an oxygen atom, then at least one of R1a, R1a′, R1c, R1c′, R1d, and R1d′ represents:
• a halogen,
• a (C1-C6)alkyl, optionally substituted by at least one halogen,
• a (C1-C6)alkyloxy optionally substituted by at least one halogen,
• a cyano, or
• an aryl optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen,
• a hydroxy,
• a (C1-C6)alkyloxy optionally substituted by at least one halogen,
• and the other represent a hydrogen;
• R2 represents —COOH;
• and
• R3 represents:
• a 5-10 membered ring, saturated or unsaturated selected from the group consisting of:
• an aryl optionally fused to a dioxole,
• a heteroaryl,
• a cycloalkyl,
• a heterocycloalkyl, and
• a 5-10 membered bridged carbocyclyl or heterocyclyl,
• said 5-10 membered ring is optionally substituted by at least one radical selected from the group consisting of:
• a halogen,
• a (C1-C6)alkyl optionally substituted by at least one halogen, or a (C1-C6)alkyloxy,
• a —NH—(C1-C6)alkyl or a —N—((C1-C6)alkyl)2, optionally substituted by a heterocycloalkyl or a (C1-C6)alkyloxy,
• a —NH-heterocycloalkyl, a —NH-cycloalkyl, a —N((C1-C6)alkyl)-heterocycloalkyl or a —N((C1-C6)alkyl)-cycloalkyl, optionally substituted by a (C1-C6)alkyloxy or a —CO—R4 with R4 being a hydrogen or a (C1-C6)alkyl,
• a hydroxy, a —CO—R4 or a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl,
• a (C1-C6)alkyloxy optionally substituted by at least one radical selected from the group consisting of a halogen, a hydroxy, a (C1-C6)alkyloxy, a —NR5R6 with R5 and R6 independently being a hydrogen or a (C1-C6)alkyl, a —NHCOR7, a —NHCO2R7, with R7 being a (C1-C6)alkyl, a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl, and a heterocycle,
• a —NHCOR7 or —NHCO2R7 with R7 being a (C1-C6)alkyl, and
• a heterocycloalkyl, a heterocycloalkyloxy or a spiroheterocycloalkyl, optionally substituted by a (C1-C6)alkyloxy, a hydroxy, a halogen or a (C1-C6)alkyl optionally substituted by a (C1-C6)alkyloxy, or
• a (C1-C6)alkyl or a (C2-C6)alkenyl, optionally substituted by a 5-10 membered ring as defined above or a —CO2R4 with R4 being a hydrogen or a (C1-C6)alkyl;
• and the stereoisomers, and the pharmaceutical salts thereof.

A compound selected from the group consisting of:

• 6-tert-Butyl-2-[(4-methoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #1);
• 6-tert-Butyl-2-[(3-methoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #2);
• 6-tert-Butyl-2-[(3,4-dimethoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #3);
• 6-tert-Butyl-2-[(3,4,5-trimethoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzo thiophene-3-carboxylic acid (Compound #4);
• 6-tert-Butyl-2-[(2-fluoro-4-methoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #5);
• 6-tert-Butyl-2-[(2,3-difluoro-4-methoxy-benzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #6);
• 6-tert-Butyl-2-[[4-(difluoromethoxy)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #7);
• 6-tert-Butyl-2-[[4-(trifluoromethoxy)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #8);
• 6-tert-Butyl-2-[(4-morpholinobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #9);
• 6-tert-Butyl-2-[(4-chlorobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #10);
• 2-[[4-[3-(tert-Butoxycarbonylamino)propoxy]benzoyl]amino]-6-tert-butyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #11);
• 6-tert-Butyl-2-[[4-(2-hydroxyethoxy)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #12);
• 2-[(2-Methylbenzoyl)amino]-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #45);
• 2-Benzamido-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #46);
• 2-[(3,4-Dimethoxybenzoyl)amino]-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #48);
• 2-[(4-Hydroxybenzoyl)amino]-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #49);
• 2-[[4-(2-Hydroxyethoxy)benzoyl]amino]-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #50);
• 2-[[4-(2-Methoxyethoxy)benzoyl]amino]-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #51);
• 2-Benzamido-6-tert-butyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #71);
• 6-tert-Butyl-2-[(4-fluorobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #236);
• 6-tert-Butyl-2-[(2-fluorobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #73);
• 4-Methyl-2-[(4-morpholinobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #70);
• 6-tert-Butyl-2-(pyridine-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #72);
• 2-Benzamido-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #74);
• 2-[[4-(Difluoromethoxy)benzoyl]amino]-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #75);
• 2-[(2-Fluoro-4-methoxybenzoyl)amino]-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #76);
• 2-[(3,4-Dimethoxybenzoyl)amino]-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #81);
• 6-tert-Butyl-2-[(2-methylbenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #82);
• 6-tert-Butyl-2-[(3-fluorobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #83);
• 6-Methyl-2-[(2-methylbenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #86);
• 6-tert-Butyl-2-[(2-methylcyclohexanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #89);
• 6-tert-Butyl-2-[(5-methoxypyridine-2-carbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #91);
• 2-[(4-Acetamidobenzoyl)amino]-6-tert-butyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #93);
• 6-tert-Butyl-2-[[2-(trifluoromethyl)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #100);
• 6-tert-Butyl-2-[(2,2-difluoro-1,3-benzodioxole-5-carbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #99);
• 6-tert-Butyl-2-[(1-methylpyrazole-4-carbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #101);
• 2-[[3-(Difluoromethoxy)benzoyl]amino]-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #102);
• 2-Benzamido-6-iso-propoxy-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #103);
• 6-tert-Butyl-2-[(2-methoxybenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #104);
• 2-(2,2-Dimethylpropanoylamino)-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #106);
• 6-tert-Butyl-2-[(2-chlorobenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #107);
• 2-[[4-(Difluoromethoxy)benzoyl]amino]-4-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #108);
• 6-tert-Butyl-2-[(3-methylfuran-2-carbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #110);
• 6-tert-Butyl-2-[(2-methylbenzoyl)amino]benzothiophene-3-carboxylic acid (Compound #111);
• 2-Benzamido-4-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #112);
• 6-tert-Butyl-2-(cyclohexanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #115);
• 6-tert-Butyl-2-[(2,6-dimethylbenzoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #118);
• 6-tert-Butyl-2-(piperidine-1-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #120);
• 2-Benzamido-6-(4-hydroxyphenyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #122);
• 6-tert-Butyl-2-(pyridine-4-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #123);
• 2-[[4-(3-Aminopropoxy)benzoyl]amino]-6-tert-butyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid hydrochloride salt (Compound #124);
• 6-tert-Butyl-2-[(2-phenylacetyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #125);
• 6-tert-Butyl-2-[[4-(6-methoxy-6-oxo-hexoxy)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #172);
• and
• 2-Benzamido-5-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (Compound #240).