Thiophene derivatives as antiviral agents

1. A method of treating a viral infection caused by Influenza virus A comprising the administration, to a subject infected by Influenza virus A, of a compound that has formula (I):

wherein:

R 1 and R 2 form together a 5-7 membered ring, saturated or unsaturated,

said 5-7 membered ring optionally comprises one or more heteroatoms chosen among:

N, optionally substituted by a radical selected from the group consisting of:

a (C 1 -C 6 )alkyl, a (C 2 -C 6 )alkenyl, a (C 2 -C 6 )alkynyl,

a 5-10 membered ring, saturated or unsaturated, selected from the group consisting of cycloalkyl, aryl, heterocycloalkyl, and heteroaryl,

a saturated or unsaturated (C 1 -C 6 )alkylcycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocycloalkyl), or (C 1 -C 6 )alkylheteroaryl, and

a CO—(C 1 -C 6 )alkyl, a CO 2 —(C 1 -C 6 )alkyl, a CO—(C 1 -C 6 )alkylaryl, a CO-aryl, a CO-heteroaryl, a SO 2 -aryl, or a SO 2 -heteroaryl,

said radical is optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy,

O, and

S, and

said 5-7 membered ring is optionally substituted by:

a (C 1 -C 6 )alkyl, a (C 1 -C 6 )alkyloxy, a (C 2 -C 6 )alkenyl, a (C 2 -C 6 )alkynyl, optionally substituted by at least one halogen, or —OH,

a 5-10 membered ring, saturated or unsaturated, selected from the group consisting of cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy,

a saturated or unsaturated (C 1 -C 6 )alkylcycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocycloalkyl), or (C 1 -C 6 )alkylheteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy,

a halogen, —CN, or —NO 2 ,

—C(O)R, —C(O) 2 R, —C(O)NRR′, —CONHOR, —CONHSO 2 R, —NRR′, —N(R)C(O)R′, —N(R)NR′R″, —N(R)C(O) 2 R′, —N(R)C(O)NR′R″, —N(R)S(O) 2 R′, —OR, —SR, —S(O)R, —S(O 2 )R, —S(O)NRR′, or —S(O) 2 NRR′, R, R′, and R″ being independently H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C 1 -C 6 )alkylcycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocycloalkyl), (C 1 -C 6 )alkylheteroaryl, or R and R′ or R′ and R″ form a 5-7 membered ring, optionally interrupted by one or several heteroatoms, said 5-7 membered ring is optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy;

R 3 represents:

a cyclohexyl

being substituted in the vicinal position with respect to the CO of the —NH—CO—R 3 group by at least one group (A) selected from the group consisting of:

—C(O)R, —C(O) 2 R, —C(O)NRR′, —CONHOR, and

—CONHSO 2 R, R and R′ are as above defined;

R 4 represents a radical selected from the group of:

a 5-14 membered ring, saturated or unsaturated, selected from the group consisting of a cycloalkyl, an aryl, a heterocycloalkyl, a heteroaryl, a fused arylheterocycloalkyl, and a fused arylcycloalkyl,

a (C 1 -C 6 )alkylcycloalkyl, a (C 1 -C 6 )alkylaryl, a (C 1 -C 6 )alkylheterocycloalkyl, and a (C 1 -C 6 )alkylheteroaryl, and

a (C 1 -C 6 )alkyl,

said radicals being optionally substituted by at least one group (B) selected from the group consisting of:

a (C 1 -C 6 )alkyl or a (C 1 -C 6 )alkoxy, optionally substituted by at least one OH, one halogen or one —NRR′, R, R′, and R″ are as defined above,

a halogen, —CN, or —NO 2 ,

a 5-10 membered ring, saturated or unsaturated, selected from the group consisting of a cycloalkyl, an aryl, a heterocycloalkyl, and a heteroaryl, optionally substituted by at least one OH, one halogen, one (C 1 -C 6 )alkyl, one (C 1 -C 6 )alkyloxy or one —NRR′, R, R′, and R″ are as defined above,

a saturated or unsaturated (C 1 -C 6 )alkylcycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkylheterocycloalkyl, or (C 1 -C 6 )alkylheteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy,

 —C(O)R, —C(O) 2 R, —C(O)NRR′, —CONHOR, —CONHSO 2 R, —NRR′, —N(R)C(O)R′, —N(R)NR′R″, —N(R)C(O) 2 R′, —N(R)C(O)NR′R″, —N(R)S(O) 2 R′, —OR, —SR, —S(O)R, —S(O 2 )R, —S(O)NRR′, or —S(O) 2 NRR′, R, R′, and R″ are as defined above; and

R 5 represents H, a (C 1 -C 6 )alkyl, a (C 2 -C 6 )alkenyl, or a (C 2 -C 6 )alkynyl; or

R 4 and R 5 form together a 5-14 membered ring, optionally interrupted by one or several heteroatoms, said 5-14 membered ring is optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, cycloalkyl, or a 5-10 membered ring selected from the group of an aryl, a heterocycloalkyl, and a heteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy;

and the pharmaceutical salts thereof.

2. The method according to claim 1 , wherein:

R 1 and R 2 form together a 5- or 6-membered ring, saturated or unsaturated, selected from the group of a cycloalkyl and an aryl,

said 5- or 6-membered ring optionally comprises one O or one S, and

said 5- or 6-membered ring is optionally substituted by a (C 1 -C 6 )alkyl.

3. The method according to claim 1 , wherein:

R 1 and R 2 form together a cyclopentyl, a cyclohexyl, a tetrahydro-2H-pyran, a tetrahydrofuran optionally substituted by a (C 1 -C 6 )alkyl, a methyl, a thiophene, a tetrahydro-thiophene, a phenyl, or a cyclopentyl.

4. The method according to claim 1 , wherein:

R 4 represents a radical selected from the group consisting of:

a 5-10 membered ring, saturated or unsaturated, selected from the group consisting of:

a cycloalkyl or a cyclohexyl, optionally substituted by at least one group (B) selected from the group consisting of:

a (C 1 -C 6 )alkyl or a methyl, optionally substituted by at least one halogen, or one hydroxy,

a (C 1 -C 6 )alloy or a methoxy,

a halogen or a fluorine,

a cyano,

a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy, and

—C(O)R or —S(O 2 )R with R being a (C 1 -C 6 )alkyl,

an aryl or a phenyl, optionally substituted by at least one group (B) selected from the group consisting of:

a (C 1 -C 6 )alkyl, a methyl, an ethyl, an isopropyl, or a tert-butyl, optionally substituted by at least one halogen, a fluorine, or one hydroxy,

a (C 1 -C 6 )alloy or a methoxy, optionally substituted by at least one fluorine,

a halogen, a fluorine or a chlorine,

a cyano,

a cycloalkyl, a heterocycloalkyl, a morpholine, an aryl, a phenyl, or a heteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy, and

—C(O)R or —S(O 2 )R with R being a (C 1 -C 6 )alkyl or a methyl,

a heteroaryl, a pyridine, a pyrazine, or a thiazole, optionally substituted by at least one group (B) selected from the group consisting of:

a halogen or a chlorine,

a (C 1 -C 6 )alkyl, a methyl, or a (C 1 -C 6 )alkoxy, optionally substituted by at least one halogen, a fluorine, or one hydroxy,

a cyano,

a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, optionally substituted by at least one —OH, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy, and

—C(O)R or —S(O 2 )R with R being a (C 1 -C 6 )alkyl,

a fused arylheterocycloalkyl, a benzodioxole or an isobenzofurane, and

a fused arylcycloalkyl or an indane,

a radical selected from the group consisting of:

(C 1 -C 6 )alkylcycloalkyl or a methylcyclohexyl, and

a (C 1 -C 6 )alkylaryl or a methylphenyl,

said radical is optionally substituted by at least one halogen a chlorine, one (C 1 -C 6 )alkyl or one (C 1 -C 6 )alkoxy, optionally substituted by at least one halogen, and

a (C 1 -C 6 )alkyl or a pentyl; and

R 5 represents H or a (C 1 -C 6 )alkyl or a methyl; or

R 4 and R 5 form together a heterocycloalkyl or a piperazine, optionally substituted by an aryl or a phenyl optionally substituted by at least one halogen or a chlorine.

5. The method according to claim 1 , wherein:

R 3 represents:

a cyclohexyl and

said cyclohexyl being substituted in the vicinal position with respect to the CO of the —NH—CO—R 3 group by at least one group (A) selected from the group consisting of a —C(O) 2 R, and a —C(O)NRR′ with R and R′ being H.

6. The method according to claim 1 , wherein said at least one group (A) is —C(O) 2 R with R being H.

7. The method according to claim 1 , wherein said compound is selected from the group consisting of:

Compound 1—2-[[3-[(3,4-Dimethylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 2—2-[[3-[(6-Chloro-3-pyridyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 3—2-[[3-(1,3-Benzodioxol-5-ylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 4—2-[[3-[(4-Fluorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 5—2-[[3-[(4-Chlorophenyl)methylcarbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 6—2-[[3-[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 7—2-[[3-[(4-Chloro-2-methyl-phenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 8—2-[[3-[(Trans-4-methoxycyclohexyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 9—2-[[3-[[4-(2-Hydroxyethyl)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 10—2-[[3-[(4-Phenylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 11—2-[[3-[(3-Chlorophenyl)methylcarbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 12—2-[[3-[(3-Acetylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 13—2-[[3-[(4-Chloro-3-methyl-phenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 14—2-[[3-[(3-chloro-4-methyl-phenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 15—2-[[3-[(4-Morpholinophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 16—2-[[3-[(3,4-Difluorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 17—2-[[3-[(3-Chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 18—2-[[3-[(4,4-Difluorocyclohexyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 19—2-[[3-[[4-(Hydroxymethyl)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 20—2-[[3-[[4-(Trifluoromethoxy)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 21—2-[[3-[(4-tert-Butylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 22—2-[[3-(pentylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 23—2-[[3-(Indan-1-ylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 24—2-[[3-(Cyclohexylmethylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 25—2-[[3-[(4-Isopropylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 26—2-[[3-[(5-Chloropyrazin-2-yl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 27—2-[[3-[[4-(Trifluoromethyl)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b] thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 28—2-[[3-[(4-Cyanophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 29—2-[[3-[(5-Chlorothiazol-2-yl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 30—2-[[3-(1,3-Dihydroisobenzofuran-5-ylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 31—2-[[3-[(4-Methylsulfonylphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 32—2-[[3-[[6-(Trifluoromethyl)-3-pyridyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 33—2-[[3-[(5-Methyl-3-pyridyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 34—2-[[3-[(4-Chlorophenyl)-methyl-carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 35—2-[[3-[(4-Methylcyclohexyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 36—2-[[3-[4-(4-chlorophenyl)piperazine-1-carbonyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 37—2-[[3-[(4-Chlorophenyl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 38—2-[[3-[(4-Chlorophenyl)carbamoyl]-4,6-dihydrothieno[3,4-b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 39—2-[[3-[(4-Chlorophenyl)carbamoyl]-4-methyl-4,6-dihydrothieno[2,3-c]furan-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 40—2-[[4-[(4-Chlorophenyl)carbamoyl]-2,3-dihydrothieno[2,3-b]thiophen-5-yl]carbamoyl] cyclohexanecarboxylic acid;

Compound 41—2-[[3-[(4-Chlorophenyl)carbamoyl]benzothiophen-2-yl]carbamoyl]cyclohexane carboxylic acid;

Compound 42—2-[[3-[(4-Chlorophenyl)carbamoyl]thieno[3,4-b]thiophen-2-yl]carbamoyl] cyclohexanecarboxylic acid;

Compound 49—2-[[3-[(4-Chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexane-trans-carboxylic acid;

Compound 55—N2-[3-[(4-Chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]cyclohexane-1,2-dicarboxamide;

Compound 57—2-[[3-[(4-Chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexane-cis-carboxylic acid;

Compound 58—2-[[3-(m-Tolylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 61—2-[[3-[(4-Chlorophenyl)carbamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]carbamoyl]cyclohexane-cis-carboxylic acid;

Compound 63—2-[[3-(Benzylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 64—2-[[3-[(3-Methoxyphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid:

Compound 65—2-[[3-(Cyclohexylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 66—2-[[3-(p-Tolylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 67—2-[[3-(o-Tolylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 69—2-[[3-(m-Tolylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 74—2-[[3-(Phenylcarbamoyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 76—2-[[3-[(4-Methoxyphenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid; and

Compound 77—2-[[3-[[3-(Trifluoromethyl)phenyl]carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 79—2-[[6-tert-butyl-3-[(4-chlorophenyl)carbamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]carbamoyl]cyclohexanecarboxylic acid;

Compound 88—N1-[3-[(4-chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]-thiophen-2-yl]-N2-methoxy-cyclohexane-1,2-dicarboxamide; and

Compound 90—N-(4-chlorophenyl)-2-[[2-(hydroxycarbamoyl) cyclohexanecarbonyl] amino]-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide.

8. The method according to claim 1 , wherein the viral infection is an infection by Influenza virus A subtypes selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, and H10N7.

9. The method according to claim 1 , wherein said compound is selected from the group consisting of:

Compound 41—2-[[3-[(4-Chlorophenyl)carbamoyl]benzothiophen-2-yl]carbamoyl]cyclohexane carboxylic acid;

Compound 42—2-[[3-[(4-Chlorophenyl)carbamoyl]thieno[3,4-b]thiophen-2-yl]carbamoyl] cyclohexanecarboxylic acid; and

Compound 57—2-[[3-[(4-Chlorophenyl)carbamoyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl]carbamoyl]cyclohexane-cis-carboxylic acid.