2-Acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof

A compound of formula (IIb),

• or a (C1-C4) aliphatic ester or benzyl ester of a compound of formula (IIb), where the phenyl portion of the benzyl portion of the benzyl ester is unsubstituted, or substituted with a methoxy group, wherein:
• R′3 represents a group (C1-C4)alk-A or a group -B, where A represents a group NR5R6;
• and B represents a group
• R5 and R6 each represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl, allyl, (C2-C4)alk-O—(C1-C4)alkyl, (C2-C4)alk-OH, (C1-C3) alk-CON(R4)2, (C2-C3) alk-NHCO—(C1-C4)alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkylmethyl, —CO—(C1-C4)alkyl, benzyl, pyrrolidinyl optionally substituted with a —CO—(C1-C4)alkyl group, tetrahydropyranyl, tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl or tetrahydrofurylmethyl group;
• or R5 and R6, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl, tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and 2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals being unsubstituted or substituted with a phenyl, halophenyl, trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy, hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, a group —NR4R7, tetrahydropyran-4-ylamino, —CON(R4)2, —CONR4R′4, —CH2CON(R4)2, (C1-C4)alkyl-CONR4—, (C3-C8) cycloalkyl-CONR4—, (C1-C4) alkyl-OCONR4—, (C3-C8)cycloalkyl-OCONR4—, ((C1-C4)alkyl-OCO)2N— or (C1-C4)alkyl-COO—, or substituted with one or more methyl groups;
• R4 represents a hydrogen atom or a (C1-C4) alkyl group;
• R′4 represents a group (CH2)s linked to the carbon atom bearing —CONR4R′4;
• R7 represents a hydrogen atom, a (C1-C4)alkyl or an —SO2CH3 group or R4 and R7, together with the nitrogen atom to which they are attached, constitute a pyrrolidinyl or piperidinyl radical;
• p represents 1, 2, 3, 5 or 5;
• q represents 0, 1 or 2;
• s represents 2 or 3;
• p+q being less than or equal to 5;
• and
• alk represents an alkylene;
• or R′3 represents a precursor of a group (C1-C4)alk-A or a group -B, in which any amine or hydroxyl functions on (C1-C4)alk-A or -B that may be present are protected;
• provided that when (C1-C4)alk represents a methylene, B is other than piperidinyl;

A compound of the formula (IIe),

• or a (C1-C4) aliphatic ester or benzyl ester of a compound of formula (IIe), where the phenyl portion of the benzyl portion of the benzyl ester is unsubstituted, or substituted with a methoxy group, wherein:
• R′3 represents —CONR4—(C1-C4)alk-B, —CONR4-E, —CO-D-(C1-C2) alk-A, —CO-G-A,
• where
• A represents a group NR5R6;
• B represents a group
• R5 and R6 each represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl, allyl, (C2-C4)alk-O—(C0-C4)alkyl, (C2-C4)alk-OH, (C1-C3) alk-CON(R4)2, (C2-C3) alk-NHCO—(C1-C4)alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkylmethyl, —CO—(C1-C4)alkyl, benzyl, pyrrolidinyl optionally substituted with a —CO—(C1-C4)alkyl group, tetrahydropyranyl, tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl or tetrahydrofurylmethyl group;
• or R5 and R6, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl, tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and 2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals being unsubstituted or substituted with a phenyl, halophenyl, trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy, hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, a group —NR4R7, tetrahydropyran-4-ylamino, —CON(R4)2, —CONR4R′4, —CH2CON(R4)2, (C1-C4)alkyl-CONR4—, (C3-C8)cycloalkyl-CONR4—, (C1-C4)alkyl-OCONR4—, (C3-C8)cycloalkyl-OCONR4—, ((C1-C4)alkyl-OCO)2N— or (C1-C4)alkyl-COO—, or substituted with one or more methyl groups;
• R4 represents a hydrogen atom or a (C1-C4) alkyl group;
• R′4 represents a group (CH2)s linked to the carbon atom bearing —CONR4R′4;
• R7 represents a hydrogen atom, a (C1-C4)alkyl or an —SO2CH3 group or R4 and R7, together with the nitrogen atom to which they are attached, constitute a pyrrolidinyl or piperidinyl radical;
• p represents 1, 2, 3, 5 or 5;
• q represents 0, 1 or 2;
• r represents 1 or 2;
• s represents 2 or 3;
• p+q being less than or equal to 5;
• p+r being less than or equal to 5;
• and
• alk represents an alkylene;
• or R′3 represents a precursor of R3 as defined in this claim 14, in which any amine or hydroxyl functions on R3 that may be present are protected.

A compound of formula (IV),

• wherein:
• R′1 and R′2 represent, respectively, R1 or R2 or precursors of R1 and R2;
• where
• R1 represents a hydrogen or halogen atom or a (C1-C4)alkyl, trifluoroethyl, hydroxyl, (C1-C4)alkoxy, trifluoromethoxy, trifluoroethoxy, (C3-C8)cycloalkyloxy, allyloxy, cyclopropylmethoxy or (C1-C4)alkylthio group;
• R2 represents a hydrogen or halogen atom or a (C1-C8)alkyl, trifluoroethyl, perfluoro(C1-C4)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C8)alkoxy, trifluoromethoxy, trifluoroethoxy, allyloxy, (C3-C8)cycloalkylmethoxy, (C3-C8)cycloalkyloxy or (C3-C8) cycloalkylmethyl group;
• R′3 represents
• —OPg, where Pg is a protecting group;
• or R′3 represents
• —O—(C1-C3)alk-Q, —(C1-C3)alk-Q, or —CONH—(C1-C3)alk-Q, where Q is a dimethoxymethyl, diethoxymethyl or formyl group;
• or R′3 represents
• —O—(C2-C4)alk-OX, where X is a hydrogen atom, a tetrahydropyranyl group or a group SO2R′, where R′ is a methyl or tolyl group;
• or R′3 represents
• —(C1-C4)alk-Hal, where Hal represents a halogen atom;
• or R13 represents
• —I, —COOH, or —COOR where R represents a hydrogen atom, a (C1-C4)alkyl or a benzyl which is unsubstituted or substituted on the phenyl portion of the benzyl with a methoxy group;
• or R13 represents
• —O— (C2-C4)alk-A′;
• —O— (C1-C4)alk-B′;
• —O-E′;
• —(C1-C4) alk-A′;
• -B′;
• —(C1-C4) alk-NR4— (C2-C3) alk-A′;
• —(C1-C4) alk-NR4— (C1-C3) alk-B′;
• —CONR4— (C2-C4) alk-A′;
• —CONR4— (C1-C4) alk-B′;
• —CONR4-E′;
• —CO-D-(C1-C2) alk-A′;
• —CO-G-A′;
• A′ represents NGpR6;
• Gp represents a protecting group for nitrogen;
• alk represents an alkylene;
• R4 represents a hydrogen atom or a (C1-C4)alkyl group;
• R6 represents a hydrogen atom or (C1-C6)alkyl, allyl, (C2-C4) alk-O—(C1-C4) alkyl, (C2-C4)alk-OH, (C1-C3) alk-CON(R4)2, (C2-C3)alk-NHCO—(C1-C4)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkylmethyl, —CO—(C1-C4)alkyl, benzyl, pyrrolidinyl optionally substituted with a —CO—(C1-C4)alkyl group, tetrahydropyranyl, tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl or tetrahydrofurylmethyl group;
• p represents 1, 2, 3, 4 or 5;
• q represents 0, 1 or 2;
• r represents 1 or 2;
• p+q being less than or equal to 5;
• and
• p+r being less than or equal to 5.