Novel imidazole compounds as transforming growth factor (TGF) inhibitors

A compound of formula (Ia):

• 53
• or a pharmaceutically acceptable salt, prodrug, tautomer, hydrate, or solvate thereof, wherein:
• R1 is a saturated, unsaturated, or aromatic C3-C20 mono-, bi- or polycyclic ring optionally containing at least one heteroatom selected from the group consisting of N, O and S, wherein R1 can optionally be further independently substituted with at least one moiety independently selected from the group consisting of:
• carbonyl, halo, halo(C1-C6)alkyl, perhalo(C1-C6)alkyl, perhalo(C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, oxo, mercapto, (C1-C6)alkylthio, (C1-C6)alkoxy, (C5-C10)aryl or (C5-C10)heteroaryl, (C5-C10)aryloxy or (C5-C10)heteroaryloxy, (C5-C10)ar(C1-C6)alkyl or (C5-C10)heteroar(C1-C6)alkyl, (C5-C10)ar(C1-C6)alkoxy or (C5-C10)heteroar(C1-C6)alkoxy, HO—(C═O)—, ester, amido, ether, amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, (C5-C10)heterocyclyl(C1-C6)alkyl, (C1-C6)alkyl- and di(C1-C6)alkylamino, cyano, nitro, carbamoyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C5-C10)arylcarbonyl, (C5-C10)aryloxycarbonyl, (C1-C6)alkylsulfonyl, and (C5-C10)arylsulfonyl;
• each R3 is independently selected from the group consisting of:
• hydrogen, halo, halo(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C5-C10)heteroaryl, (C5-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C5-C10)heteroaryl-O—, (C5-C10)heterocyclic-O—, (C3-C10)cycloalkyl-O—, (C1-C6)alkyl-S—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-NH—SO2—, O2N—, NC—, amino, Ph(CH2)1-6HN—, (C1-C6)alkyl HN—, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2—NH—, amino(C═O)—, aminoO2S—, (C1-C6)alkyl-(C═O)—NH—, (C1-C6)alkyl-(C═O)—[(((C1-C6)alkyl)-N]—, phenyl-(C═O)—NH—, phenyl-(C═O)—[((C1-C6)alkyl)-N]—, (C1-C6)alkyl-(C═O)—, phenyl-(C═O)—, (C5-C10)heteroaryl-(C═O)—, (C5-C10)heterocyclic-(C═O)—, (C3-C10)cycloalkyl-(C═O)—, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, H2N(C═O)—, (C1-C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2-N—(C═O)—, phenyl-NH—(C═O)—, phenyl-[((C1-C6)alkyl)-N]—(C═O)—, (C5-C10)heteroaryl-NH—(C═O)—, (C5-C10)heterocyclic-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)— and (C1-C6)alkyl-(C═O)—O—;
• where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R3 is optionally substituted by at least one substituent independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo, H2N—, Ph(CH2)1-6HN—, and (C1-C6)alkylHN—;
• s is an integer from one to five;
• R4 is independently selected from the group consisting of:
• hydrogen, halo, halo(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C5-C10)heteroaryl, (C5-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C5-C10)heteroaryl-O—, (C5-C10)heterocyclic-O—, (C3-C10)cycloalkyl-O—, (C1-C6)alkyl-S—, (C1-C6)alkyl-S—(C1-C6)alkyl-, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-NH—SO2—, O2N—, NC—, amino, aminoalkyl, Ph(CH2)1-6HN—, (C1-C6)alkylHN—, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2—NH—, amino(C═O)—, aminoO2S—, (C1-C6)alkyl-(C═O)—NH—, (C1-C6)alkyl-(C═O)—((C1-C6)alkyl)-N—, phenyl-(C═O)—NH—, phenyl-(C═O)—[((C1-C6)alkyl)-N]—, (C1-C6)alkyl-(C═O)—, phenyl-(C═O)—, (C5-C10)heteroaryl-(C═O)—, (C5-C10)heterocyclic-(C═O)—, (C3-C10)cycloalkyl-(C═O)—, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, H2N(C═O)—, (C1-C6)alkyl-NH—(C═O)—, ((C1-C6)alkyl)2-N—(C═O)—, phenyl-NH—(C═O)—, phenyl-[((C1-C6)alkyl)-N]—(C═O)—, (C5-C10)heteroaryl-NH—(C═O)—, (C5-C10)heterocyclic-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)—, (C1-C6)alkyl-(C═O)—O—, (C1-C6)alkyl-(C═O)—NH—(C1-C6)alkyl, (C1-C6)alkyl-NH—(C═O)—(C1-C6)alkyl, and (C1-C6)alkyl-(C═O)—(C1-C6)alkyl;
• where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R4 is optionally substituted by at least one substituent independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo, H2N—, NC—, HO—, Ph (CH2)1-6HN—, (C1-C6)alkylHN—, (C5-C10)heteroaryl and (C5-C10)heterocyclyl;
• R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, (C5-C10)heteroaryl, (C5-C10)heterocyclic, (C3-C10)cycloalkyl, (C1-C6)alkyl-(SO2)—, (C1-C6)alkyl-(SO2)—(C1-C6)alkyl, phenyl-(SO2)—, H2N—(SO2)—, (C1-C6)alkyl-NH—(SO2)—, (C1-C6)alkyl-(SO2)—NH—(C1-C6)alkyl, (C1-C6)alkyl-NH—(SO2)—(C1-C6)alkyl, ((C1-C6)alkyl)2N—(SO2)—, phenyl-NH—(SO2)—, (phenyl)2N—(SO2)—, (C1-C6)alkyl-(C═O)—, (C1-C6)alkyl-(C═O)—(C1-C6)alkyl, phenyl-(C═O)—, (C5-C10)heteroaryl-(C═O)—, (C5-C10)heterocyclic-(C═O)—, (C3-C10)cycloalkyl-(C═O)—, (C3-C10)cycloalkyl-(C═O)—(C3-C10)cycloalkyl, (C1-C6)alkyl-O—(C═O)—, (C5-C10)heterocyclic-O—(C═O)—, (C3-C10)cycloalkyl-O—(C═O)—, H2N—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, (C1-C6)alkyl-NH—(C═O)—(C1-C6)alkyl, (C1-C6)alkyl-(C═O)—NH—(C1-C6)alkyl, phenyl-NH—(C═O)—, (C5-C10)heteroaryl-NH—(C═O)—, (C5-C10)heterocyclic-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)—(C3-C10)cycloalkyl, (C3-C10)cycloalkyl-(C═O)—NH—(C3-C10)cycloalkyl, ((C1-C6)alkyl)2N—(C═O)—, (phenyl)2N—(C═O)—, phenyl-[((C1-C6)alkyl)-N]—(C═O)—, (C5-C10)heteroaryl-[((C1-C6)alkyl)-N]—(C═O)—, (C5-C10)heterocyclic-[((C1-C6)alkyl)-N]—(C═O)—, and (C3-C10)cycloalkyl-[((C1-C6)alkyl)-N]—(C═O)—;
• where alkyl, alkenyl, alkynyl, phenyl, benzyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R6 is optionally substituted with at least one moiety independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C5-C10)heterocyclic, (C5-C10)heteroaryl, (C1-C6)alkyl-SO2—, formyl, NC—, (C1-C6)alkyl-(C═O)—, (C3C10)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C5-C10)heterocyclic-(C═O)—, (C5-C10)heteroaryl-(C═O)—, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, (C3-C10)cycloalkyl-O—(C═O)—, (C5-C10)heterocyclic-O—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C5-C10)heterocyclic-NH—(C═O)—, (C5-C10)heteroaryl-NH—(C═O)—, ((C1-C6)alkyl)2-N—(C═O)—, phenyl-[((C1-C6)alkyl)-N]—(C═O)—, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-O—, phenoxy, (C5-C10)heterocyclic-O—, (C5-C10)heteroaryl-O—, (C1-C6)alkyl-(C═O)—O—, (C3-C10)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—, (C5-C10)heterocyclic-(C═O)—O—, (C5-C10)heteroaryl-(C═O)—O—, O2N—, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2-amino, formamidyl, (C1-C6)alkyl-(C═O)—NH—, (C3-C10)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C5-C10)heterocyclic-(C═O)—NH—, (C5-C10)heteroaryl-(C═O)—NH—, (C1-C6)alkyl-(C═O)—[((C1-C6)alkyl)-N]—, phenyl-(C═O)—[(C1-C6)alkyl-N]—, (C1-C6)alkyl-SO2NH—, (C3-C10)cycloalkyl-SO2NH—, phenyl-SO2NH—, (C5-C10)heterocyclic-SO2NH— and (C5-C10)heteroaryl-SO2NH—;
• wherein the phenyl or heteroaryl moiety of a R6 substituent is optionally further substituted with at least one radical independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl and perfluoro(C1-C6)alkoxy,
• with the proviso that when R4 is a substituted phenyl group, then (a) R1 is not a naphthyl, anthracenyl or phenyl and (b) if R1 is a phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms independently selected from N, O and S, then the fused cyclic ring of said R1 moiety is substituted;
• and
• with the proviso that when R4 is hydrogen, then (a) R1 is not a naphthyl or phenyl and (b) if R1 is a phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms independently selected from N, O and S, then the fused cyclic ring of said R1 moiety is substituted;
• and
• with the proviso that when R4 is not hydrogen or substituted phenyl, then (a) R1 is not a naphthyl, anthracenyl or phenyl and (b) if R1 is a phenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms independently selected from N, O and S, and is optionally substituted by oxo, then the fused cyclic ring of said R1 moiety contains at least one substituted heteroatom.