6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives as PDE3A and PDE3B inhibitors for treating cancer

A method of preparing a compound of general formula (I) having the structure:

• said method comprising the step of allowing an intermediate compound of general formula (II) to react:
• in which
• R1 is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group;
• R2 is selected from a hydrogen atom and a halogen atom;
• and
• X=F, Cl, Br, or I
• to form the compound of general formula (I);
• wherein
• a) if X=Cl, Br, or I, with the prerequisite that R1/R2 is not Cl, Br, or I, the method comprises allowing the compound of Formula (II) to react under transmetal catalyzed coupling conditions with a boronic acid of formula (IIIa)
• (Rx)B(OH)2 (IIIa)
• whereby Rx is
• a C1-C6-alkoxy group,
• a C2-C6-alkenyl group,
• a C3-C6-cycloalkyl group,
• a C5-C6-cycloalkenyl group,
• a 3- to 7-membered heterocycloalkyl group, which is optionally substituted with one, two, or three substituents and each substituent is independently selected from a halogen atom, a C1-C3-alkyl group, a hydroxy group, NR4R5 group, a C1-C3-haloalkyl group and a C1-C3-haloalkoxy group,
• a 5- to 7-membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents and each substituent is independently selected from an oxo group (═O), a C1-C3-alkyl group and a halogen atom,
• an aryl group which is optionally substituted with one, two, three or four substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkoxy group, a —C(O)NR4R5 group and a NR4R5 group;
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, a C1-C3-alkoxy group, and a NR4R5 group;
• or
• a NR6R7 group,
• R4/R5 is independently selected from a hydrogen atom, a C1-C6-alkyl group, a —C1-C5-alkylen-O—C1-C5-alkyl group, a —C1-C5-alkylen-S—C1-C5-alkyl group, C3-C6-cycloalkyl group, and a 3- to 5-membered heterocycloalkyl group;
• R6/R7 is independently selected from a hydrogen atom, a C1-C6-alkyl group, a —C1-C5-alkylen-O—C1-C5-alkyl group, a —C1-C5-alkylen-S—C1-C5-alkyl group, a —C1-C5-alkylen-NR8—C1-C5-alkyl group, a —C1-C5-hydroxyalkylen-(C1-C3-haloalkyl) group, a C3-C6-cycloalkyl group, and a 3- to 5-membered heterocycloalkyl group,
• or R6 and R7 together form a 3-, 4-, 5-, 6- or 7-membered ring optionally containing one or two additional heteroatoms selected from the group consisting of —O—, —S— and —NR8—,
• and which is optionally substituted one, two, or three times with a substituent selected from a halogen atom, a hydroxy group, and a C1-C3-alkyl group
• and if R6 and R7 together form a 5-, 6- or 7-membered ring, said ring can optionally contain a bridging group selected from a bond, —O—, —NR8—, —CH2—, —CH2—CH2—, —O—CH2—, —NR8—CH2 —;
• R8 is a hydrogen atom or a C1-C3-alkyl group;
• or
• a boronic ester of formula (IIIb)
• (Rx)B(ORY)2 (IIIb)
• wherein Rx is as defined for the boronic acid above and
• Ry is C1-C6-alkyl, or the two residues Ry together form a pinacol ester, /potassium carbonate/a palladium catalyst selected from the following list:
• dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(II) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium dimer, allyl(chloro)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)palladium, palladium(II) acetate/dicyclohexyl(2′,4′,6′-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), or (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), preference being given to chloro(2-dicyclohexylphosphino-2′, 4′, 6′-triisopropyl-1, 1′-biphenyl)[2-(2′-amino-1, 1′-biphenyl)]palladium(II) in order to obtain a compound of formula (I) wherein R3 is Rx
• or
• b) if X=F, with the prerequisite that R1 is selected from a hydrogen atom, a halogen atom, a cyano group, and a C1-C3-haloalkyl group, and R2 is selected from a hydrogen atom and a halogen atom,
• the method comprises allowing the compound of Formula (II) to react with HNR7R8;
• optionally in the presence of a base, and optionally in the presence of an inert solvent, and optionally heat, up to the boiling point of the present solvent;
• in order to obtain a compound of formula (I) wherein R3 is NR7R8.