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

Patent metadata

Field	Value
Publication number	US-11897867-B2
Application number	US-201816635513-A
Country	US
Kind code	B2
Filing date	Aug 2, 2018
Priority date	Aug 4, 2017
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

Abstract

The present invention provides 6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives of formula (I): The present invention provides 6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives of formula (I):

First claim

The invention claimed is:

1. 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
R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, and a C 1 -C 3 -haloalkoxy group;
R 2 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 R 1 /R 2 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)
(R x )B(OH) 2    (IIIa)

whereby R x is
a C 1 -C 6 -alkoxy group,
a C 2 -C 6 -alkenyl group,
a C 3 -C 6 -cycloalkyl group,
a C 5 -C 6 -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 C 1 -C 3 -alkyl group, a hydroxy group, NR 4 R 5 group, a C 1 -C 3 -haloalkyl group and a C 1 -C 3 -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 C 1 -C 3 -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 C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, a C 1 -C 3 -haloalkoxy group, a —C(O)NR 4 R 5 group and a NR 4 R 5 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 C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, and a NR 4 R 5 group; or
a NR 6 R 7 group,
R 4 /R 5 is independently selected from a hydrogen atom, a C 1 -C 6 -alkyl group, a —C 1 -C 5 -alkylen-O—C 1 -C 5 -alkyl group, a —C 1 -C 5 -alkylen-S—C 1 -C 5 -alkyl group, C 3 -C 6 -cycloalkyl group, and a 3- to 5-membered heterocycloalkyl group;
R 6 /R 7 is independently selected from a hydrogen atom, a C 1 -C 6 -alkyl group, a —C 1 -C 5 -alkylen-O—C 1 -C 5 -alkyl group, a —C 1 -C 5 -alkylen-S—C 1 -C 5 -alkyl group, a —C 1 -C 5 -alkylen-NR 8 —C 1 -C 5 -alkyl group, a —C 1 -C 5 -hydroxyalkylen-(C 1 -C 3 -haloalkyl) group, a C 3 -C 6 -cycloalkyl group, and a 3- to 5-membered heterocycloalkyl group,
or R 6 and R 7 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 —NR 8 —,
and which is optionally substituted one, two, or three times with a substituent selected from a halogen atom, a hydroxy group, and a C 1 -C 3 -alkyl group
and if R 6 and R 7 together form a 5-, 6- or 7-membered ring, said ring can optionally contain a bridging group selected from a bond, —O—, —NR 8 —, —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 —, —NR 8 —CH 2 —;

R 8 is a hydrogen atom or a C 1 -C 3 -alkyl group; or
a boronic ester of formula (IIIb)
(R x )B(OR Y ) 2    (IIIb)

wherein R x is as defined for the boronic acid above and
R y is C 1 -C 6 -alkyl, or the two residues R y 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 R 3 is R x
or
b) if X=F, with the prerequisite that R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, and a C 1 -C 3 -haloalkyl group, and R 2 is selected from a hydrogen atom and a halogen atom,
the method comprises allowing the compound of Formula (II) to react with HNR 7 R 8 ;
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 R 3 is NR 7 R 8 .

2. The method according to claim 1 wherein the transmetal catalyzed coupling conditions are suitable for Negishi couplings, Kumada couplings, and Stille couplings.

3. The method according to claim 1 wherein the transmetal catalyzed coupling conditions are suitable for Suzuki couplings.

Assignees

• Bayer Ag
• Bayer Pharma AG
• Broad Inst Inc

Inventors

• Ellermann Manuel
• Lewis Timothy

Classifications

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D237/04

  having less than three double bonds between ring members or between ring members and non-ring members · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D405/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title