Dihydrooxadiazinones

1. A compound having the structure of general formula (II):

in which

R 1 is selected from CF 3 and a fluorine atom;

R 2 is a hydrogen atom;

R 4 is selected from a hydrogen atom, and a C 1 -C 3 -alkyl group;

and X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a group selected from (C 1 -C 4 -alkylsulfonyl)oxy, (C 1 -C 4 -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, C1-C4-alkyl and C1-C4-alkoxy.

2. A method comprising:

the step A of allowing the compound of general formula (II)

to react under transition metal catalysed coupling conditions with an organoboron compound in the presence of a base and a palladium catalyst and, optionally, an additional ligand;

wherein the compound of formula (II) has the structure:

where

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;

R 4 is selected from a hydrogen atom, and a C 1 -C 3 -alkyl group;

X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a group selected from (C 1 -C 4 -alkylsulfonyl)oxy, (C 1 -C 4 -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy;

with the prerequisite that and if X is a chlorine atom, a bromine atom or an iodine atom then R 1 and R 2 is not chlorine, bromine or iodine; and

the organoboron compound is selected from

a boronic acid of formula (Ma)

(R x )B(OH) 2   (IIIa),

a boronic ester of formula

(R x )B(OR Y ) 2   (IIIb),

and a tetrafluoroborate salt of formula

(R x )BF 4   (IIIc),

whereby

R x is a C 1 -C 6 -alkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a hydroxy group, a C 1 -C 4 -alkoxy group, and a 3- to 7-membered heterocycloalkyl group,

a C 2 -C 6 -alkenyl group which is optionally substituted with an C 1 -C 4 -alkoxy group,

a C 5 -C 9 -cycloalkenyl group, which is optionally substituted with a hydroxy group,

a 3- to 9-membered heterocycloalkyl group, comprising one, two or three heteroatoms which are independently selected from —O—, —S—, —S(O)—, S(O) 2 , and —NR 9 —,

and said heterocycloalkyl group optionally further comprising a bridging group selected from —O—, —NR 9 —, —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR 9 —CH 2 —, and —CH 2 —NR 9 —;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom;

a oxo(═O) group;

a cyano group;

a hydroxy group;

a C 1 -C 3 -alkyl group which is optionally further substituted with a hydroxy 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 5 R 6 group and

a NR 5 R 6 group,

a 5- to 9-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 a —C(O)R 5 R 6 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, and a NR 5 R 6 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 C 1 -C 3 -alkyl group, a cyano group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, a hydroxy group, and a NR 5 R 6 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and

R y is C 1 -C 6 -alkyl, or the two residues R y together are a C 2 -C 6 -alkylene group; and

the palladium catalyst is selected from: dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(II) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bi s(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),

palladium (II) acetate and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] palladium(II);

in order to form a compound of general formula (I):

wherein R 3 is R x .

3. The method according to claim 2 , wherein

for the compound: le is trifluoromethyl and R 2 is a hydrogen atom,

and

Suzuki coupling conditions are used and the palladium catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), and the ligand is 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl.

4. A method comprising:

the step B of allowing an intermediate compound of general formula (II) to react with an amine selected from HNR 7 R 8 and a cyclic amine featuring one N—H as a ring atom,

wherein

R 7 /R 8 are independently selected from

a hydrogen atom, with the proviso that R 7 =R 8 =hydrogen is excluded,

a C 1 -C 6 -alkyl group,

which is optionally substituted with one, two, three or four substituents and said substituent is independently selected from

a halogen atom, a cyano group, a hydroxy group, a C(O)NR 5 R 6 group, a NR 5 R 6 group,

a C 1 -C 3 -alkoxy group,

a C 3 -C 7 -cycloalkyl group which is optionally substituted with one or two substituents and said substituents are independently selected from a C 1 -C 3 -alkylgroup, an oxo (═O) group, a hydroxy group, and a C 1 -C 3 -hydroxyalkyl group;

a 3- to 7-membered heterocycloalkyl group which itself is optionally substituted with a C 1 -C 3 -alkyl group or an oxo (═O) group,

a heteroaryl group, which itself is optionally substituted with a C 1 -C 3 -alkyl group;

a —C 1 -C 5 -alkylene-O—C 1 -C 5 -alkyl group,

a —C 1 -C 5 -alkylene-S—C 1 -C 5 -alkyl group,

a —C 1 -C 5 -alkylene-NR 5 —C 1 -C 5 -alkyl group,

a C 3 -C 6 -cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3- to 6-membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent independently selected from C 1 -C 3 -alkyl group and a hydroxy group,

a 3- to 9-membered heterocycloalkane containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a 3- to 9-membered heterocycloalkyl group as defined for R 3 supra, with the proviso it contains one N—H as a ring atom,

a partially unsaturated 3- to 9-membered heterocycloalkane containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a partially unsaturated 3- to 9-membered heterocycloalkyl group, as defined for R 3 supra, with the proviso it contains one N—H as a ring atom, and

a heteroarene containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a heteroaryl group as defined for R 3 supra, with the proviso it contains one N—H as a ring atom; and

said cyclic amine being selected from a 3- to 9-membered heterocycloalkane, a partially unsaturated 3- to 9-membered heterocyloalkane, and a heteroarene, containing one N—H as a ring atom, respectively, and

the compound of formula (II) has the structure:

where

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;

R 4 is selected from a hydrogen atom, and a C 1 -C 3 -alkyl group;

X is F or C 1 , with the proviso that if X is C 1 , R 1 or R 2 cannot be F; and at least one of R 1 and R 2 exerts an electron withdrawing effect;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; and

optionally in the presence of a base, and optionally the presence of an inert solvent, and at temperature ranging from RT to 160° C., in order to form a compound of general formula (I):

wherein R 3 is selected from —NR 7 R 8 , an N-linked 3- to 9-membered heterocycloalkyl group, an N-linked, partially unsaturated 3- to 9-membered heterocyloalkyl group, and an N-linked heteroaryl group.

5. The method according to claim 4 wherein

for the compound of formula (II): R 1 is trifluoromethyl and R 2 is a hydrogen atom, and

two residues R y together are —C(CH 3 ) 2 —C(CH 3 ) 2 — to form a pinacol ester, the base is potassium carbonate or potassium acetate.

6. A method comprising:

the step C of allowing an intermediate compound of general formula (II) to react with

an amine, optionally as a free base or as a salt, in the presence of a base, and a palladium catalyst optionally with a ligand in an inert solvent, and at a temperature ranging from 60° C. to 160° C.;

wherein the amine is selected from HNR 7 R 8 and cyclic amine featuring one N—H as a ring atom, said cyclic amine being selected from a 3- to 9-membered heterocycloalkane, a partially unsaturated 3- to 9-membered heterocyloalkane, and a heteroarene, containing one N—H as a ring atom, respectively,

in which

R 7 /R 8 are independently selected from

a hydrogen atom, with the proviso that R 7 =R g =hydrogen is excluded,

a C 1 -C 6 -alkyl group,

which is optionally substituted with one, two, three or four substituents and said substituent is independently selected from

a halogen atom, a cyano group, a hydroxy group, a C(O)NR 5 R 6 group, a NR 5 R 6 group, a C 1 -C 3 -alkoxy group,

a C 3 -C 7 -cycloalkyl group which is optionally substituted with one or two substituents and said substituents are independently selected from a C 1 -C 3 -alkylgroup, a oxo (═O) group, a hydroxy group, and a C 1 -C 3 -hydroxyalkyl group;

a 3- to 7-membered heterocycloalkyl group which itself is optionally substituted with a C 1 -C 3 -alkyl group or an oxo (═O) group,

a heteroaryl group, which itself is optionally substituted with a C 1 -C 3 -alkyl group;

a —C 1 -C 5 -alkylene-O—C 1 -C 5 -alkyl group,

a —C 1 -C 5 -alkylene-S—C 1 -C 5 -alkyl group,

a —C 1 -C 5 -alkylene—NR 5 —C 1 -C 5 -alkyl group,

a C 3 -C 6 -cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3- to 6-membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent independently selected from C 1 -C 3 -alkyl group and a hydroxy group,

a 3- to 9-membered heterocycloalkane containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a 3- to 9-membered heterocycloalkyl group as defined for R 3 supra, with the proviso it contains one N—H as a ring atom,

a partially unsaturated 3- to 9-membered heterocycloalkane containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a partially unsaturated 3- to 9-membered heterocycloalkyl group, as defined for R 3 supra, with the proviso it contains one N—H as a ring atom, and

a heteroarene containing one N—H as a ring atom is to be understood as a cyclic amine corresponding to a heteroaryl group as defined for R 3 supra, with the proviso it contains one N—H as a ring atom; and

the compound of formula (II) has the structure:

where

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 fluorine atom;

R 4 is selected from a hydrogen atom, and a C 1 -C 3 -alkyl group;

X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a group selected from (C 1 -C 4 -alkylsulfonyl)oxy, (C 1 -C 4 -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy being optionally substituted with one, two, three, four or five substituents, each of them independently selected from halogen, nitro, cyano, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy;

with the prerequisite that and if X is a chlorine atom, a bromine atom or an iodine atom then R 1 and R 2 is not chlorine, bromine or iodine;

in order to form a compound of general formula (I):

wherein R 3 is selected from —NR 7 R 8 , N-linked 3- to 9-membered heterocycloalkyl group, an N-linked, partially unsaturated 3- to 9-membered heterocyloalkyl group, and an N-linked heteroaryl group.

7. The method according to claim 2 , wherein

for the compound (II): le is trifluoromethyl and R 2 is a hydrogen atom, and

the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0) and the ligand is 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl or 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene.

8. The compound according to claim 1 , wherein

R 4 is selected from a hydrogen atom and a methyl group.

9. The compound according to claim 1 , wherein the compound is selected from:

5-(3,4-Difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one;

5-[4-Chloro-3-(trifluoromethyl)phenyl]hydro-2H-1,3,4-oxadiazin-2-one;

5-(4-Chloro-3-fluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one;

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one;

(rac)-5-[4-Chloro-3 4trifluoromethyl)phenyl]ethyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one;

(6 S)-5-[4-Chloro-3-(trifluoromethyl)phenyl]ethyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one;

(6S)-5-(-[(4-Fluoro-3-(trifluoromethyl)phenyl)-)]methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one; and

5-[4-Bromo-3-(trifluoromethyl)phenyl]hydro-2H-1,3,4-oxadiazin-2-one.

10. The method according to claim 2 , wherein R x is a methyl group which is optionally substituted with a 3 to 7 membered heterocycloalkyl group.

11. The method according to claim 2 , wherein the two residues R y together are —C(CH 3 ) 2 —C(CH 3 ) 2 .