HK1141790B - Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics - Google Patents

Description

Derivatives of 7-alkynyl-1, 8-naphthyridinones, preparation thereof and use thereof in therapeutics

The present invention relates to 7-alkynyl-1, 8-naphthyridinone derivatives, their preparation and their use in therapeutics.

Objects of the present invention are compounds corresponding to formula (I):

wherein

R ₁ And R ₂

(1)Represent, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl, -CO- (C1-C7) alkyl or C3-C8 cycloalkyl, wherein said alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from halogen atoms and hydroxyl and alkoxy groups,

or phenyl optionally substituted with one or more groups selected from: halogen atom, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -haloalkoxy, -haloalkyl, -CN or-NRR ', wherein R and R' are as defined below,

heteroaryl optionally substituted at any position (including on the nitrogen atom of the heteroaryl) with one or more groups selected from: halogen atoms, C1-C4 alkyl groups and NRR 'groups, wherein R and R' are as defined below,

(2) or R1 and R2 form, together with the carbon atom bearing them:

or C4-C8 cycloalkyl,

or a 4-8 membered saturated heterocyclic group containing a heteroatom selected from N, O and S atom,

and the heterocyclic group may be fused with a phenyl group;

R ₃ represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: halogen atoms and hydroxy, alkoxy, -NRR', -haloalkyl and-SO₂- (C1-C4) alkyl, wherein R and R' are as defined below,

or- (CH)₂)_n-a heterocyclic group, wherein n is 0, 1, 2 or 3, wherein the heterocyclic group comprises 4 to 8 mer and comprises at least one heteroatom selected from N, O and S atom, wherein the heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0, 1, 2 or 3, wherein the heteroaryl comprises 5 or 6 mer and comprises oneOne or more heteroatoms selected from nitrogen, oxygen and sulfur.

R4 representsA hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,

r and R'Independently of one another, represents a hydrogen atom, a C1-C4 alkyl group.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may thus exist as enantiomers, diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures thereof, form part of the present invention.

The compounds of formula (I) may be present as bases or as salts with acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts form part of the present invention. These salts are advantageously prepared using pharmaceutically acceptable acids or bases, but salts of other acids or bases, for example, for purifying or isolating the compounds of formula (I), also form part of the invention.

The compounds according to the invention may also be present in the form of hydrates or solvates, i.e. bound or associated with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the present invention.

In the context of the present invention, unless otherwise specified herein:

-an alkyl group: a saturated aliphatic group comprising from 1 to 7 carbon atoms, advantageously from 1 to 4 carbon atoms, and which is linear or, when the alkyl chain comprises at least 3 carbon atoms, may be linear, branched or partially cyclized. As examples, there may be mentioned methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methylene-cyclopropyl, methylene-cyclohexyl, pentyl, 2-dimethylpropyl, hexyl, heptyl and the like;

-a cycloalkyl group: cyclic alkyl groups containing 3 to 8 carbon atoms, wherein all carbon atoms are included in the ring. Mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

-an alkoxy group: -O-alkyl, wherein alkyl is as defined above;

halogen atoms are understood as: fluorine, chlorine, bromine or iodine.

-haloalkyl groups: an alkyl group whose one or more hydrogen atoms have been substituted with a halogen atom; by way of example, mention may be made of-CF 3;

-haloalkoxy groups: alkoxy groups whose one or more hydrogen atoms have been substituted with halogen atoms; by way of example, mention may be made of-OCF 3;

-aryl: monocyclic aryl, such as phenyl;

-heteroaryl: aryl containing 5 or 6 mer and containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. For example, pyridyl, furyl, thienyl, pyrimidinyl, pyrazinyl and thiazolyl may be mentioned; and

-a heterocyclic group: cyclic alkyl groups containing 4 to 8 mer and containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Mention may be made, for example, of piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothienyl.

Among the compounds of formula (I) object of the present invention, mention may be made of the subclasses of compounds defined as follows:

r1 and R2

(3) Represents, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl, -CO- (C1-C7) alkyl or C3-C8 cycloalkyl, wherein said alkyl and cycloalkyl groups are optionally substituted with one or more groups selected from halogen atoms and hydroxyl and alkoxy groups,

or phenyl optionally substituted with one or more groups selected from: halogen atom, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -OCF₃、-CF₃A group, -CN, -NRR ', wherein R and R' are as defined below,

or heteroaryl optionally substituted at any position (including on the nitrogen atom of the heteroaryl) with one or more groups selected from: halogen atoms, C1-C4 alkyl groups and NRR 'groups, wherein R and R' are as defined below,

(4) or R₁And R₂Together with the carbon atom bearing them form:

or C4-C8 cycloalkyl,

or a 4-8 membered saturated heterocyclic group containing a heteroatom selected from N, O and S atom,

and the heterocyclic group may be fused with a phenyl group;

R ₃ represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: halogen atom and hydroxy, alkoxy, -NRR', CF₃and-SO₂- (C1-C4) alkyl, wherein R and R' are as defined hereinafter,

or- (CH)₂)_n-a heterocyclic group, wherein n ═ 0, 1, 2 or 3 and wherein the heterocyclic group contains 4 to 8 mer and contains at least one heteroatom selected from N, O and S atoms, wherein said heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0, 1, 2 or 3 and wherein the heteroaryl contains 5 or 6 mer and contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R ₄ representsA hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group;

r and R'Independently of one another, represents a hydrogen atom or a C1-C4 alkyl group.

Among the compounds of formula (I) object of the present invention, mention may be made of the subclasses defined below:

r1 and R2

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl, -CO- (C1-C7) alkyl, or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or a heteroaryl group, or a pharmaceutically acceptable salt thereof,

(2) or R₁And R₂Together with the carbon atom bearing them form:

or C4-C8 cycloalkyl,

or a 4-8 membered saturated heterocyclic group containing a heteroatom selected from N, O and S atom,

and the heterocyclic group may be fused with a phenyl group;

and/or

R ₃ Represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: hydroxy, alkoxy, NRR', haloalkyl and SO₂- (C1-C4) alkyl, wherein R and R' are as defined hereinafter,

or- (CH)₂)_n-a heterocyclic group, wherein N ═ 0, 1, 2 or 3 and wherein the heterocyclic group contains 4 to 8 mer and contains at least one member selected from the group consisting of N anda heteroatom of an O atom, wherein the heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1 and wherein the heteroaryl comprises 5 or 6 mer and comprises one or more nitrogen heteroatom;

and/or

R ₄ RepresentsC₁-C₄Alkyl or C₁-C₄An alkoxy group;

and/or

R and R'Each represents a linear or branched C1-C4 alkyl group.

Among the compounds of formula (I) object of the present invention, there may be mentioned another subclass of compounds defined as follows:

R ₁ and R ₂

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl, -CO- (C1-C7) alkyl, or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or heteroaryl

(2) Or R₁And R₂Together with the carbon atom bearing them form:

or C4-C8 cycloalkyl,

a saturated heterocyclic group of 4 to 8 members containing an oxygen heteroatom,

and the heterocyclic group may be fused with a phenyl group;

and/or

R ₃ Represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: hydroxy, alkoxy, NRR', haloalkyl and SO₂- (C1-C4) alkyl, wherein R and R' are as defined below;

or- (CH)₂)_n-a heterocyclic group, wherein N is 0, 1, 2 or 3, wherein the heterocyclic group comprises 4 to 8 mer and comprises at least one heteroatom selected from N and O atoms, wherein the heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1 and wherein the heteroaryl comprises 5 or 6 mer and comprises one or more nitrogen heteroatom;

and/or

R ₄ RepresentsC1-C4 alkyl or C1-C4 alkoxy;

and/or

R and R'Each represents a linear or branched C1-C4 alkyl group.

Among the compounds of formula (I) object of the present invention, mention may be made of a third subclass of compounds defined as follows:

R ₁ and R ₂

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl or C3-C8 cycloalkyl, wherein the alkyl is optionally substituted with one or more groups selected from hydroxy and alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or heteroaryl

(2) Or R₁And R₂Together with the carbon atom bearing them, form a C4-C8 cycloalkyl group;

and/or

R ₃ Represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: hydroxy, alkoxy, haloalkyl and-SO₂- (C1-C4) alkyl;

or- (CH)₂)_n-a heterocyclic group, wherein n is 0, 1, 2 or 3 and wherein the heterocyclic group contains 4-8 mer and contains at least one heteroatom selected from N, O atoms, wherein the heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1 and wherein the heteroaryl comprises 5 or 6 mer and comprises one or more nitrogen heteroatom;

and/or

R ₄ RepresentsC1-C4 alkyl;

and/or

R and R'Each represents a linear or branched C1-C4 alkyl group.

Among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,

R ₁ and R ₂

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl, -CO- (C1-C7) alkyl, or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or heteroaryl

(2) Or R1 and R2 form, together with the carbon atom bearing them:

or C4-C8 cycloalkyl,

or a 4-8 membered saturated heterocyclic group containing a heteroatom selected from N, O and S atom,

and the heterocyclic group may be fused with a phenyl group;

more particularly, among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,R ₁ and/or R ₂ Represents pyridyl, thienyl, thiazolyl or pyrazinyl or imidazolyl.

More particularly, among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which R is₁And R₂Together with the carbon atom bearing them, form a heterocyclic group selected from tetrahydrofuranyl or tetrahydropyranyl, wherein said heterocyclic group may be fused with phenyl.

Among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,

R ₃ represents:

or straightA chain or branched C1-C7 alkyl or C3-C7 alkyl cyclized with at least 3 carbon atoms thereof, said alkyl being optionally substituted with one or more groups selected from: hydroxy, alkoxy, NRR', haloalkyl and SO₂- (C1-C4) alkyl, wherein R and R' are as defined below,

or- (CH)₂)_n-a heterocyclic group, wherein N is 0, 1, 2 or 3, wherein the heterocyclic group comprises 4 to 8 mer and comprises at least one heteroatom selected from N and O atoms, wherein the heterocyclic group is optionally substituted with an oxo group,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1, wherein the heteroaryl comprises 5 or 6 mer and comprises one or more nitrogen heteroatom.

More particularly, among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,R ₃ representsA C3-C7 alkyl group, cyclized with at least 3 carbon atoms, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and methylene-cyclopropyl.

More particularly, among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,R ₃ represents-(CH₂)_n-a heterocyclic group, wherein n ═ 0, 1, 2 or 3, and wherein the heterocyclic group is selected from tetrahydropyranyl, tetrahydrofuranyl and pyrrolidinyl.

More particularly, among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,R ₃ represents-(CH₂)_n-heteroaryl, wherein n ═ 1 and wherein heteroaryl represents pyridyl.

Among the compounds of formula (I) object of the present invention, mention may be made of a small class of compounds for which,R ₄ representsC1-C4 alkyl or C1-C4 alkoxy.

Among the compounds of formula (I) object of the present invention, there may be mentioned oneA subclass of compounds, for which,r and R'Each represents a linear or branched C1-C4 alkyl group.

Among the compounds of interest according to the invention, mention may in particular be made of the following compounds:

■ 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ (1-hydroxycyclopentyl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxybut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxy-3-methyl-pent-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-cyclopentyl-3-hydroxypropan-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-cyclopropyl-3-hydroxypropan-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ 2-amino-1-ethyl-7- [ (1-hydroxycyclobutyl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ 2-amino-1-ethyl-7- [ 3-hydroxy-4-methoxy-3- (methoxymethyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1- (cyclopropylmethyl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-methoxyphenyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (4-methoxyphenyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1- (3-methoxypropyl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-cyclopentyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1-isopropyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1-isobutyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ 2-amino-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -1- (3-methoxypropyl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-phenylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1- (tetrahydropyran-4-yl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-cyclohexyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (1, 3-thiazol-2-yl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (methoxymethyl) pent-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- [3- (2-oxopyrrolidin-1-yl) propyl ] -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1-propyl-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (2, 2, 2-trifluoroethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (tetrahydrofuran-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- (3-hydroxy-3-pyrazin-2-ylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-cyclopropyl-3-hydroxy-4-methoxybut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (2-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (2-methoxyphenyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-cyclopentyl-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (4-ethoxy-3-hydroxy-3-methylbut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1- (trans-4-hydroxycyclohexyl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-1- [3- (methylsulfonyl) propyl ] -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1- (cyclopropylmethyl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1- (cyclopropylmethyl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1- (3-methoxypropyl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1- (3-methoxypropyl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-cyclopentyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-cyclopentyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1-isopropyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1-isopropyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-cyclohexyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-cyclohexyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1-propyl-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1-propyl-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (2, 2, 2-trifluoroethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (2, 2, 2-trifluoroethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (methoxymethyl) pent-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (methoxymethyl) pent-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide.

According to the present invention, the compounds of formula (I) may be prepared according to the methods represented in scheme 1.

FIG. 1 shows a schematic view of a

According to FIG. 1, a 2, 6-dihalonicotinic acid of formula (II), wherein the X group represents a halogen atom, preferably chlorine or bromine, is prepared commercially available or according to methods known to those skilled in the art, in a protic solvent (such as an alcohol or water) at a temperature of between 20 ℃ and 150 ℃ with the formula R in the 2-position₃-NH₂Is monosubstituted (wherein R is₃As defined above for the compounds of formula (I) object of the invention), optionally in sealed tubes. 2-aminonicotinic acid derivatives of formula (III) are obtained, which are converted to acyl fluorides of formula (IV) under the action of cyanuric fluoride in the presence of a base such as triethylamine or pyridine and in an inert solvent such as dichloromethane at ambient temperature, as described by G.Olah et al in Synthesis (1973), 487, or by other methods known to those skilled in the art such as those described by Mukai yama and Tanaka in chem.Lett. (1976), 303, or by Ishikawa and Sasaki in chem.Lett. (1976), 1407. The highly reactive but stable acid fluoride of formula (IV) is then reacted with the N-substituted cyanoacetamide of formula (V) in the presence of a strong base, such as sodium hydride, in a polar aprotic solvent, such as dimethylformamide.

If both equivalents of sodium hydride are used, beta-c-cyano acetamide of the formula (VI) is obtained after overnight at ambient temperature, which is subsequently cyclized by heating to a temperature of 90-125 ℃ in a polar solvent (e.g.n-butanol, dimethyl sulfoxide or dimethylformamide) (method A) or by treatment with a strong base (e.g.potassium tert-butoxide) in an aprotic solvent (preferably tetrahydrofuran) (method B) at ambient temperature to give amino-pyrido [2, 3-B ] pyridinones of the formula (VII).

When two equivalents of sodium hydride are used in the condensation step of derivative (IV) with derivative (V), and then a third equivalent of NaH is introduced after stirring for 10-16 hours at ambient temperature, the deprotonated compound (VI) formed undergoes cyclization in situ at the same temperature to obtain directly the amino-pyrido [2, 3-b ] pyridone of formula (VII), in good yield (method C).

The N-alkylcyanoacetamides of formula (V) are prepared by reacting cyanoacetic acid with an alkyl chloroformate, such as isobutyl or ethyl chloroformate, in the presence of a base, such as triethylamine, at a temperature less than or equal to 0 deg.C, and the intermediate mixed anhydride formed is then reacted with an excess of the compound of formula R₄-NH₂Amine reaction (wherein R₄As defined above for the compounds of formula (I) which are objects of the present invention).

To obtain pyrido [2, 3-b ] of formula (I) for the purposes of the invention](iv) pyridones, halogenation of intermediates of formula (VII) with propargyl alcohols R of formula (VIII) according to methods known to those skilled in the art₁R₂Coupling of suitable derivatives of CH (OH) CCH, wherein R₁，R₂As defined for the compounds of formula (I). For example, in PdCl₂(PPh₃)₂Intermediate (VII) is subjected to Sonogashira coupling reaction with a suitable alkyne of formula (VIII) in the presence of cuprous iodide, triethylamine and dimethylformamide at a temperature of 80 ℃ to 120 ℃. The reaction can be carried out in a sealed tube and under microwave radiation.

If desired, during the reaction steps represented in scheme 1, the carboxyl Groups or certain reactive functional Groups located on the R1, R2, and R3 Groups can be temporarily protected with protecting Groups known to those skilled in the art, as described in "Protective Groups in organic Synthesis", Green et al, 2 nd edition (John Wiley & Sons Inc., New York).

In FIG. 1, the starting compounds and the reactants, when their preparation is not described, are commercially available or described in the literature or can be prepared according to the methods described therein or known to those skilled in the art.

According to another aspect of the invention, the invention also relates to a compound of formula (VII) as defined in figure 1. These compounds are useful as intermediates in the synthesis of compounds of formula (I).

The following examples illustrate the preparation of certain compounds according to the invention. These examples are not limiting and serve only to illustrate the invention. The numbers of the exemplified compounds correspond to the numbers given in the following table, which illustrates the chemical structures and physical properties of some of the compounds according to the invention.

The following abbreviations and empirical formulas were used:

CuI cuprous iodide

CH₂Cl₂Methylene dichloride

CLHP high performance liquid chromatography

CL/SM liquid chromatography/Mass Spectrometry

DMF dimethyl formamide

DMSO dimethyl sulfoxide

Et₃N-Triethylamine

h hours

HCl hydrochloric acid

MHz megahertz

MeOH methanol

MgSO₄Magnesium sulfate

NaCl sodium chloride

NH₄Cl ammonium chloride

NH₄OH ammonium hydroxide

NaHCO₃Sodium bicarbonate

Na₂SO₄Sodium sulfate

ppm parts per million

THF tetrahydrofuran

Example 1: 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.2)

1.12- (aminoethyl) -6-chloronicotinic acid

A solution of 18.0g (84.4 mmol) of 2, 6-dichloronicotinic acid in 180ml of 70% ethylamine in water is stirred at ambient temperature for 72 hours. The excess amine was then evaporated under reduced pressure and then 10% aqueous acetic acid was added until the product precipitated. The beige solid was dehydrated, rinsed with cold water and dried in an oven. 10.5g of the expected product are obtained. Melting point: 158 ℃ and 160 ℃. The yield was 62%.

1.2: 2- (aminoethyl) -6-chloronicotinyl fluoride

2ml (24.8 mmol) of pyridine and 4.2ml (49.8 mmol) of 2, 4, 6-trifluoro-triazine are added to a suspension of 5.0g (24.8 mmol) of 2- (aminoethyl) -6-chloronicotinic acid in 125ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 3 hours and then filtered. The solid was rinsed with 50ml dichloromethane and washed twice with 60ml of frozen water. Organic phase in Na₂SO₄Dried above and the solvent evaporated under reduced pressure. 5.01g of product are obtained in the form of an orange oil. The yield was 99%.

1.3: n-methyl cyanoacetamide

12.28ml (128.44 mmol) of ethyl chloroformate was added dropwise to a solution of 10.0g (116.38 mmol) of 99% cyanoacetic acid and 16.3ml (116.9 mmol) of triethylamine in 100ml of anhydrous THF, cooled to-30 ℃ and then stirred at-30 ℃ for 1 hour and 30 minutes. 300ml of methanol saturated with gaseous methylamine are then added dropwise and stirred at ambient temperature overnight. The solvent was evaporated under reduced pressure and the product was purified by filtration on silica gel, eluting with a dichloromethane: alcohol (95: 5) mixture. 10.0g of product are obtained in the form of a beige solid. The melting point was 99 ℃. The yield was 87%.

Method a (sections 1.4 and 1.5 below).

1.4: 3- [ 6-chloro-2- (ethylamino) -3-pyridinyl ] -2-cyano-3-hydroxy-N-methyl-2-propenamide

3.98g (100 mmol) of 60% sodium hydride in mineral oil are added in small portions to a solution of 9.80g (100 mmol) of N-methylcyano-acetamide in 100ml of anhydrous dimethylformamide, cooled to 0-5 ℃. After the evolution of hydrogen had ended, the mixture was stirred at ambient temperature for 10 minutes and then cooled to 0-5 ℃. A solution of 10.09g (49.8 mmol) 2- (aminoethyl) -6-chloronicotinyl fluoride in 60ml dimethylformamide is then added and the medium is stirred at ambient temperature overnight. 2.85ml (49.8 mmol) of acetic acid were added and the volatiles were evaporated under reduced pressure. The residue was dissolved in water and the product was extracted twice with a dichloromethane: methanol (95: 5) mixture and once with an ethyl acetate: THF (2: 1) mixture. The combined organic phases were MgSO₄Drying was carried out and then the solvent was evaporated under reduced pressure. 19.0g of product was obtained, which was used as such in the following step.

1.5: 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

A solution of 19.0g of the crude product (49.8 mmol) obtained at the end of step 7.4 in 600ml of n-butanol is heated at 110 ℃ for 48 hours. The solvent was evaporated under reduced pressure and the obtained solid was triturated in methanol. The solid is then dewatered and dried in an oven. 7.9g of the expected product are obtained in the form of a pale yellow solid. Melting point: 283 ℃ and 286 ℃. The yield was 57%.

Method C (section 1.6 below instead of sections 1.4 and 1.5).

1.6: 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

0.394g (9.95 mmol) of 60% sodium hydride in mineral oil are added in small portions to a solution of 0.483g (4.93 mmol) of N-methylcyanoacetamide in 7ml of anhydrous dimethylformamide, cooled to 0-5 ℃. Stirring is continued at this temperature for 10 minutes, after which 1.0g (4) are added93 mmoles) of 2- (aminoethyl) -6-chloronicotinyl fluoride in 5ml of dimethylformamide. The medium is stirred at ambient temperature overnight and then 0.197g (4.93 mmol) of 60% sodium hydride are added in small portions. Stirring is continued for 10 minutes at this temperature and then 0.56ml (9.78 mmol) of acetic acid are added. Then 60ml of water was added and the solid was dewatered, rinsed with water and then dried in an oven. 1.30g of the expected product are obtained. Melting point: 283 ℃ and 284 ℃. MH⁺281. The yield was 94%.

1H NMR (DMSO-d6, 400 MHz): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.45(d, 1H); 8.10(s, 1H wide); 7.40(d, 1H); 4.40(q, 2H); 2.80(d, 3H); 1.25(t, 3H).

1.7: 2-amino-1-ethyl-7- (3-methyl-3-trimethylsilyloxy-but-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

In a 2 l three-necked flask, 40.7g 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro- [1, 8%]Naphthyridine-3-carboxamide (0.145 mol) and 56.2ml [ (1, 1-dimethyl-2-propynyl) oxy]Trimethylsilane (0.290mol) was introduced into a mixture of 365ml of dimethylformamide and 365ml of triethylamine in this order. The reaction mixture was bubbled with argon for 15 minutes then 0.983g of CuI (5.16 mmol) and 5.1g of bis (triphenylphosphine) palladium (II) dichloride (7.2 mmol) were added in that order. The reaction mixture was heated at 90 ℃ for 15 hours and then concentrated under reduced vacuum (vide duit). The residue was dissolved in 500ml ethyl acetate/NaHCO₃(V/V-1/1) aqueous mixture and filtered over a plug of celite, rinsing with ethyl acetate. The aqueous phase was extracted with dichloromethane (3 × 50ml) and the organic phases were then combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude reaction product was purified by chromatography on a silica column (eluting with a gradient of dichloromethane: ethyl acetate 80: 20 to 50: 50, then dichloromethane: methanol 95: 5 to 90: 10) to yield 36.2g of the expected product (yield ═ 62.3%) and 7.4g of the desilylated product described in the next step (yield ═ 15.5%).

1.8: 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

15g of 2-amino-1-ethyl-7- (3-methyl-3-trimethylsilyloxy-but-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (37.4 mmol) were dissolved in 815ml of tetrahydrofuran. The solution was cooled to 0 ℃ and then 13.0g tetrabutylammonium fluoride trihydrate (41.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 minutes. The evaporation to dryness and the residue dissolved in an ethyl acetate/tetrahydrofuran/water mixture. The aqueous phase is extracted with dichloromethane, and the organic phases are then combined, dried over sodium sulfate, filtered and concentrated in vacuo. 15g of crude product are obtained, which is dissolved in 1 l of methanol at elevated temperature, 6.75g of activated carbon are then added and the mixture is stirred at 70 ℃ for 5 hours. After filtration over celite and evaporation under vacuum, 11.9g of the desired product are obtained as a white solid.

Melting point 255 ℃. MH⁺329. The yield was 82.9%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.40(d, 1H); 8.00(s, 1H, wide); 7.40(d, 1H); 5.62(s, 1H, wide); 4.4(q, 2H); 2.75(d, 3H); 1.45(s, 6H); 1.20(t, 3H).

■ example 2: (±) -2-amino-1-ethyl-7- [ (3-hydroxytetrahydrofuran-3-yl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.7)

2.1: (±) -3-ethynyltetrahydro-3-furylphenol (±) -3-ethinyltetrahydrol-3-furanol)

A solution of 3-oxotetrahydrofuran (4.97 mmol; prepared as described in Tetrahedron 1991, 47, 6975-6980) in tetrahydrofuran) in 20ml of tetrahydrofuran was added to 20ml of a commercially available solution of 0.5M ethynylmagnesium bromide in tetrahydrofuran (10 mmol, Aldrich) which had been previously cooled to 0 ℃. Then stirred at ambient temperature for 4 hours and addedInto NH₄Saturated aqueous solution of Cl. Extraction with ethyl acetate is carried out, and the organic phases are then combined, washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. After purification by chromatography on a silica column, 319mg (2.79 mmol) of (. + -.) -3-ethynyltetrahydro-3-furanphenol were obtained in 57% yield as yellow oil.

2.2: (±) -2-amino-1-ethyl-7- [ (3-hydroxytetrahydrofuran-3-yl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

A suspension of 0.3g (2.24 mmol) 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro [1, 8] naphthyridine-3-carboxamide in 17ml dimethylformamide/triethylamine (V/V; 2/1) mixture was placed in a 10ml microwave tube. This suspension was bubbled with argon for 10 minutes and then 0.319g (2.79 mmol) (. + -.) -3-ethynyltetrahydro-3-furanphenol, 0.043g CuI (0.23 mmol) and 0.079g bis (triphenylphosphine) palladium (II) dichloride (0.11 mmol) were added in that order.

The sealed tubes were placed in a microwave (CEM device, Discover type) and the mixture was heated under pressure at 90 ℃ for 60 minutes (P ═ 100W) then cooled and evaporated to dryness. Dissolving with ethyl acetate, sequentially using NaHCO in organic phase₃The saturated aqueous solution was then washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica (gradient elution with dichloromethane: methanol from 98: 2 to 95: 5). 0.412g of the expected product is obtained in the form of a pale yellow solid.

Melting point 253 ℃. MH⁺357. The yield was 52%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.45(d, 1H); 8.00(s, 1H, wide); 7.4(d, 1H); 5.6(d, 1H); 4.55-4.30(m, 3H); 3.95-3.80(m, 4H); 2.8(d, 3H); 2.20(m, 1H); 1.9-1.35(m, 8H); 1.25(t, 3H).

■ example 3: (±) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.8)

3.1: preparation of (±) -1-methoxy-2-methyl-3-butyn-2-ol

1400 ml (0.7 mol) of a commercially available 0.5M solution of ethynylmagnesium chloride (ethynylmagnesium bromide) in tetrahydrofuran was poured into a three-neck flask under argon. The solution was cooled to 2 ℃ with an ice bath and a solution of 30g (0.327mol) of methoxyacetone in 600ml of tetrahydrofuran (exothermic) was slowly added. Stirred at 2 ℃ for 1 hour and then poured onto ice/NH₄Cl saturated aqueous mixture. Extraction with diethyl ether is carried out, and the organic phases are then combined, dried over sodium sulfate, filtered and concentrated under a limited vacuum. 38g of the expected product are obtained as a brown oil (quantitative crude product yield), which is used in the next step without subsequent purification.

3.2: (±) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

3g (10.69 mmol) 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro [1, 8%]Naphthyridine-3-carboxamide in 20ml DMF/Et₃A suspension of the N mixture (V/V; 1/1) was placed in an 80ml microwave tube. This suspension was bubbled with argon for 10 minutes and then 1.83g (. + -.) -1-methoxy-2-methyl-3-butyn-2-ol (16.03 mmol), 0.081g CuI (0.43 mmol) and 0.375g bis (triphenylphosphine) palladium (II) dichloride (0.53 mmol) were added in that order.

The sealed tubes were placed in a microwave oven (CEM device, Discover type) and the mixture was heated at 90 ℃ under pressure for 60 minutes (P ═ 100W) then cooled and evaporated to dryness. The residue was dissolved in an ethyl acetate/THF mixture and washed with 0.1N aqueous HCl. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo.

The residue obtained is purified by chromatography on silica (solid precipitate; elution with a gradient of cyclohexane: ethyl acetate from 30: 70 to 20: 80). 2.49g of the expected product are obtained in the form of a pale yellow solid.

The product can be recrystallized from ethanol to obtain white crystals.

Melting point 211 ℃. MH⁺358. The yield was 65%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.45(d, 1H); 8.00(s, 1H, wide); 7.4(d, 1H); 5.8(s, 1H); 4.4(q, 2H); 3.5-3.3(m + s, 5H); 2.8(d, 3H); 1.45(s, 3H); 1.2(t, 3H).

■ example 4: (±) -2-amino-7- (3-cyclopentyl-3-hydroxypropan-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.10)

4.1: (±) -1-cyclopentylprop-2-yn-1-ol

A solution of 0.87ml of cyclopentanecarboxaldehyde (8.15 mmol; Aldrich) in 10ml of tetrahydrofuran was added to 18ml of a commercially available solution of 0.5M ethynylmagnesium bromide in tetrahydrofuran (10 mmol; Aldrich) which had been cooled to 0 ℃ beforehand. Then stirred at ambient temperature for 2 hours and NH was added₄Saturated aqueous solution of Cl. Extraction with ethyl acetate is carried out, and the organic phases are then combined, washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. 0.931g of (. + -.) -1-cyclopentylprop-2-yn-1-ol were obtained in 92% yield as a light brown oil.

4.2: (±) -2-amino-7- (3-cyclopentyl-3-hydroxypropan-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

A suspension of 1g (3.56 mmol) 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro [1, 8] naphthyridine-3-carboxamide in 25ml dimethylformamide/triethylamine (V/V; 2.5/1) mixture was placed in a 10ml microwave tube. To this suspension was bubbled with argon for 10 minutes and then 0.931g (7.5 mmol) (. + -.) -1-cyclopentylprop-2-yn-1-ol, 0.068g CuI (0.36 mmol) and 0.125g bis (triphenylphosphine) palladium (II) dichloride (0.18 mmol) were added in that order.

The sealed tubes were placed in a microwave oven (CEM device, Discover type) and the mixture was heated under pressure at 80 ℃ for 17 minutes (P ═ 50W). The evaporation to dryness was followed by dissolving the residue in ethyl acetate. Organic phase is sequentially treated with NaHCO₃The saturated aqueous solution was then washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica (gradient elution with dichloromethane: methanol from 98: 2 to 95: 5). 0.73g of the expected product is obtained in the form of a pale yellow solid.

Melting point 253 ℃. MH⁺369. The yield was 56%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.45(d, 1H); 8.00(s, 1H, wide), 7.45(d, 1H); 6.05(s, 1H); 4.4(q, 2H); 3.95-3.80(m, 4H); 2.8(d, 3H); 2.35-2.10(m, 2H); 1.45(s, 3H); 1.25(t, 3H).

■ example 5: (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.47)

5.1: 6-chloro-2- [ (pyridin-2-ylmethyl) amino ] nicotinic acid

4g of 2, 6-dichloronicotinic acid (20.83 mmol, Aldrich) and 10.74ml of 2- (aminomethyl) pyridine (104.17 mmol) are placed in an 80ml sealed test tube containing 40ml of tert-butanol. Heat at 100 ℃ overnight and evaporate to dryness. The residue was dissolved in water and acidified by pouring 10% aqueous acetic acid. The precipitate was isolated by filtration and after drying in an oven under reduced vacuum, 4.35g of the desired product was obtained as a yellow powder. (yield 79%).

5.2: 6-chloro-2- [ (pyridin-2-ylmethyl) amino ] nicotinoyl fluoride

2.27ml of triethylamine (16.31 mmol) and 1.65ml of 2, 4, 6-trifluorotriazine (19.57 mmol) were added successively to 4.3g of 6-chloro-2- [ (pyridin-2-ylmethyl) amino group]Suspension of nicotinic acid (16.31 mmol) in 90ml dichloromethane. The mixture was stirred at ambient temperature for 1 hour and then a dichloromethane/ice water mixture was added. The organic phase is treated with ice-cold NaHCO₃Washed 3 times with aqueous solution and then with Na₂SO₄Dried, filtered and concentrated under vacuum. 3.97g of the expected product are obtained in the form of an orange solid. The yield was 92%.

5.3: 2-amino-7-chloro-N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

1.12g (28.06 mmol) of 60% sodium hydride in mineral oil are added in small portions to a solution of 1.31g (13.36 mmol) of N-methylcyano-acetamide (prepared according to 1.3) in 20ml of anhydrous dimethylformamide cooled to 0-5 ℃. Stirring is continued for ten minutes at this temperature and then 3.55g (4.93 mmol) of 6-chloro-2- [ (pyridin-2-ylmethyl) amino are added]A solution of nicotinoyl fluoride in 20ml of dimethylformamide. The medium is stirred at ambient temperature overnight and then 0.561g (14.03 mmol) of 60% sodium hydride are added in small portions (par frictions). Stirring was continued for 1 hour at this temperature, then the reaction mixture was poured onto ice and acidified to pH5-6 with 10% aqueous acetic acid. The precipitate was isolated by filtration and, after drying in an oven, 3.98g of the desired product was obtained as a beige solid. MH⁺344. The yield was 87%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 9.20(s, < 1H, very wide); 8.85(s, 1H); 8.30(m, 1H); 8.10-7.85(m, 2H, wide); 7.80(d, 1H); 7.75(s, 1H, wide); 6.90(d, 1H); 4.90(s, 2H); 2.95(s, 3H).

5.4: (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide hydrochloride

A suspension of 1g 2-amino-7-chloro-N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (2.91 mmol) in a mixture of 20ml dimethylformamide and 5.7ml triethylamine was placed in an 80ml microwave tube. Argon was bubbled through this suspension and then 0.498g (. + -.) -1-methoxy-2-methyl-3-butyn-2-ol (4.36 mmol), 0.055g CuI (0.29 mmol) and 0.102g bis (triphenylphosphine) palladium (II) dichloride (0.15 mmol) were added in that order.

The sealed tube was placed in a microwave oven (CEM device, Discover type) and the mixture was heated under pressure at 80 ℃ for 45 minutes (P ═ 100W) then cooled and evaporated to dryness. The residue was dissolved in ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3 times), then the organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo.

The residue obtained is purified by chromatography on silica (solid precipitate; using CH)₂Cl₂/MeOH/NH₄98/2/0.2 to 95/5/0.5 gradient of aqueous OH). After trituration in ether, 0.425g of the expected product are obtained in the form of a yellow solid.

Melting point 169 ℃. MH⁺422. The yield was 35%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.65(s, < 1H, very wide); 11.00(q, 1H, wide); 8.50-8.35(m, 2H); 8.00(s, 1H, wide); 7.75(ddd, 1H); 7.45-7.20(m, 3H); 5.80(s, 2H, wide); 5.70(s, 1H); 3.45-3.25(m + s, 5H); 2.80(d, 3H); 1.40(s, 3H).

■ example 6: (±) -2-amino-1-ethyl-7- (3-hydroxy-3-pyrazin-2-ylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.48)

6.1: (±) -2-pyrazin-2-ylbut-3-yn-2-ol

A solution of 0.5M ethynylmagnesium chloride in tetrahydrofuran (31.90 mmole Aldrich) was diluted with 50ml tetrahydrofuran and then cooled to 0 ℃. Then adding the mixture in multiple times3g of 1-pyrazin-2-yl ethanone (24.56 mmol, Lancaster) and the mixture is stirred at 0 ℃ for 4 hours. The mixture was cooled again with an ice bath and NH was added slowly₄Aqueous Cl solution. Extracted twice with ethyl acetate, then the organic phases are combined, dried over sodium sulfate, filtered and concentrated under limited vacuum. The oily residue obtained is purified by chromatography on silica (elution with cyclohexane: ethyl acetate, gradient 70: 30 to 50: 50) to yield 2.9g of the expected product in the form of a yellow oil (yield ═ 80%).

6.2: (±) -2-amino-1-ethyl-7- (3-hydroxy-3-pyrazin-2-ylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

1g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro [1, 8%]Naphthyridine-3-carboxamide in 25ml DMF/Et₃A suspension in the N (V/V; 2.5/1) mixture was placed in a 10ml microwave tube. To this suspension was bubbled with argon for 10 minutes and then 0.792g (. + -.) -2-pyrazin-2-ylbut-3-yn-2-ol (5.34 mmol), 0.068g CuI (0.36 mmol) and 0.125g bis (triphenylphosphine) palladium (II) dichloride (0.18 mmol) were added in that order.

The sealed tube was placed in a microwave oven (CEM device, Discover type) and the mixture was heated under pressure at 80 ℃ for 2 × 45 minutes (P ═ 50W). After returning to ambient temperature, the evaporation was carried out to dryness and the residue was dissolved with ethyl acetate. Organic phase is sequentially treated with NaHCO₃The saturated aqueous solution was then washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica (elution with dichloromethane: methanol, gradient from 100: 0 to 98: 2). 0.2g of the impure desired product is obtained in the form of a brown solid. Further purification was carried out by chromatography on a silica column (eluting with cyclohexane: ethyl acetate, gradient 20: 80 to 0: 100) to obtain finally 0.068g of the expected product in the form of a yellow solid.

The melting point was 271 ℃. MH⁺393. The yield was 4.9%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 9.0(s, 1H); 8.65(m, 1H); 8.40(d, 1H); 8.00(s, 1H, wide); 7.40(d, 1H); 6.85(s, 1H); 4.4(q, 2H); 2.75(d, 3H); 1.80(s, 3H); 1.20(t, 3H).

■ example 7: (±) -2-amino-7- (3-cyclopropyl-3-hydroxy-4-methoxybut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.50)

7.1: (±) -2-cyclopropyl-1-methoxybut-3-yn-2-ol

7.1.1: N-methoxy-N-methyl-2-methoxyacetamide

35.96ml of triethylamine (258 mmol) and then a solution of 14g of methoxyacetyl chloride (Aldrich, 129 mmol) in 250ml of dichloromethane are added to a solution of N-methyl-O-methylhydroxylamine hydrochloride in 250ml of dichloromethane cooled to 0 ℃. The mixture was stirred for 3 hours while it was returned to ambient temperature. 1N aqueous HCl was added and the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. 13.14g of the desired product are obtained in the form of an oil, which is used without subsequent purification (crude yield 76%).

7.1.2: 1-methoxy-4- (trimethylsilyl) but-3-yn-2-one

A solution of 14.75ml of trimethylsilylacetylene (103.62 mmol) in 250ml of tetrahydrofuran was cooled to-70 ℃ and then 64.76ml of a 1.6M n-BuLi (103.62 mmol) in hexane was added. Stirring is carried out at-70 ℃ for 25 minutes and then a solution of 13.14g N-methoxy-N-methyl-2-methoxyacetamide (98.69 mmol) in 250ml of tetrahydrofuran is added rapidly. During the addition, the temperature rose to-50 ℃, then the cold bath (bain free) was removed and the mixture was stirred at ambient temperature for 2 hours. 1N aqueous HCl was added and extracted 4 times with ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. 13.4g of 1-methoxy-4- (trimethylsilyl) but-3-yn-2-one are obtained as a light brown oil, which is used without subsequent purification (yield of crude product: 80%).

7.1.3: (±) -2-cyclopropyl-1-methoxy-4- (trimethylsilyl) but-3-yn-2-ol

52.85ml of 0.5M cyclopropylmagnesium bromide (26.43 mmol, Aldrich) were added to a solution of 3g of 1-methoxy-4- (trimethylsilyl) but-3-yn-2-one (17.62 mmol) in 160ml of diethyl ether. The mixture was stirred at ambient temperature overnight, then cooled with a water/ice bath and NH was added₄Aqueous Cl solution and ethyl acetate. The mixture was extracted 3 times with ethyl acetate, then the organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was purified by chromatography on a silica column, eluting with a gradient of cyclohexane: ethyl acetate 100: 0 to 80: 20, to give 1.9g of (. + -.) -2-cyclopropyl-1-methoxy-4- (trimethylsilyl) but-3-yn-2-ol in 51% yield as an oil.

7.1.4: (±) -2-cyclopropyl-1-methoxybut-3-yn-2-ol

10.9mg of potassium carbonate (0.08 mmol) are added to a solution of 1.67g (. + -.) -2-cyclopropyl-1-methoxy-4- (trimethylsilyl) but-3-yn-2-ol (7.86 mmol) in methanol and the mixture is stirred at ambient temperature overnight. Methanol was evaporated and dissolved with an ethyl acetate/water mixture. Extracted 3 times with ethyl acetate, then the organic phases are combined, dried over sodium sulfate, filtered and concentrated in vacuo. 0.434g of (±) -2-cyclopropyl-1-methoxybut-3-yn-2-ol was obtained as an oil, which was used without subsequent purification (crude yield ═ 40%).

7.2: (±) -2-amino-7- (3-cyclopropyl-3-hydroxy-4-methoxybut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

A suspension of 0.47g (1.68 mmol) 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1, 4-dihydro [1, 8] naphthyridine-3-carboxamide in a mixture of 8.4ml dimethylformamide and 3ml triethylamine was placed in a 10ml microwave tube. To this suspension was bubbled with argon for 10 minutes and then 0.433g (. + -.) -2-cyclopropyl-1-methoxybut-3-yn-2-ol (3.09 mmol), 0.032g CuI (0.17 mmol) and 0.059g bis (triphenylphosphine) palladium (II) dichloride (0.08 mmol) were added in that order.

The sealed tubes were placed in a microwave oven (CEM device, Discover type) and the mixture was heated under pressure at 80 ℃ for 30 minutes (P ═ 50W) and then cooled and evaporated to dryness. The residue was redissolved with ethyl acetate and the organic phase was successively treated with NaHCO₃The saturated aqueous solution was then washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica, eluting with a gradient of dichloromethane: methanol from 100: 0 to 97: 3. After trituration in ether and filtration, 0.316g of the expected product are obtained in the form of a pale yellow solid.

The melting point was 208 ℃. MH⁺385. The yield was 49%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.75(s, < 1H, very wide); 11.00(q, 1H, wide); 8.45(d, 1H); 8.00(s, 1H, wide); 7.40(d, 1H); 5.60(s, 1H); 4.4(q, 2H); 3.50(s, 2H); 3.40(s, 3H); 2.75(d, 3H); 1.20(t, 3H); 0.6-0.3(m, 4H).

■ example 8: (±) -2-amino-1-cyclopentyl-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide (Compound No.53)

8.1: (±) -2-methylbut-3-yne-1, 2-diol

A commercially available solution of 0.5M ethynylmagnesium chloride in tetrahydrofuran was diluted with 200ml of tetrahydrofuran and then cooled to 0 ℃. Then a solution of hydroxyacetone in 200ml tetrahydrofuran was added and stirred at ambient temperature for 3 hours. The reaction mixture was cooled and then NH was added₄Aqueous Cl solution. Extracting with ethyl acetate 3 times, then combining the organic phases, drying over sodium sulfate, filtering andconcentrate under vacuum (about 200 mbar). Finally, 20g of the expected product were obtained as a brown oil, which was used without subsequent purification (quantitative crude product yield).

8.2: 2- (aminocyclopentyl) -6-chloronicotinic acid

15g of 2, 6-dichloronicotinic acid (70.31 mmol, Aldrich) and 34.7ml of cyclopentylamine (351.56 mmol) were placed in a sealed tube containing 40ml of tert-butanol. The mixture was heated at 100 ℃ overnight and evaporated to dryness. The residue was dissolved in water and acidified by pouring 10% aqueous acetic acid solution, followed by extraction with chloroform. The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The solid residue was triturated in an ether/pentane mixture to give 5g of the desired product as an off-white solid (yield 29.5%).

8.3: 2- (aminocyclopentyl) -6-chlorocarbonyl fluoride

0.34ml (4.15 mmol) of pyridine and 0.53ml (6.23 mmol) of 2, 4, 6-trifluoro-triazine are added to a suspension of 1.0g (4.15 mmol) of 2- (aminocyclopentyl) -6-chloronicotinic acid in 12ml of dichloromethane. The mixture was stirred at ambient temperature for 2 hours and then diluted with dichloromethane. The organic phase was cooled with ice-cold NaHCO₃Washed twice with aqueous solution and then Na₂SO₄Drying, filtration and concentration under reduced pressure were carried out. 1g of product was obtained as a brown oil, which was used directly in the next step. Quantitative crude product yield.

Method a (section 8.4 below).

8.4: 3- [ 6-chloro-2- (cyclopentylamino) -3-pyridinyl ] -2-cyano-3-hydroxy-N-methyl-2-propenamide + 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

0.349g (8.72 mmol) of sodium hydride (60% in mineral oil) is added in small amounts to a solution of 0.427g (4.36 mmol) of N-methylcyano-acetamide (prepared as described in 1.3) in 10ml of anhydrous DMF, cooled to 0-5 ℃. After no more hydrogen evolution, the mixture was stirred at ambient temperature for 10 minutes and then cooled again to 0-5 ℃. A solution of 1.0g (4.15 mmol) of 2- (aminocyclopentyl) -6-chloronicotinyl fluoride in 10ml of DMF is then added and the medium is stirred at room temperature for 1 hour. 0.174mg (4.35 mmol) of 60% sodium hydride in mineral oil is added and the mixture is stirred at ambient temperature overnight. The reaction mixture was poured onto an ice/0.1N aqueous HCl mixture and the precipitate was isolated by filtration. After rinsing with water and drying in an oven, 1.2g of a pale green solid was obtained, consisting of 2/1 mixture of 3- [ 6-chloro-2- (cyclopentylamino) -3-pyridinyl ] -2-cyano-3-hydroxy-N-methyl-2-acrylamide and 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide.

Method B (section 8.5 below).

8.5: 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

A commercially available solution of 1.0M potassium tert-butoxide in tetrahydrofuran (7.48 mmol; Aldrich) was added to a solution of 1.2g of the mixture described in 8.4 (3.74 mmol) in 40ml of anhydrous tetrahydrofuran. The mixture was stirred at ambient temperature for 15 minutes then 0.1n hcl aqueous solution was added and the mixture was extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. After trituration in ether and drying in an oven, 0.53g of the desired product are obtained in the form of a yellow solid (yield 44%). Melting point 256-. MH⁺＝321。

8.6: (±) -2-amino-1-cyclopentyl-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

In a 500ml three-necked flask, 15g of 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1, 4-dihydro [1, 8] -naphthyridine-3-carboxamide (53.44 mmol) and 11.11g (±) -2-methylbut-3-yne-1, 2-diol (83.39 mmol) were introduced in this order into 267ml of dimethylformamide and 104ml of triethylamine. The reaction mixture was bubbled with argon for 15 minutes, then 1.02g of CuI (5.34 mmol) and 1.87g of bis (triphenylphosphine) palladium (II) dichloride (2.67 mmol) were added in that order. The reaction mixture was heated at 100 ℃ for 30 minutes and then concentrated under reduced vacuum. The residue was dissolved in chloroform/water mixture and insoluble material was filtered off. 20g of solid are obtained which are purified by chromatography on silica (solid deposit after dissolution in a tetrahydrofuran methanol mixture and subsequent elution with a gradient of dichloromethane/methanol from 99: 1 to 80: 20) to give 7.5g of the expected product in the form of a beige solid.

Melting point 210.5 ℃. MH⁺385. The yield was 42%.

1H NMR (DMSO-d6, 400MHz, delta (ppm)): δ 11.6(s, < 1H, very wide); 11.05(q, 1H, wide); 8.40(d, 1H); 7.35(d, 1H); 5.5(s, 1H); 5.15(m, 1H); 5.0(t, 1H); 3.45(m, 2H); 2.80(d, 3H); 2.3-2.1(m, 4H); 2.05-1.8(m, 2H); 1.75-1.5(m, 2H); 1.4(s, 3H).

The chemical structures and physical properties of some of the compounds of formula (I) according to the invention are illustrated in the following table. In this table:

the symbol ". star". sup. "(in R)₁And R₂Together form a ring (heterocyclic or cycloalkyl) a carbon through which the ring is attached to an adjacent carbon of the acetylenic bond,

me and Et represent methyl and ethyl, respectively,

in the column "salt" - "denotes the compound in free base form and" HCl "denotes the compound in hydrochloride form,

column PF represents the melting point (. degree. C.) of the compound and

in the column CL/SM, the high performance liquid chromatography (A, B or C), retention time (minutes) of the compound and MH identified by mass spectrometry used, described in detail below, are indicated in turn⁺A peak value.

Method A:

column: kromasil, 50X 2.1mm, 3.5 μm

Solvent A: h₂O/ACN/TFA (1000/30/0.5); solvent B: ACN/TFA (1000/0.5); flow rate 0.5 ml/min

Gradient: 100/0(0 min.) to 0/100(12 min.) to 0/100(15 min.)

And (3) detection: 220nM

Ionization: ESI +

Method B:

column: gemini, 50X 3mm, 3 μm

Solvent A: h₂O+0.1％HCO₂H; solvent B: ACN + 0.1% HCO₂H; flow rate of 1 ml/min

Gradient: 95/5(0 min.) to 0/100(5.5 min.) to 0/100(7.5 min.)

And (3) detection: 220nM

Ionization: ESI +

Method C:

column: kromasil, 50X 2.1mm, 3.5 μm

Solvent A: CH (CH)₃CO₂NH₄5 mM; solvent B: ACN; flow rate 0.5 ml/min

Gradient: 100/0(0 min.) to 0/100(13 min.) to 0/100(16 min.)

And (3) detection: 220nM

Ionization: ESI +

In the chiral CL column, for optically pure compounds (> 95% enantiomeric purity), the high performance liquid chromatography analytical method (D or E) used, and the retention time (minutes) of the compound, are indicated in the following sequence and detailed below.

Method D:

column: chiralpak AD-H, 250X 4.6mm, 5. mu.M

Solvent A: 2-propanol/TFA (1000/1); solvent B: heptane/2-propanol (1000/30)

Constant solvent: 50% A + 50% B

Flow rate: 0.8 ml/min

And (3) detection: 220nM

Method E:

column: chiralpak AD-H, 250X 4.6mm, 5. mu.M

Solvent A: 2-propanol/TFA (1000/1); solvent B: heptane/2-propanol (1000/30)

Constant solvent: 20% A + 80% B

Flow rate: 0.8 ml/min

And (3) detection: 220nM

In the chiral column, "/" is an achiral compound, (±) is a compound in the form of a racemic mixture, (-) is a compound in the form of an optically pure levorotatory enantiomer (> 95% enantiomeric purity) and a (+) optically pure dextrorotatory enantiomer (> 95% enantiomeric purity). In the case of optically pure compounds, the value of optical activity is measured at 20 ℃ (where, in parentheses, the concentration c of the compound and the solvent used).

To obtain optically pure enantiomers, the corresponding racemic mixtures were subjected to preparative chromatographic separation using chiral stationary phases (Chiralpak AD-H column, 250 x 21mm, 5mm), using as mobile phase:

or CO₂2-propanol (70%/30%) at a flow rate of 60 ml/min under a pressure of 100bar

Or an isohexane/ethanol (70/30) mixture with 0.3% TFA at a flow rate of 120 ml/min.

After elution and evaporation, each enantiomer is separated, and the chemical purity and enantiomeric purity of each is determined by analytical methods known to those skilled in the art.

Watch (A)

The compounds according to the invention are used as subjects of pharmacological tests which allow their inhibitory effect on the VEGFR-3 enzyme to be determined.

Measurement of tyrosine kinase Activity of VEGFR-3 by ELISA

The enzymatic activity of VEGFR-3 was assessed by measuring the intensity of phosphorylation of the polyglulu-Tyr substrate using an ELISA assay. The effect of this product was quantified by the concentration that reduced the total activity of the enzyme by 50% (IC 50). For the determination of the IC50 values, the product was diluted in DMSO with a concentration range of 3-1000 nM. The day before this procedure, 125. mu.l of the substrate for poly Glu-Tyr (250. mu.g/ml Ca-free in 1 xPBS)²⁺Or Mg²⁺Or sodium bicarbonate) is placed in each well of an ELISA plate (e.g., an ELISA plate of the sigma protein Tyrosine Kinase Assay kit, ref. The plate was then covered with an adhesive film and incubated overnight at 37 ℃. The following day, the wells were emptied by inversion, washed by adding 300 μ l of buffer solution (PBS + 0.05% Tween20) and dried by incubating the plate for a further 2 hours at 37 ℃. Place 90 microliters of reaction mixture in each well. This mixture contained 1 Xkinase buffer to which 30. mu.M ATP and the desired concentration of inhibitor had been added. Then 20. mu.l of VEGFR-3-TK (Cell Signaling, Ref.7790) without ATP pre-diluted in kinase buffer was added (except for negative control wells (puits)Add 20. mu.l of enzyme-free buffer) to the well in addition to n. The plates were then incubated for 30 minutes at ambient temperature with gentle stirring. On-going slowAfter 3 washes of the wash solution (300. mu.l/well per wash), 100. mu.l of anti-phosphotyrosine antibody-HRP (1/30000) was added to each well and incubated for an additional 30 minutes at ambient temperature with gentle stirring. After 3 washes in buffer solution (300. mu.l/well per wash), phosphorylation of the substrate was visualized by adding 100. mu.l OPD substrate, 1OPD tablet and 1 urea tablet (prepared extemporaneously in 20ml water) per well (protected from light). After incubation for 7 minutes at ambient temperature and in the absence of light, the reaction was incubated by adding 100. mu.l of 1.25M (2.5N) H per well₂SO₄Stop and read absorbance at 492 nm. Total activity was assessed by the difference in optical density obtained for samples incubated in the presence (stimulated) and in the absence (non-stimulated) of VEGFR-3.

The compounds according to the invention showed IC50 values below 10 μ M, mostly below 1 μ M. For example, IC50 values for certain compounds of table 1 are shown in table 2 below.

TABLE 2

Numbering of Compounds (Table 1)	Cl50(nM)
		2	23
3	46
		11	37
12	21
		16	257
24	6
		37	34
46	40
		47	65
60	43
		62	14
70	5
		72	23
80	2
		81	38

It is therefore evident that the compounds according to the invention have inhibitory activity on the VEGFR-3 enzyme; they can therefore be used for the preparation of medicaments, in particular VEGFR-3 inhibitors.

Thus, according to another of its aspects, the invention relates to a medicament comprising a compound of formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid or base, or a hydrate or solvate, and enantiomers or diastereomers (here mixtures of compounds of formula (I)).

Another aspect of the invention comprises a combination of at least one compound according to the invention and at least one chemotherapeutic agent.

In particular, the compounds of the invention may be used alone or as a mixture with at least one chemotherapeutic agent, which may be selected from:

an alkylating agent, which is a polymer,

an intercalating agent, which is capable of intercalating the dye,

an antimicrobial agent, which is a compound of the formula,

an anti-mitotic agent which is capable of inducing mitosis,

an antimetabolite agent, which is an active ingredient,

an anti-proliferative agent which is capable of inhibiting the growth of a tumor,

an antibiotic agent, which is capable of inhibiting the growth of the cell,

an immune modulator, which is capable of modulating immune activity,

an anti-inflammatory agent, which is,

an inhibitor of a kinase, which is,

an anti-angiogenic agent, which is capable of inhibiting the growth of a tumor,

anti-vascular agents (anti vascularities),

a combination of a female hormone and a male hormone,

and prodrugs of the above agents or derivatives.

The compounds according to the invention can also be combined with radiation therapy.

The combination of a compound of the invention with a chemotherapeutic agent and/or radiation as described above is another object of the invention.

The chemotherapeutic agents and/or radiation described above may be administered simultaneously, separately or sequentially. The treatment will be adjusted by the medical practitioner according to the patient to be treated.

These medicaments may be used therapeutically, in particular for the treatment and/or prevention of:

cancer and its metastases, such as: glioblastomas, multiple myeloma, myelodysplastic syndrome, kaposi's sarcoma, cutaneous angiosarcoma, solid tumors, lymphomas, melanoma, breast cancer, colorectal cancer, lung cancer, including non-small cell cancers (caners non-peptide cancers cells), pancreatic cancer, prostate cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, respiratory and chest organ cancers (caners de l' apareitoire et thoracique), or other VEGFR-3 expressing tumors or tumors involving angiogenesis or lymphangiogenesis processes.

-non-tumoral proliferative diseases and pathological angiogenesis associated with VEGFR-3, such as arthrosis, restenosis, psoriasis, hemangioma, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, thrombotic microangiopathy syndromes (syndromes), cirrhosis, atherosclerosis, organ transplant rejection, ocular diseases involving angiogenesis or lymphangiogenesis processes, such as diabetic retinopathy or macular degeneration.

Or for the treatment and prevention of inflammation (chronic or non-chronic) due to microbial infections and autoimmune diseases, such as rheumatoid polyarthritis.

-also or alternatively for the treatment of rare diseases, such as lymphangiosarcoidosis.

According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising a compound according to the invention as active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient.

The excipients are selected from among those known to those skilled in the art according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its optional salt, solvate or hydrate thereof, may be administered in unit administration form in admixture with conventional pharmaceutical excipients to animals and humans for the treatment or prevention of the disorders or diseases mentioned above.

Suitable unit administration forms include administration by the oral route, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention may be used as creams, gels, ointments or lotions.

For example, a unit dosage form of a compound according to the invention in the form of a tablet may comprise the following components:

compound according to the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

According to another aspect of the present invention, it also relates to a method of treating the pathologies indicated above, which comprises administering to the patient an effective dose of a compound according to the present invention, or one of its pharmaceutically acceptable salts or its hydrates or its solvates.

Claims (23)

1. A compound of formula (I):

wherein

R ₁ And R ₂

(1)Represent, independently of one another:

or a hydrogen atom,

or C1-C7 alkyl or C3-C8 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more groups selected from hydroxy and C1-C4 alkoxy,

or phenyl optionally substituted with one or more groups selected from: C1-C4 alkyl, C1-C4 alkoxy or hydroxy,

or an aryl group comprising 5 or 6 mer and comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur,

(2) or R₁And R₂Together with the carbon atom bearing them form:

a C4-C8 cycloalkyl group,

R ₃ represents:

or a linear or branched C1-C7 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: hydroxy or C1-C4 alkoxy,

or- (CH)₂)_n-a heterocyclic group, wherein n is 0 or 1, and wherein the heterocyclic group contains 4 to 8 mer and contains at least one heteroatom selected from N, O and S atom,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1, wherein the heteroaryl comprises 5 or 6 mer and comprises one or more heteroatoms selected from nitrogen, oxygen and sulfur;

r4 representsA hydrogen atom or a C1-C4 alkyl group,

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

2. A compound of formula (I) according to claim 1, characterized in that

R ₁ And R ₂

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C4 alkyl or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and C1-C4 alkoxy,

or phenyl optionally substituted with one or more groups selected from C1-C4 alkoxy,

or an aryl group comprising 5 or 6 mer and comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur,

(2) or R₁And R₂Together with the carbon atom bearing them form:

a C4-C8 cycloalkyl group,

R ₃ represents:

or a linear or branched C1-C4 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: a C1-C4 alkoxy group,

or- (CH)₂)_n-a heterocyclic group, wherein N ═ 0 or 1 and wherein the heterocyclic group contains 4 to 8 mer and contains at least one heteroatom selected from N and O atoms,

or- (CH)₂)_n-heteroaryl, wherein n ═ 0 or 1 and wherein the heteroaryl contains 5 or 6 mer and contains one or more nitrogen heteroatom;

R ₄ representsC1-C4 alkyl;

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

3. A compound of formula (I) according to claim 1, characterized in that

R ₁ And R ₂

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C4 alkyl or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and C1-C4 alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or a 5-or 6-membered heteroaryl group selected from pyridyl, furyl, thienyl, pyrimidinyl, pyrazinyl and thiazolyl,

(2) or R1 and R2 form, together with the carbon atom bearing them:

a C4-C8 cycloalkyl group,

R ₃ represents:

or a linear or branched C1-C4 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: C1-C4 alkoxy;

or- (CH)₂)_n-a heterocyclic group, wherein n is 0 or 1, wherein the heterocyclic group contains 4 to 8 mer and contains at least one heteroatom selected from O atoms,

or- (CH)₂)_n-heteroaryl, wherein n ═ 1 and wherein the heteroaryl comprises 5 or 6 mer and comprises one or more nitrogen heteroatom;

R ₄ representsC1-C4 alkyl;

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

4. A compound of formula (I) according to claim 1, characterized in that

R1 and R2

(1) Represents, independently of one another:

or a hydrogen atom,

or C1-C4 alkyl or C3-C8 cycloalkyl, wherein said alkyl is optionally substituted with one or more groups selected from hydroxy and C1-C4 alkoxy,

or phenyl optionally substituted with one or more C1-C4 alkoxy groups,

or a 5-or 6-membered heteroaryl selected from thienyl,

(2) or R₁And R₂Together with the carbon atom bearing them form:

a C4-C8 cycloalkyl group,

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

5. A compound of formula (I) according to claim 1, characterized in that

R ₃ Represents:

or a linear or branched C1-C4 alkyl group or a C3-C7 alkyl group cyclized with at least 3 carbon atoms thereof, said alkyl group being optionally substituted with one or more groups selected from: C1-C4 alkoxy, wherein the C3-C7 alkyl group in which at least 3 carbon atoms are cyclized is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and methylene-cyclopropyl,

or- (CH)₂)_n-a heterocyclic group, wherein n is 0 or 1, wherein the heterocyclic group is selected from tetrahydropyranyl, tetrahydrofuranyl and pyrrolidinyl,

or- (CH)₂)_n-heteroaryl, wherein n ═ 1, wherein the heteroaryl contains 5 or 6 mer and contains one or more nitrogen heteroatom and is pyridyl;

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

6. A compound of formula (I) according to claim 1, characterized in thatR ₄ Represents a methyl group;

in the form of a base or of an addition salt with an acid, and the enantiomers, diastereomers and mixtures thereof.

7. A compound of formula (I) according to claim 1, characterized in that it is selected from:

■ 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ (1-hydroxycyclopentyl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-cyclopropyl-3-hydroxypropan-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ 2-amino-1-ethyl-7- [ (1-hydroxycyclobutyl) ethynyl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-methoxyphenyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -1- (3-methoxypropyl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-1- (tetrahydropyran-4-yl) -7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (tetrahydrofuran-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (±) -2-amino-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1- (pyridin-2-ylmethyl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-7- (3, 4-dihydroxy-3-methylbut-1-yn-1-yl) -1-ethyl-N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-cyclohexyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- (3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl) -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (+) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide

■ (-) -2-amino-1-ethyl-7- [ 3-hydroxy-3- (3-thienyl) but-1-yn-1-yl ] -N-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxamide.

8. A compound of formula (VII)

Wherein X is a halogen atom and R₃And R₄As defined in any one of the preceding claims.

9. Process for the preparation of the compounds of the formula (I) according to any one of claims 1 to 7, characterized in that a compound of the formula (VII)

Wherein X is a halogen atom and R₃And R₄As defined in any one of the preceding claims, with a compound of (VIII)

Wherein R is₁And R₂As defined in any one of the preceding claims.

10. Pharmaceutical, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7 or an addition salt of such a compound with a pharmaceutically acceptable acid, or an enantiomer, diastereomer or mixture thereof of a compound of formula (I).

11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, or an enantiomer or diastereomer of such a compound, mixtures thereof, and at least one pharmaceutically acceptable excipient.

12. A combination of a compound of formula (I) according to any one of claims 1 to 7 with at least one chemotherapeutic agent selected from:

● an alkylating agent is added to the mixture,

● an intercalating agent, which is capable of intercalating,

● the use of an antimicrobial agent,

● an anti-mitotic agent which is selected from the group consisting of,

● an antimetabolite agent which is an active ingredient,

● an antiproliferative agent in the form of a composition,

● the use of an antibiotic for the treatment of,

● an immune-modulating agent which is selected from the group consisting of,

● an anti-inflammatory agent, in particular,

● an inhibitor of a kinase enzyme, wherein,

● an anti-angiogenic agent in an amount sufficient to prevent angiogenesis,

● the use of an anti-vascular agent,

● female and male hormones.

13. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of all diseases in which VEGFR-3 is involved.

14. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of cancer and its metastases.

15. Use of a compound of formula (I) according to claim 14 for the preparation of a medicament for the treatment and/or prophylaxis of glioblastomas, multiple myeloma, myelodysplastic syndrome, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, renal cancer, head and neck cancer, liver cancer, ovarian cancer, cancers of the respiratory and thoracic organs, or other VEGFR-3 expressing tumors or tumors involving angiogenic or lymphangiogenic processes.

16. Use of a compound of formula (I) according to claim 14 for the preparation of a medicament for the treatment and/or prevention of solid tumors.

17. The use of a compound of formula (I) according to claim 14 for the preparation of a medicament for the treatment and/or prophylaxis of kaposi's sarcoma, cutaneous angiosarcoma, lymphoma, melanoma and lung cancer.

18. The use according to claim 17, wherein the lung cancer is non-small cell cancer.

19. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of non-tumor proliferative diseases and pathological angiogenesis associated with VEGFR-3.

20. The use of a compound of formula (I) according to claim 19 for the preparation of a medicament for the treatment and/or prevention of a disease selected from: arthrosis, restenosis, psoriasis, hemangioma, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, thrombotic microangiopathy syndromes, cirrhosis of the liver, atherosclerosis, organ transplant rejection, ocular diseases involving angiogenesis or lymphangiogenesis processes.

21. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of chronic or non-chronic inflammation due to microbial infections and autoimmune diseases.

22. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of chronic or non-chronic inflammation due to rheumatoid polyarthritis.

23. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of lymphangiosarcoidosis.