HK1117831A - Pyrido-pyrimidine derivatives, preparation thereof, therapeutic use thereof - Google Patents

Description

Pyrido-pyrimidine derivatives, their preparation and their therapeutic use

The present invention relates to pyrido [2, 3-d ] pyrimidine derivatives, their preparation and their therapeutic use.

International patent applications WO 01/55147 and WO 03/000011 and patents EP-B-790997 and US 5733913 describe compounds derived from pyrido [2, 3-d ] pyrimidines. These compounds have potential use in the treatment of cell proliferative disorders.

According to a first aspect, the object of the present invention is a compound corresponding to formula (I) below:

in the formula:

-R₁is selected from (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl radical, CH₂COR₄Phenyl or substituted by hydroxy and/or halogen and/or (C)₁-C₆) Alkyl-substituted phenyl;

-R₄represents a hydroxyl group, (C)₁-C₄) Alkoxy, amino, (C)₁-C₄) Alkylamino or di (C)₁-C₄) An alkylamino group;

-Ar₁represents a group selected from:

-R₅represents cyano, hydroxy (C)₁-C₄) Alkyl or (C)₁-C₆) Alkoxy (C)₁-C₆) Alkyl, or (CH)₂)_nNR₇R₈、CO₂R₇、CONHNR₇R₈、CONR₇R₈、CONR₈OR₉、(CH₂)_nNR₇COR₈、(CH₂)_nNR₇COOR₈A group;

-R₆represents a hydrogen atom, (C)₁-C₄) Alkyl or R₅One of (1)A value;

-or R₅And R₆As previously defined, they are joined together to form a 4-7 mer ring, each mer containing 0-2 heteroatoms selected from N and O, said 4-7 mer ring being optionally substituted with one or more substituents independently selected from halogen, (C) and₁-C₄) Alkyl, halo (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl group, (CH)₂)_mNR₇R₈Or a tert-butoxycarbonyl group;

-R₇and R₈Independently of one another represent a radical selected from H, (C)₁-C₄) Alkyl, (C)₁-C₄) alkyl-OH, (C)₃-C₇) Cycloalkyl, - (C)₃-C₇) cycloalkyl-NH₂、-(C₁-C₄) Alkyl radical- (C)₃-C₇) Cycloalkyl, C (═ NH) NH₂、SO₂(C₁-C₆) Alkyl, SO₂-substituents of phenyl, R₈And may also represent a tert-butoxycarbonyl or benzyloxycarbonyl group;

-or R₇And R₈Together with the nitrogen atom they carry form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical, said radical being unsubstituted or substituted by (C)₁-C₆) Alkyl, (C)₁-C₄) alkyl-OH, COO (C)₁-C₆) Alkyl, F group substitution one or more times;

-R₉represents a hydrogen atom or (C)₁-C₄) An alkyl group;

-Ar₂represents unsubstituted phenyl or phenyl substituted 1 to 5 times by similar or different substituents selected from halogen atoms, (C)₁-C₄) Alkyl, trifluoromethyl or (C)₁-C₄) An alkoxy group;

-n represents 1, 2 or 3;

-m represents 0, 1, 2 or 3.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, they may exist as enantiomers or diastereomers. Such enantiomers, diastereomers and mixtures thereof, including racemic mixtures, are all part of this invention.

The compounds of formula (I) can be present in the form of a base or in the form of an addition salt with an acid. When the compounds of formula (I) contain a free acid function, for example a carboxylic, sulphonic or phosphonic acid function, said acid function can be converted into an addition salt with a base. Said addition salts are also part of the present invention.

It is advantageous to prepare addition salts of these acids or bases using pharmaceutically acceptable acids or bases, respectively, but salts of other acids or bases that are useful, for example, in purifying or isolating the compounds of formula (I) are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates or solvates, i.e. associated with or combined with one or more water molecules or solvents. Said hydrates or solvates are also part of the present invention.

Within the scope of the invention, it should be understood that:

-a halogen atom: a fluorine, chlorine, bromine or iodine atom;

-an alkyl group: a straight or branched chain saturated aliphatic group. Examples thereof include the following groups: methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, 1-dimethylethyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-dimethylbutyl group, 2, 3-dimethylbutyl group, 3-dimethylbutyl group, 1, 2-trimethylpropyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 1, 2, 2-trimethylpropyl, 1-ethyl, 1-methylpropyl, 1-ethyl, 2-methylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-dimethylpentyl, 1, 2-dimethylpentyl, 1, 3-dimethylpentyl, 1, 4-dimethylpentyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 3-dimethylpentyl, 3, 4-dimethylpentyl, 4-dimethylpentyl, 1, 2-trimethylbutyl, 1, 3-trimethylbutyl, 1-ethylbutyl, 2-methylpropyl, 1-ethylbutyl, 2-dimethylpropyl, 1-ethylbutyl, 1, 2, 2-trimethylbutyl, 1, 2, 3-trimethylbutyl, 1, 3, 3-trimethylbutyl, 2, 2, 3-trimethylbutyl, 2, 3, 3-trimethylbutyl, 1, 2, 2-tetramethylpropyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-ethyl, 1-methylbutyl, 1-ethyl, 2-methylbutyl, 1-ethyl-3-methylbutyl, 2-ethyl, 1-methylbutyl, 2-ethyl, 2-methylbutyl, 2-ethyl, 3-methylbutyl, 1-propylbutyl, 1- (1-methylethyl) butyl, 1- (1-methylethyl), 2-methylpropyl;

-a cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, cyclooctyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, adamantyl (adamantyl).

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

-R₁represents tert-butyl, ethyl or phenyl;

-and/or Ar₁Represents a group selected from:

-and/or R₅Is represented by (CH)₂)_nNR₇R₈、CONHNR₇R₈、CONR₇R₈Hydroxy (C)₁-C₄) Alkyl or (CH)₂)_nNR₇COR₈A group;

-and/or R₆Represents a hydrogen atom, a methyl group, or (CH)₂)_nNR₇R₈A group or a hydroxymethyl group;

-and/or Ar₂Represents aryl substituted by 1 or 2 substituents independently selected from halogen, (C)₁-C₄) Alkyl or (C)₁-C₄) An alkoxy group;

-n、m、R₇and R₈As defined above for compounds of formula (I);

the above compounds are in the form of a base or an addition salt with an acid, as well as in the form of a hydrate or solvate.

The products of the invention advantageously contain a compound selected from (CH)₂)_nNR₇R₈、CONR₇R₈And (CH)₂)_nNR₇COR₈Substituent R of₅。

The products of the invention may be in achiral or racemic form, or enriched in one stereoisomer (enrichie eno-isom) or in one enantiomer (enrichie enriche nantiom); it may optionally be in the form of a solvate or hydrate, and may optionally be salified.

In a second aspect, the present invention relates to a process for the preparation of a synthetic intermediate for use in the preparation of the product of the first aspect of the invention, said intermediate corresponding to the formula:

in the formula R₁And Ar₂As defined above.

In a third aspect, the present invention relates to a process for the preparation of intermediates of the first and second aspects of the invention, which corresponds to the formula:

in the formula R₁And Ar₂As defined above.

In a fourth aspect, the present invention relates to a process for the preparation of the intermediates of the first, second and third aspects of the invention, which corresponds to the formula:

in the formula Ar₂As defined above.

The synthetic intermediate of aspects 2 to 4 of the present invention contains a substituent Ar₂Selected from the group consisting of phenyl, 2-methoxyphenyl, 2, 6-dichlorophenyl, 3, 5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 2, 6-dibromophenyl, 2-bromo-6-chlorophenyl, 2, 4-dichlorophenyl and 3, 5-dichlorophenyl.

The synthesis intermediates of the second and third aspects of the invention contain a substituent R1 selected from ethyl, tert-butyl and phenyl.

According to the invention, the compounds of formula (I) can be prepared by a process which is characterized in that the following compounds are reacted:

(i) a compound of the formula:

in the formula R₁₀Is a leaving group (group partial), for example: (a) halogen, especially Cl or Br, or (b) an alkaneradical-S (O)_m-, where m is 0, 1 or 2; r₁₁Is NHC (═ R)₁₂)-NH-R₁In the formula, R₁₂O or S; and

(ii) ar 'of formula'₁NH₂(III) amine, formula Ar'₁Represents Ar as defined under (I)₁Or Ar₁A precursor of (a); if necessary, the radicals Ar 'in the compound are thus obtained'₁Conversion to the group Ar₁。

R₁₀Is halogen or alkyl-S (O)_m-, where m ═ 2, the reaction is carried out in the following solvents, preferably in polar solvents, at a temperature ranging from room temperature to the reflux temperature of the solvent:

(i) for example tetrahydrofuran, dimethyl sulfoxide or ethanol, optionally in the presence of trace amounts of an acid (e.g. hydrochloric acid); or

(ii) In dimethyl sulfoxide in the presence of a strong base (e.g., tBuOK).

R₁₀Is alkyl-S (O)_mWhere m is 0 or 1, it is preferably reacted with Ar' in the molten state in the absence of a catalyst at a temperature close to 200 ℃.₁NH₂(III) carrying out the reaction.

Ar 'of Compound (III), if necessary'₁The amine functions present in the group have been previously salified or protected.

Ar₁Precursors are understood to be groups a), b), c), d) or e) as defined above under (I), wherein the substituents R₅And/or R₆As defined above for (I) or R₆And/or R₆A precursor of (2).

The compound of formulｃA (II) is prepared in the manner described in scheme 1 below, using the procedures described in European patent EP-A-0790997 and U.S. Pat. No. 5, 5733913:

scheme 1

mCPBA: meta-chloroperbenzoic acid.

The amine of formula (III) is known or, using known methods, the corresponding nitro derivative Ar'₁NO₂(IV) preparing the amine of formula (III) by reduction reaction either (i) in an acidic medium in the presence of a metal such as iron or zinc powder, or (ii) using hydrogen in the presence of a catalyst such as Pd/C.

The compounds of formula (IV) are known or may be prepared by known methods.

Thus, by the action of methyl dichloroacetate with 4-nitro-catechol (4-nitrobenzene-1, 2-diol) it is possible to prepare compounds with R in the 2-position₅Mono-substituted 5-nitro-1, 3-benzodioxoles (benzodioxoles) as methoxycarbonyl group.

5-nitro-1, 3-benzodioxoles which are gem-disubstituted in the 2-position can be prepared according to Pharmazie, 2003, 58(1), 13-17 by reacting ethyl dibromomalonate with 4-nitrocatecholic acid (4-nitrophenyl-1, 2-diol).

R substituted in the 2-or 3-position may be prepared by the method described in International patent WO 01/021577 using 4-nitrocatechol or by known chemical conversion methods₅And R₆Substituted 7-nitro-2, 3-dihydro-1, 4-benzodioxines.

In l. j.med.chem., 1978,21965. sup. 978 describe 1, 3-dihydro-2-benzofuran-5-amine; in journal of organic chemistry (j. org. chem.), 1994,59(4) 754-757 4H-1, 3-benzodioxin-6-amine; in "therapeutic chemistry" Chimie therapeutics ", 1972,7443-449 describes 4H-1, 3-benzodioxin-7-amines.

For converting R of the compound of the formula (IV)₅And/or R₆Radical, according to the considered substituent R of the compound of formula (I)₅And/or R₆The operation can be carried out by a known method as described in March's advanced Organic Chemistry, 5 th edition, 2005, ISBN 0471585890. It is also possible to convert the radical R of the compound of the formula (I)₅And/or R₆To give R with the desired substituent₅And/or R₆The novel compounds of (I).

Thus, the radical R can be prepared by methods known to those skilled in the art₅＝CO₂Me can prepare compounds of the formula (IV) or (I), in which R₅Represents CO₂H、CN、CH₂OH、CONR₇R₈、CONHNR₇R₈、CONR₈OR₉Or CH₂NR₇R₈A group.

Using a compound containing the group R₅＝(CH₂)_n-OH, wherein n is 1, 2, or 3, a compound of formula (IV) or (I), wherein R is 1, 2, or 3, can be prepared by the action of methanesulfonyl chloride₅Artesunate, then by HNR₇R₈(in the formula, R₇And R₈As defined for the compound of formula (I) to prepare a compound of formula (IV) or (I) wherein R is₅＝-CH₂NR₇R₈。

To obtain the compound of the invention in racemic form; optically pure isomers can then be prepared by separation methods known to those skilled in the art, such as crystallization using chiral agents to form salts. Optically pure compounds of the invention may also be prepared by asymmetric or stereospecific syntheses, or by chromatographic techniques using chiral phases. In addition, the products of the invention can be isolated by forming diastereomers, isolating them and then decomposing the pharmacologically useful diastereomer into its enantiomerically pure active product. Enzymatic techniques may also be employed. Known assisted separation techniques may be employed. They include the techniques discussed in the following references: enantiomers, racemic compounds and solubilities (Enantiomers, Racemates, and resolution), John Wiley and Sons, New York (1981).

The compounds of the present invention can be prepared in stereoisomerically enriched form by preparing synthetic intermediates. Thus, the isolation of the amine enantiomer of formula (III) or the nitro precursor (IV) may be carried out using one of the methods described above.

The following examples describe the preparation of certain intermediates and compounds of the invention. These examples are not limiting and are intended to be illustrative of the invention.

The following abbreviations are used in these examples:

f: melting Point

Boc: tert-butoxycarbonyl group

BOP: benzotriazol-1-yl-oxy-tris (dimethylamino) * hexafluorophosphate

THF: tetrahydrofuran (THF)

TA: at room temperature

DCM: methylene dichloride

MeOH: methanol

DCCI: dicyclohexylcarbodiimide (dicyclohexylcarbodiimide)

DIPEA: diisopropylethylamine

KHSO₄/K₂SO₄：5％KHSO₄/K₂SO₄Solutions of

Z: benzyloxycarbonyl group

In DMSO-d, unless otherwise indicated₆Proton Nuclear Magnetic Resonance (NMR) spectra were recorded at 200MHz or 250 MHz. DMSO-d₆The signal was at 2.5ppm and served as a reference. The following abbreviations are used in the explanation of the spectra: s: single line, d: double line, t: triplet, m: bulk peak, mt: multiple lines, se: splay single line, dd: split doublet, qd: quadruple lines, qt: the quintuple line.

Preparation of the Compound of formula (II)

Preparation 1

N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylsulfonyl) pyrido [2, 3-d ] pyrimidin-7-yl ] urea.

1.14-amino-2- (methylthio) pyrimidine-5-carboxylic acid ethyl ester.

To a suspension of 50.7g of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate in 400ml of EtOH was added 140ml of 20% NH over 20 minutes₄OH solution, the temperature being maintained at about 20 ℃. After stirring at room temperature for 20 hours, the reaction medium is concentrated almost to dryness in vacuo, the residue is then dissolved in 350ml of water, stirred for 20 minutes, filtered, washed with 3X 60ml of water and then washed in P₂O₅Vacuum drying is carried out in the presence. A white solid was obtained: f-134-135 deg.C, and m-39.9 g.

1.2[ 4-amino-2- (methylthio) pyrimidin-5-yl ] methanol.

To 39.68g of the ester obtained in the preceding step dissolved in 1 l of THF are added 210ml of 1M LiAlH over 45 minutes₄Solution in THF while maintaining the temperature below 30 ℃. Stirring was continued for a further 1 hour, after which the temperature was lowered to 5 ℃ and 9ml of water, 6.5ml of 5N sodium hydroxide and then 32ml of water were added dropwise. After stirring for 10 minutes, the solid was filtered and rinsed with THF. The filtrate was concentrated in vacuo and the residue redissolved in 600ml of boiling toluene, filtered quickly hot to remove a little insoluble material and the filtrate was allowed to cool overnight. The white crystals obtained are filtered, washed with a little toluene, then with ether and dried. F ═ 124-.

1.34-amino-2- (methylthio) pyrimidine-5-carbaldehyde (carbald hyde).

Over 2 minutes, to a suspension of 23.8g of the alcohol obtained in the preceding step in 1600ml of chloroform, 79.5g of active MnO were added₂Then stirred overnight at room temperature; the solid was filtered and washed with 3X 75ml of CHCl₃Washing, and vacuum concentrating the filtrate to dryness; the white solid residue was dissolved in ether, filtered and evaporated. F184-186 ℃ and m 21.05 g.

1.46- (2, 6-dichlorophenyl) -2- (methylthio) pyrido [2, 3-d ] pyrimidin-7-amine.

After a solution of 21g of the aldehyde obtained in the preceding step in 240ml of DMF had been cooled to 5 ℃ over 5 minutes, 5.47g of 60% NaH were added thereto, followed by 29.05g of 2, 6-dichlorophenylacetonitrile over 20 minutes. Stirred at 5 ℃ for 30 minutes and then at room temperature overnight. The reaction medium is cooled to 5 ℃ and 65ml of NH are added₄A saturated solution of Cl, followed by the addition of 500ml of a water/ice mixture; the resulting red precipitate was filtered, washed twice with water, most thoroughly dehydrated, washed with ether, 100ml chloroform and then ether and dried to give a light brown solid. F is 250-253 deg.C, and m is 29.92 g.

The washed ether and chloroform phases are concentrated to dryness and then dissolved in a small amount of chloroform, to which solution ether: a second 3.15g portion was obtained, with a total of 33.07 g.

1.5N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylthio) pyrido [2, 3-d ] pyrimidin-7-yl ] urea.

4.6g of 60% NaH are added to a solution of 29.9g of the amine obtained above in 300ml of DMF, the temperature being kept below 25 ℃ over a period of 10 minutes; the solution was stirred for a further 20 minutes, then 12.2ml of tert-butyl isocyanate were added over 20 minutes, followed by stirring overnight. The reaction medium is slowly poured into 800ml of a water/ice mixture +100ml of 6N HCl; the precipitate formed is filtered, washed with water, dewatered, stirred in 300ml of ether for 1 hour, then filtered, washed with ether and dried. A light brown solid was obtained. 195-196 deg.C (decomposition), and 26.5 g.

6N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylsulfonyl) pyrido [2, 3-d ] pyrimidin-7-yl ] urea.

27g of m-chloroperbenzoic acid were added over 25 minutes to the previously obtained solution of 21.95g of urea in 300ml of chloroform, while the temperature was kept below 25 ℃. A precipitate formed. After 2 hours, the reaction medium is diluted with 1 l of dichloromethane and Na is added₂SO₄Followed by the addition of 14g Ca (OH)₂(ii) a After stirring for 30 minutes, filtering the solid, washing with dichloromethane, and then concentrating the filtrate to dryness; the residue is triturated hot in 80ml of ether; it was allowed to cool, then the white solid was filtered, washed with ether and dried. F ═ 138-.

A compound of the following formula (II) was prepared in the same manner as described for preparation 1:

Ar 2	R 1	NMR
			2, 6-dichlorophenyl	Tert-butyl radical	1,40：s：9H；3,50：s：3H；7,50-7,70：m：3H；8,55：s：1H；9,10：s：1H；9,60：s：1H；9,95：s：1H.
2, 6-dichlorophenyl	Phenyl radical	3,50ppm：s：3H；7,10ppm：t：1H；7,40ppm：t：2H；7,55-7,75ppm：m：5H；8,60ppm：s：1H；9,60ppm：s：1H；9,80ppm：s：1H；11,90ppm：s：1H.
			3, 5-Dimethoxyphenyl	Tert-butyl radical	1,40ppm：s：9H；3,50ppm：s：3H；3,80ppm：s：6H；6,65-6,80ppm：mt：3H；7,75ppm：s：1H；8,45ppm：s：1H；9,60ppm：s：1H；9,80ppm：s：1H.
2, 6-dichlorophenyl	Ethyl radical	1,20ppm：t：3H；3,40ppm：qd：2H；3,50ppm：s：3H；7,50ppm-7,75ppm：m：3H；8,55ppm；s：1H；9,40ppm：s：1H；9,60ppm：s：1H；9,70ppm：s：1H.
			3, 4-Dimethoxyphenyl	Tert-butyl radical	1.40ppm：s：9H；3.45ppm：s：3H；3.80ppm：s：3H；3.90ppm：s：3H；7.10-7,20ppm：m：3H；7.75ppm：s：1H；8.45ppm：s：1H；9.55ppm：s：1H；9.80ppm：s：1H.
Phenyl radical	Tert-butyl radical	1,40ppm：s：9H；3,50ppm：s：3H；7,60ppm：se：6H；8,45ppm：s：1H；9,40ppm：s：1H；9,80ppm：s：1H.
			2-methoxyphenyl radical	Tert-butyl radical	1,40ppm：s：9H；3,.50ppm：s：3H；3,80ppm：s：3H；7,10-7,40ppm：mt：4H；7,60ppm：t：1H；8,40ppm：s：1H；9,60ppm：s：1H；9,80ppm：s：1H.
2, 6-dibromophenyl	Tert-butyl radical	1,40ppm：s：9H；3,50ppm：s：3H；7,40ppm：t：1H；7,85ppm：d：2H；8,50ppm：s：1H；9,00ppm：s：1H；9,60ppm：s：1H；10,00ppm：s：1H.
			2-bromo-6-chlorophenyl	Tert-butyl radical	1,40ppm：s：9H；3,45ppm：s：3H；7,50ppm：t：1H；7,65ppm：d：1H；7,80ppm：d：1H；8,50ppm：s：1H；9,00ppm：s：1H；9,50ppm：s：1H；9,90ppm：s：1H.
2, 6-dibromophenyl	Ethyl radical	1,15 ppm: t: 3H; 3,30 ppm: qd: 2H (denoted by DOH); 3,50 ppm: s: 3H; 7,40 ppm: t: 1H; 7,85 ppm: d: 2H; 8,50 ppm: s: 1H; 9,25 ppm: s: 1H; 9,60 ppm: s: 1H; 9,70 ppm: s: 1H.
			2-bromo-6-chlorophenyl	Phenyl radical	(DMSO+TFA)3,55ppm：s：3H；7,10ppm：t：1H；7,30-7,90ppm：m：7H；8,60ppm：s：1H；9,65ppm：s：1H.

2, 6-dibromophenyl	Phenyl radical	3,55ppm：s：3H；7,10ppm：t：1H；7,35ppm：qd：3H；7,60ppm：d：2H；7,85ppm：d：2H；8,60ppm：s：1H；9,70ppm：s：1H；9,80ppm：s：1H；12,00ppm：s：1H.
			2, 4-dichlorophenyl	Tert-butyl radical	1,35ppm：s：9H；3,50ppm：s：3H；7,45-7,60ppm：mt：2H；7,80ppm：s：1H；8,40ppm：s：1H；8,80ppm：s：1H；9,55ppm：s：1H；9,80ppm：s：1H.

Preparation of the Compound of formula (III)

The preparation numbers used are associated with the compound numbers of tables 1 and 2 below. Unless otherwise indicated, these compounds are obtained in racemic form when they contain asymmetric carbon atoms.

Preparation 2

2.15-Nitro-1, 3-benzodioxole (benzodioxole) -2-carboxylic acid methyl ester.

31.0g of 4-nitrocatechol were added to a suspension of 17.6g of 60% NaH in 300ml of DMF over 1 hour, while cooling and maintaining the temperature below 30 ℃. After stirring for 15 minutes, 104ml of methyl dichloroacetate were added over 1 hour and stirred at 90 ℃ for 4 hours. The reaction medium is poured into 2 l of an ice/water mixture and extracted 4 times with 400ml of AcOEt. The combined organic phases were washed once with saturated NaCl solution and concentrated in vacuo (evaporation of DMF). The residue was dissolved in AcOEt/H₂O mixture with Na₂CO₃Adjusting the pH to 8.6; the organic phase was decanted with saturated NaHCO₃、H₂O、5％KHSO₄/K₂SO₄、H₂Washing with saturated NaCl solution and dryingAnd vacuum evaporation; a semi-solid residue was obtained which was redissolved and then triturated in heptane to give a solid. m 27.7g and F90-92 ℃.

2.25-amino-1, 3-benzodioxole-2-carboxylic acid methyl ester.

900mg of the ester obtained in the preceding step are dissolved in 30ml of THF, and 3.92g of zinc dust are added. After cooling to-5 ℃ 4ml of acetic acid diluted with 4ml of THF are added over 30 minutes, and the temperature is then raised again. After 1 * h, filtration was carried out and the solid was washed with a small amount of THF and methanol. The filtrate was diluted with AcOEt and H₂O, saturated NaHCO₃Solution, H₂Washing with saturated NaCl solution; after drying, concentration in vacuo gave a yellow wax, which was identified by NMR. And m is 800 mg.

Preparation 3

15-Nitro-1, 3-benzodioxole-2-carboxamide (carboxamide).

20ml of a 2M ammonia solution in methanol are poured into 1.12g of the methyl ester obtained in preparation 2.1. After 25 min, concentration was carried out in vacuo and the solid residue taken up in Et2O, filtered and dried. m is 0.99 g; f202 and 207 ℃.

25-amino-1, 3-benzodioxole-2-carboxamide.

To a solution of 0.98g of the amide obtained in preparation 3.1 in 35ml of THF was added 4.57g of zinc dust, and after cooling to-5 ℃ 5ml of acetic acid diluted in 5ml of THF was added over 30 minutes. After addition, the temperature was increased. After 1 hour, the solid was filtered and washed with a small amount of THF, methanol, AcOEt solution. The filtrate was diluted with AcOEt, to which water was added and saturated NaHCO was used₃The solution was adjusted to pH 6. The precipitate formed is removed by filtration, the filtrate is decanted and the organic phase is then washed with saturated NaHCO₃Solution, H₂Washing with saturated NaCl solution, drying and evaporating; a wax is obtained which hardens on cooling. And m is 0.63 g.

Preparation 4

4.15-Nitro- (1, 3-benzodioxol-2-yl) methanol.

To a solution of 5.02g of the methyl ester obtained in preparation 2.1 in 25ml of THF at-5 ℃ over 1 hour and 15 minutes was added 22.3ml of 1M LiAlH₄A solution in THF; 20 minutes after the completion of the addition, 20ml of AcOEt was added dropwise, then 9ml of 1N NaOH was added dropwise, the resulting precipitate was removed by filtration, and the precipitate was washed with AcOEt; the filtrate was diluted with AcOEt and then with H₂O、5％ KHSO₄/K₂SO₄、H₂Washing with saturated NaCl solution; after drying and concentration in vacuo, crystalline wax was obtained. m 2.74g, F80-82 deg.C.

In the subsequent step, the nitro derivative obtained in preparation 4.1 is reduced by the method described above to give the amine of formula (III) of preparation 4.2.

Preparation 5

5.1 (5-nitro-1, 3-benzodioxol-2-yl) methanesulfonate.

4.12g of the alcohol obtained in preparation 4.1 was dissolved in 30ml of CH at 5 deg.C₂Cl₂To the solution in (1), 3ml of triethylamine was added, followed by addition of 1.85g of methanesulfonyl chloride over 15 minutes. After 15 minutes, the ice bath was removed. After 55 minutes, use CH₂Cl₂And water to dilute the reaction medium; the organic phase is decanted with H₂And O, washing with saturated NaCl solution, drying and evaporating. After trituration in heptane, a brown solid was obtained. m 5.20g, F112-115 ℃.

5.2[ (5-nitro-1, 3-benzodioxol-2-yl) methyl ] diethylamine.

To a solution of 2.91g of the mesylate obtained in the previous step in 18ml of DMF was added 2.19g of diethylamine, which was then heated to 80 ℃. After 15 hours, 0.73g of diethylamine was added, and after 8 hours, 0.73g was further added. After a total of 48 hours, the reaction medium is diluted with AcOEt and washed first with water and then with a saturated NaCl solution; after drying, AcOEt is evaporated off and the residue is dissolved in 40ml Et₂O +10ml AcOEtAnd then extracted twice with 60ml of 0.25N HCl; the acid phases were mixed, contacted with AcOEt and the pH adjusted to 9 with 10N NaOH; the organic phase is decanted, initially with H₂O, washed with saturated NaCl solution, dried and evaporated. An oil is obtained. And m is 1.55 g.

5.3[ (5-amino-1, 3-benzodioxol-2-yl) methyl ] diethylamine.

To a solution of 1.93g of the nitro compound obtained in the preceding step in 70ml of THF were added 7.45g of zinc powder, followed by addition of 7.6ml of AcOH at-5 ℃ over 25 minutes and stirring at 0-5 ℃. After 1 * h, the solid was filtered and washed with THF and a little methanol; AcOEt + H was used for the filtrate₂Diluting with O, and adjusting the pH to 9 with 10N NaOH; removing the generated precipitate by filtration; decanting the filtrate; h for organic phase₂O, saturated NaCl solution, dried and evaporated to give a black oil. m is 1.75 g.

Preparation 6

6.11-methyl-4- ((5-nitro-1, 3-benzodioxol-2-yl) methyl) piperazine.

The reaction was carried out according to operating mode 5.2, the product being isolated in the form of the dihydrochloride.

6.22- ((methylpiperazin-1-yl) methyl) -1, 3-benzodioxol-5-amine

The reaction was carried out according to protocol 5.3.

Preparation 7

7.15-Nitro-1, 3-benzodioxole-2-carboxylic acid.

To a solution of 1.12g of the ester obtained in preparation 2.1 in 12ml of methanol was added 1.5ml of 5N NaOH over 30 minutes. 35 minutes after the addition is complete, the reaction medium is treated with AcOEt and H₂Diluting with O, and adjusting the pH to 2 with 2N HCl; the organic phase is decanted with H₂O and saturated NaCl solution were washed, then dried and evaporated to give 1.25g of oil.

2N, N-dimethyl-5-nitro-1, 3-benzodioxole-2-carboxamide.

To a solution of 0.84g of the acid obtained in the previous step in 15ml of dichloromethane were added 0.36g of dimethylamine hydrochloride, 0.77ml of DIPEA, and further 0.91g of DCCI. After stirring at room temperature for 3 hours, the reaction medium is filtered and the filtrate is taken up in CH₂Cl₂Diluted and successively further saturated NaHCO₃Solution, H₂O、5％KHSO₄/K₂SO₄、H₂Washing with saturated NaCl solution; after drying, the solvent is evaporated off and the residue is purified by chromatography on silica gel using a dichloromethane/methanol 99/1 mixture. 0.5g of solid product was obtained. F-109 ℃.

Preparation 9

9.15-Nitro-1, 3-benzodioxole-2-carbonitrile.

To 45ml of DMF cooled to 5 ℃ was added 3.7ml of POCl₃. After stirring at 5 ℃ for 30 minutes, 1.67g of the amide from preparation 3.1 were added immediately. After stirring at room temperature for 3 hours, the reaction medium is poured into 250ml of a water/ice mixture. The precipitate formed was filtered, washed with water and dried. m is 1.32 g; f105-.

25-amino-1, 3-benzodioxole-2-carbonitrile.

The NO of the product obtained in step 9.1 is reacted using the method described above, using a Zn/AcOH mixture₂Reduction to NH₂。

Preparation 11

11.15-Nitro-1, 3-benzodioxole-2, 2-dicarboxylic acid ethyl ester.

The compound was prepared using the procedure described in Pharmazie 200358(1) 13-17.

11.25-Nitro-1, 3-benzodioxole-2, 2-dicarboxamide.

To 14ml of a 2M solution of ammonia in methanol, 1.24g of the diester obtained in the preceding step are added in one portion. After stirring for 30 minutes, the reaction medium is concentrated to dryness, and the solid residue is then dissolved in ether, filtered and dried. m is 1.01 g; f231-.

Preparation 12

12.1 (5-nitro-1, 3-benzodioxole-2, 2-diyl) dimethanol.

To a solution of 1.87g of the diester from preparation 11.1 in 60ml of THF was added 1.50g of NaBH at room temperature over a period of 1 hour₄(ii) a 25 minutes after the addition was complete, the solution was diluted dropwise with 250ml of AcOEt, then 5ml of methanol, and then 40ml of water. The organic phase is decanted with H₂O、5％KHSO₄/K₂SO₄Solution, H₂O washing, and then washing with saturated NaCl solution. After evaporation to dryness, the residue is purified by chromatography on silica, eluting with chloroform/methanol mixture (98/2), yielding 0.64g of a solidified oil. F111-.

Preparation 13

13.13- (2-methyl-5-nitro-1, 3-benzodioxol-2-yl) propionic acid ethyl ester.

22.4g of phosphoric anhydride are added to a suspension of 15.51g of 4-nitrocatechol in 22.10g of ethyl acetoacetate at 70 ℃ over 15 minutes. After 1 hour and 45 minutes, the reaction medium is cooled and then extracted with 4X 150ml of warm toluene. Combining the toluene phases with H₂O、1N NaOH、H₂O、5％KHSO₄/K₂SO₄、H₂And washing with saturated NaCl solution. After drying and evaporation, the product was purified by chromatography on silica gel, eluting with chloroform, to give 2.44g of a solid. F is 76-78 ℃.

13.23- (2-methyl-5-nitro-1, 3-benzodioxol-2-yl) propan-1-ol.

To a solution of 2.33g of the ester obtained above in 40ml of THF at-5 ℃ over 45 minutes was added 8ml of 1M LiAlH₄Solution in THF. After 35 minutes, 8ml of ethyl acetate, then 1ml of water and then 1ml of 1N NaOH were added dropwise. Removing solids by filtration; the filtrate was diluted with AcOEt and H₂O、5％KHSO₄/K₂SO₄Washing with saturated NaCl solution; after drying, the organic phase is concentrated in vacuo; and m is 1.90 g.

13.33- (2-methyl-5-nitro-1, 3-benzodioxol-2-yl) propyl methanesulfonate.

To a solution of 1.89g of the alcohol obtained in the preceding step in 40ml of dichloromethane was added 1.01g of triethylamine and 1.14g of methanesulfonyl chloride over 20 minutes at 5 ℃. After the addition, the ice bath was removed and stirring was continued for 1 hour; the reaction medium is CH₂Cl₂Diluting with H₂Washing with saturated NaCl solution; after drying, the solvent is evaporated; 2.46g of wax which solidified on cooling were obtained.

4N, N-bis-ethyl-3- (2-methyl-5-nitro-1, 3-benzodioxol-2-yl) propan-1-amine.

To a solution of 1.21g of mesylate in 20ml of DMF was added 0.87g of diethylamine, which was then heated to 80 ℃. After 8 * hours, 0.44g of diethylamine was added and heating was continued for 14 hours. The reaction medium is concentrated in vacuo, the residue is redissolved in AcOEt and the pH is adjusted to 9.5 with 1N NaOH; the organic phase is decanted with H₂Washing with saturated NaCl solution and drying; after evaporation, the crude product is obtained, which is redissolved in Et 20ml₂O in 20ml of AcOEt, twice with 50ml of 0.5N HCl; mixing the two aqueous phases, contacting with AcOEt, and adjusting pH to 9 with 10N NaOH; the organic phase is decanted and then H is used₂Washing with O, and then washing with a saturated NaCl solution; drying and evaporation gave 0.66g of oil.

13.5

The NO of the product obtained in step 13.4 is reacted using the method described above using a Zn/AcOH mixture₂Reduction of substituents to NH₂To obtain a reduced product 13.5.

13.6

To a solution of 2.00g of the product from preparation 13.3 in 20ml of DMF was added 0.85g of sodium azide, stirred at room temperature for 5 days, extracted with ether and the organic phase was washed with water and then with saturated NaCl solution. An oil is obtained. m is 1.50 g. NMR was consistent.

13.7

A mixture of 1.49g of the product from preparation 13.6, 1.71g of triphenylphosphine and 0.12g of water in 25ml of THF is stirred for 24 hours. The reaction medium is then extracted with AcOEt and washed with water. The crude product obtained is dissolved in AcOEt/Et₂O mixture, and then extracted with 1N HCl aqueous solution. The aqueous acid phase was contacted with AcOEt and the pH was then adjusted to 9 with 10N NaOH. The organic phase is separated and washed first with water and then with saturated NaCl solution. The organic phase was concentrated under reduced pressure to give 1.10g of an oil.

13.8

1.09g of the amine from step 13.7 was dissolved in 10ml of Dichloromethane (DCM), and then 0.20g of triethylamine and 1.18g of Boc were added₂And O. After 5 hours, the reaction medium is diluted with DCM and successively with 5% KHSO₄/K₂SO₄The solution, water and saturated NaCl solution were washed. The separated organic phase was dried and evaporated under reduced pressure to give 1.36g of an oil.

13.9 (precursor of example 55)

Treatment of 1.35g of the product from step 13.8 with Zn/AcOH as described in preparation 2.2 to make NO₂Reduction of the radical to NH₂. 1.13g of wax was obtained.

Preparation 14

12- (2-methoxymethyl) -5-nitro-1, 3-benzodioxole.

1.45g of the hydroxymethyl group obtained in preparation 4.1 was dissolved in 25ml of THF; after cooling to 5 ℃, 353mg of 60% NaH was added in small portions; after 30 minutes, 0.92ml of methyl iodide was added, followed by stirring at room temperature overnight; 1ml of methyl iodide was added and stirring was continued for 5 hours; to the reaction medium was added 30ml of saturated NH₄Cl solution, followed by addition of water and ethyl acetate; the organic phase is decanted and then H is used₂The O was then washed with saturated NaCl solution, dried and then evaporated. The crude product was chromatographed on silica gel using 9/1 CHCl₃Heptane elution. 595mg of oil are obtained and identified by NMR.

Preparation 16

16.12- ((5-Nitro-1, 3-benzodioxol-2-yl) carbonyl) hydrazinecarboxylic acid tert-butyl ester.

A mixture of 900mg of the ester (preparation 2.1) and 2.114g of tert-butyl carbazole salt in 40ml of methanol was heated at 60 ℃ for 60 hours. 600mg of tert-butyl carbazole salt was added and heating was continued for 3 hours. The methanol was evaporated off, the residue was dissolved in ethyl acetate and washed with water, 0.2N hydrochloric acid, a saturated sodium bicarbonate solution, water and a saturated NaCl solution. A solidified wax is obtained. m is 1.27 g.

16.22- ((5-amino-1, 3-benzodioxol-2-yl) carbonyl) hydrazinecarboxylic acid tert-butyl ester.

To a solution of 1.30g of the product obtained in the preceding step in 25ml of THF was added 3.92g of zinc powder, followed by addition of 4.8g of acetic acid at-5 ℃ over 30 minutes; removing the ice bath, and continuing stirring for 2 hours; the solid was filtered and washed with a little THF followed by AcOEt(ii) a Water was added to the filtrate followed by 15% Na₂CO₃The pH of the solution is adjusted to 6.5; AcOEt decantation with saturated NaHCO₃、H₂O, saturated NaCl solution, dried and then evaporated. The desired product was obtained as a black oil. m is 1.12 g.

Preparation 21

21.1

To a solution of 2.14g of the methanesulfonate obtained in step 5.1 in 17ml of DMF was added 1.51g of sodium azide and the mixture was heated at 70 ℃ for 3 hours. The reaction mixture was extracted with AcOEt, washed first with water and then with saturated NaCl solution. An oil is obtained. m is 1.71 g.

21.2

To a solution of 1.7g of the product obtained in step 21.1 in 20ml of AcOEt was added 3.41g of triphenylphosphine in small portions, and after 10 minutes, 2.34ml of water was added and the mixture was heated to 60 ℃. After 1 hour, the reaction mixture was evaporated to dryness and then dissolved in Et₂And O. Insoluble material was removed and then excess saturated ethereal HCl was added. The resulting solid was filtered, washed with ether and then dried to give the desired product as the hydrochloride salt. The corresponding amine is obtained by liberation of the hydrochloride.

21.3

The product obtained in step 21.2 can be separated into two enantiomers:

to a solution of 2g of the amine obtained in step 21.1 in 70ml of water and 7ml of dioxane at 70 ℃ was added 1.97g of (S) (+) mandelic acid. The reaction medium was then slowly returned to 30 ℃ with magnetic stirring. The precipitate obtained is filtered, dissolved in 40ml of water and 4ml of dioxane at 70 ℃ and then slowly returned to 30 ℃ with stirring. The solid formed during cooling was filtered and dried. And m is 0.49 g. The resulting product was dissolved in 20ml of water and 100ml of AcOEt, and the pH was adjusted to 9.5 by addition of 1N NaOH. The mixture is decanted, the organic phase is isolated, water is added and then saturated NaHCO₃Washing with water several times, and dissolving with saturated NaClAnd (4) washing the solution. The organic phase was collected, dried and the solvent was evaporated under reduced pressure. Slowly hardening 0.27g of wax was obtained. [ alpha ] to]D ═ 94.7, at 25 ℃; c ═ 0.5 (MeOH); optical purity: chiral HPLC: 96/4 (optical rotatory power 102 ℃ for 100% enantiomer purification).

21.4

To a solution of the product obtained in step 21.2 in 30ml DCM was added 1.49ml triethylamine followed by 2.53g Boc in small portions₂And O. After 1 hour, the reaction medium is freed from 5% KHSO₄/K₂SO₄H2O, saturated NaCl solution. After drying, the organic phase is concentrated to dryness and the residue is triturated in heptane. 2g of solid are obtained.

21.5

To a solution of 480mg NaH in 20ml THF at 5 ℃ over 35 minutes was added a solution of 1.79g of the product obtained in step 21.4 in 15ml THF. The mixture was stirred at room temperature for 45 minutes, then 1.2ml of methyl iodide were added over 10 minutes. After 3 hours, the reaction medium is poured into 60ml of saturated aqueous citric acid solution and then extracted with ethyl acetate. The organic phase is separated, washed with water and then with saturated NaCl solution, dried and then evaporated to dryness. The crude product obtained was purified by flash chromatography, eluting with a gradient of dichloromethane in cyclohexane. A white solid was obtained. m is 1.4 g.

21.6

The product obtained in preparation 21.5 was reduced by the usual method using Zn/AcOH.

Preparation 22

22.1

A mixture of 11.65g of 4-N-Z-piperidone, 6.35g of methyl orthoformate and 40mg of p-toluenesulfonic acidThe compound was heated in a Claisen reactor at 60 ℃ for 1 hour and then at 70 ℃ for 1 hour to distill the methyl formate. The residue was taken up in AcOEt + H₂O was diluted and then a few drops of 1N sodium hydroxide were added to adjust the pH to 7. The organic phase is decanted, separated, washed with water and then with saturated NaCl solution, dried and evaporated. 14g of a colorless oil were obtained.

22.2

16.09g of the ketal obtained in step 22.1, 10.80g of 4-nitrocatechol and 60mg of p-toluenesulfonic acid were heated in 120ml of toluene while slowly distilling the toluene. After 4 hours and 30 minutes, the reaction medium is diluted with toluene, cooled, the insoluble material is removed by filtration, and the filtrate is again freed from 1N NaOH, H₂O、5％ KHSO₄/K₂SO₄Solution, H₂And washing with saturated NaCl solution. After drying and evaporation, the crude product was purified by silica gel chromatography using CHCl₃AcOEt 98/2 elution. 0.65g of the expected product is obtained.

22.3

To a solution of 0.60g of the product obtained above in 5ml of trifluoroacetic acid was added 0.5ml of thioanisole. After 3 hours, the reaction medium is concentrated in vacuo; the residue is dissolved in CH₂Cl₂And H₂In O, the pH was adjusted to 9 with 1N NaOH. After decantation, the organic phase is washed with water and then with a saturated NaCl solution. The organic phase is then dried and evaporated. The recovered crude product was purified by silica gel chromatography using CHCl₃/MeOH/NH₄OH 95/5/0.1. 100mg of the expected product are obtained as an oil.

22.4

Using 98mg BOC₂A solution of O and 20mg triethylamine in 3.5ml dichloromethane was treated with 95mg of the amine obtained in step 22.3 for 1 hour. After usual reaction and work-up, a white solid was obtained. And m is 130 mg.

22.5

According to the operating mode already described, NO is reacted using Zn/AcOH₂The group is reduced to an amine.

23.1

To a solution of 985mg of preparation 4.1 in 25ml of DCM was added 0.46ml of pyridine. A solution of 0.84ml of trifluoromethanesulfonic anhydride in 3ml of DCM was then added at 5 ℃ over 20 minutes. After 1 hour at 5 ℃, the reaction medium is washed with ice-water and then with a saturated NaCl solution. The organic phase was dried and then concentrated in vacuo. 1.42g of a solid was obtained.

23.2

To a solution of 1.15g of the product obtained in step 23.1 in 10ml DCM +0.5ml DMF was added 75mg of diethanolamine. After stirring overnight, the reaction medium is diluted with 100ml of DCM, washed with water, washed with saturated NaCl solution, dried and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 0-15% methanol in chloroform. 730mg of solid are obtained.

23.3

As described earlier, the use of Zn/AcOH to convert NO₂The radicals alsoTo form amine. Using 720mg of the product obtained in step 23.2, the desired product was obtained in the form of a gum.

Preparation 24

24.1

The product was prepared according to the procedure described in org.Lett, 2001, 3(9), 1399-.

Preparation 24.2

To a solution of 2.73g of the product obtained in step 24.1 in 30ml of DCM was added 5ml of 69% nitric acid over 2 minutes. After stirring for 2 hours 30 minutes, the reaction medium is treated with Et₂Diluting with oxygen; h for organic phase₂O twice, with 7% frozen Na₂CO₃The solution was washed twice, once with water and then with 5% KHSO₄/K₂SO₄The solution was washed once, once with water and once with saturated NaCl solution. After drying and evaporation, a white solid was obtained.

m＝3.20g。

Preparation 24.3

532mg of LiAlH were used at-5 deg.C₄A solution of 3.63g of the product obtained in the above-described manner in 80ml of THF is worked up for 1 hour. After usual work-up, 2.60g of thick oily product are isolated.

Preparation 24.4

Treatment of 2.59g of the alcohol obtained in step 24.3 with methanesulfonyl chloride according to the procedure described for preparation 13.3 gave 3.52g of the mesylate. And (4) identifying by using NMR.

Preparation 24.5

3.51g of the product obtained in step 24.4 were treated with 1.97g of sodium azide using the procedure described for preparation 13.6. 2.60g of the expected product are obtained.

Preparation 24.6

2.59g of the product obtained in step 24.5 are treated with 4.90g of triphenylphosphine and 2ml of water in the procedure described for preparation 13.7. 2g of the expected product are obtained in the form of an oil.

Preparation 24.7

Using BOC in the operating manner described for preparation 13.8₂1.99g of the product obtained in step 24.6 are O-treated. 2.41g of a solid were obtained.

Preparation 24.8

The product obtained in step 24.7 is treated with Zn/AcOH according to the usual method for the reduction of nitro groups to amino groups. 0.93g of starting product was used to give 0.84g of the desired product as a wax.

The characteristics of the compounds of formula (III) and of the intermediates of formula (IV), i.e. the benzodioxole derivatives, are listed in the table below.

For the following compounds, the compound of formula (IV) was converted to the compound of formula (III) according to preparation 5.3: 7.2, 9.1, 11.1, 12.1, 13.4 and 14.1.

TABLE 1

Preparation of the Compound of formula (III)

Preparation of	CR5R6	X＝NO2(IV)RMN	X＝NH2(III)RMN
						7,65ppm：d：1H；7,80ppm：dd：1H	6,15ppm：t：1H；6,20ppm：d：1H；6,60ppm：d：1H
7	CH-CONMe2	7.22,85ppm：s：3H；3,10ppm：s：3H；7,15ppm：d：1H；7,35ppm：s：1H；7,80ppm：d：1H；7,90ppm：dd：1H	7.32,85ppm：s：3H；3,05ppm：s：3H；4,80ppm：se：2H；6,00ppm：dd：1H；6,20ppm：d：1H；6,60ppm：d：1H；6,75ppm：s：1H
				8	CH-CONHEt	8.11,00ppm：s：3H；3,10ppm：qt：2H；6,50ppm：s：1H；7,10ppm：d：1H；7,70ppm：d：1H；7,85ppm：dd：1H；8,70ppm：te：1H	8.21,00ppm：t：3H；3,05ppm：qt：2H；4,70ppm：se：2H；5,95ppm：dd：1H；6,05ppm：s：1H；6,15ppm：d：1H；6,50ppm：d：1H；8,40ppm：te：1H
9	CH-CN	9.17,30ppm：d：1H；7,45ppm：s：1H；8,05-8,85ppm：m：2H	9.25,10ppm：se：2H；6,20ppm：dd：1H；6,45ppm：d：1H；6,85ppm d：1H；7,25ppm：s：1H
				10	CH-CONHNMe2	10.12,50ppm：s：6H；6,50ppm：s：1H；7,10-7,20ppm：m：1H；7,75-7,80ppm：m：1H；7,85-7,95ppm：m：1H；9,80ppm：se：1H	10.22,50ppm：s：6H；4,75ppm：se：2H；5,95-6,50ppm：m：4H；9,50ppm：se：1H

Preparation 18

18.1 ((7-nitro-2, 3-dihydro-1, 4-benzodioxin-2-yl) methyl) diethylamine hydrochloride.

To a solution of 1.50g of 7-nitro-2, 3-dihydro-1, 4-benzodioxin-2-yl methanesulfonate in 30ml of DMF was added 800. mu.l of diethylamine and heated to 80 ℃ as described in International patent application WO 01/021577, followed by 3 additions of 800. mu.l diethylamine at 12 hour intervals. After 48 hours, the reaction medium is evaporated to dryness; the residue was dissolved in 100ml AcOEt and then in 5ml 4N NaOH; the organic phase is decanted and washed first with water and then with saturated NaCl solution; after drying and evaporation of AcOEt, the residue was dissolved in 20ml of AcOEt and then in 50ml of 0.5N HCl and stirred, and decanted; the aqueous phase was evaporated to dryness and the residue was triturated in ether, filtered and then dried. m is 0.95g, F is 192 ℃ and 194 ℃.

18.27-amino-2, 3-dihydro-1, 4-benzodioxin-2-yl) methyl) diethylamine.

To a suspension of 0.94g of the nitro derivative obtained in the previous step in 40ml of THF was added 3.05g of zinc powder. After cooling to 0 ℃ 3.1ml nitric acid was added over 20 minutes; after 10 minutes, the ice bath was removed and stirring was continued for 2 hours. The solid was filtered and washed with THF followed by a small amount of methanol. The filtrate was evaporated to dryness, dissolved in ethyl acetate, water was added and the pH adjusted to 8 with NaOH; the precipitate formed was removed by filtration and washed with AcOEt; the filtrate was decanted, washed with saturated NaCl solution, dried and evaporated; a brown oil was obtained. And m is 0.51 g.

The compounds of formula (III) and the intermediates of formula (IV), i.e. the benzodioxin derivatives, are prepared in racemic form, their characteristics being listed in the following table:

TABLE 2

Preparation of the Compound of formula (III)

The exemplified compound numbers correspond to those listed in table 3 below, which illustrates the chemical structure and physical properties of certain compounds of the invention. When they contain asymmetric carbons, these compounds are obtained in racemic form.

Example 1: compound N2

Methyl 5- ((7- (((tert-butylamino) carbonyl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-2-yl) amino) -1, 3-benzodioxole-2-carboxylate.

A mixture of 0.97g of the compound of preparation 2.2 and 1.40g of the compound of preparation 1 is heated under reflux in 15ml of THF. After 6 hours, the reaction medium is concentrated in vacuo. The product was purified by silica gel chromatography with AcOEt/toluene (2/3) followed by silica gel chromatography with CHCl₃Purification was performed with MeOH 98/2. 0.45g of a yellow solid is obtained and is identified by mass spectrometry. MH⁺＝583。

Example 2: compound N4

5- ((7- (((tert-butylamino) carbonyl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-2-yl) amino) -1, 3-benzodioxole-2-carboxylic acid.

To a solution of 0.25g of the ester obtained in the above example in 10ml of methanol was added 0.3ml of 2N sodium hydroxide. After stirring at room temperature for 1 hour 10 minutes, the reaction medium is treated with AcOEt + H₂O was diluted and the pH was adjusted to 4 with 1N HCl. The organic phase is decanted, initially with H₂O, washed with saturated NaCl solution, dried and evaporated. The yellow solid residue was dissolved in ether, triturated, filtered and dried. 205mg of product was obtained and identified by mass spectrometry. MH⁺＝569。

Example 3: compound N3

5- ((7- (((tert-butylamino) carbonyl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-2-yl) amino) -1, 3-benzodioxole-2-carboxamide.

0.62g of the Compound of preparation 3.2 and 1.40g of the sulfone derivative of preparation 1A mixture of the organisms in 20ml of THF was heated to reflux. After 3 hours, the reaction medium is concentrated in vacuo, and the residue is chromatographed on silica gel with CHCl₃Purification was performed with MeOH97/3 (v/v). 315mg of a yellow solid are obtained and are identified by mass spectrometry. MH⁺＝568。

Example 4: compound N9

N- (tert-butyl) -N' - (6- (2, 6-dichlorophenyl) -2- ((2-hydroxymethyl) -1, 3-benzodioxol-5-yl) amino) pyrido [2, 3-d ] pyrimidin-7-yl) urea.

To a mixture of 350mg of the compound of preparation 4.2 and 937mg of the compound of preparation 1 in 15ml of EtOH, 43. mu.l of concentrated HCl was added; heated at 55 ℃ for 6 hours. The reaction medium is concentrated in vacuo, and the residue is then purified by chromatography on silica gel; 490mg of a yellow solid are obtained and are identified by mass spectrometry. MH⁺＝555。

Example 5: compound N6

5- ((7- (((tert-butylamino) carbonyl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-2-yl) amino) -1, 3-benzodioxole-2-carbonitrile.

To a solution of 1.00g of preparation 1 and 450mg of preparation 9.2 in 15ml of EtOH, 50. mu.l of concentrated HCl were added, followed by gentle reflux at elevated temperature. After 1 hour and 30 minutes, the reaction medium is concentrated in vacuo. The residue was chromatographed on silica gel with CHCl₃AcOEt (90/10, v/v) was purified. 465mg of a yellow solid are obtained and are identified by mass spectrometry. MH⁺＝550。

Example 6: compound N12

N- (2- ((aminomethyl) -1, 3-benzodioxol-5-yl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-7-yl) -N' - (tert-butyl) urea

At-10 ℃ in 30 minutes as in the previous examples530mg of the nitrile derivative were dissolved in 25ml of THF, and 1.9ml of a 1M solution of LiAlH4 was added. 15 minutes after the completion of the addition, 1.5ml of AcOEt was added, 10ml of a saturated NH4Cl solution was added, and the temperature was raised. After dilution with AcOEt, it was washed first with water and then with saturated NaCl solution. After drying, the organic phase is concentrated in vacuo and the residue is chromatographed on silica gel with CHCl₃Purification was carried out with MeOH (95/5; v/v). 165mg of a yellow solid are obtained and are identified by mass spectrometry. MH⁺＝554。

Example 7: compound N DEG 19

Tert-butyl 2- ((5- ((7- (((tert-butylamino) carbonyl) amino) -6- (2, 6-dichlorophenyl) pyrido [2, 3-d ] pyrimidin-2-yl) amino) -1, 3-benzodioxol-2-yl) carbonyl) hydrazinecarboxylate.

To a solution of 0.645g of the product from preparation 1 and 0.63g of the product from preparation 16.2 in 25ml of ethanol, 0.025ml of concentrated HCl was added, followed by stirring at 70 ℃ for 5 hours. The reaction medium is evaporated and the residue is dissolved in CHCl₃In the process, water and saturated NaHCO are used again₃The solution, water, saturated NaCl solution were washed, then dried and evaporated under vacuum; the residue was purified by silica gel chromatography. 450mg of yellow solid is obtained and is identified by mass spectrometry. MH⁺＝683。

Example 8: compound N20 degree

N- (tert-butyl) -N' - (6- (2, 6-dichlorophenyl) -2- ((2-hydrazinocarbonyl) -1, 3-benzodioxol-5-yl) amino) pyrido [2, 3-d ] pyrimidin-7-yl) urea.

360mg of the compound of the previous example in 4ml CH₂Cl₂And 14ml TFA for 45 minutes; the reaction medium is evaporated in vacuo and the residue is dissolved in CHCl₃Then with H₂O、15％ Na₂CO₃Aqueous solution, H₂Washing with saturated NaCl solution; after drying, the chloroform was evaporated in vacuo and the residue was triturated in ether, filtered and dried. 225mg of yellow are obtainedA colored solid. MH⁺＝583。

Example 9: compound N DEG 34

431mg of compound N.cndot.33 are stirred at room temperature for 30 minutes in 5ml of DCM and 5ml of TFA. After evaporation, the residue was dissolved in chloroform/water mixture and then purified by addition of 15% Na₂CO₃The aqueous solution adjusted the pH to 9. The organic phase is decanted, washed with water and then with saturated NaCl solution, dried and concentrated under reduced pressure. 116mg of solid are obtained. [ M + H ]]⁺＝568°

Example 10: compound N degree 35

Step 1:

this step was carried out according to the procedure described in organometallic chemistry (j. organometall. chem.)1996, 507, 1-21.

Step 2:

this step is performed according to 1988, 31, 84-91, j.med.chem.

And step 3:

to a solution of 2.91g of the product obtained in the preceding step in 40ml of methanol at 8 ℃ over 35 minutes, 800mg of sodium borohydride are added. After 50 minutes, the reaction medium is poured into 150ml of water/ice and400ml of ethyl acetate; after stirring for 5 minutes, the organic phase is freed from 5% KHSO₄/K₂SO₄The solution, water and saturated NaCl solution were washed, dried and the organic phase was evaporated to separate a brown solid. m is 2.25 g.

And 4, step 4:

to a solution of 2.24g of the alcohol obtained above in 60ml of DCM were successively added 1.43g of triethylamine, followed by 1.67g of methanesulfonyl chloride over 25 minutes. After 45 minutes, the reaction medium is diluted with 100ml of DCM; washed twice with ice water and once with saturated NaCl solution, then dried and the organic phase concentrated in vacuo. A brown solid was obtained. And m is 3.01 g.

Step 5

A mixture of 3.0g of the product obtained in step 4 and 1.82g of sodium azide was heated at 65 ℃ for 7 hours and 30 minutes. The reaction medium is then poured into 75ml of ice-water and 300ml of ether. The organic phase is separated, washed several times with water and then with saturated NaCl solution. The organic phase was dried and concentrated in vacuo to give a brown solid. m is 2.20 g.

Step 6:

to a solution of 2.19g of the product obtained in step 5 in 50ml of ethyl acetate, 4.33g of triphenylphosphine were added over 15 minutes, and then after 10 minutes, 1.8ml of water were added over 2 minutes.The reaction medium is stirred at 60 ℃ for 1 hour 40 minutes and then diluted with 150ml of ethyl acetate. The solution thus obtained was washed twice with water, once with saturated NaCl solution, dried and evaporated. The residue obtained by evaporation is dissolved in a mixture of 50ml of ethyl acetate and 50ml of diethyl ether and then extracted twice with 50ml of 1N HCl. The acidic aqueous phases are combined, extracted with a mixture of 25ml of ethyl acetate and 25ml of diethyl ether, brought into contact with 300ml of ethyl acetate and then adjusted to pH 9 with 10N NaOH. After decantation, the organic phase is washed with water, saturated NaHCO₃The solution, water, saturated NaCl solution wash. The remaining organic phase was dried and then concentrated in vacuo. An oil is obtained. m is 1.40 g.

And 7:

to a solution of 1.39g of the amine obtained in step 6 in 35ml of DCM at 5 ℃ over 10 minutes was added 0.35g of triethylamine followed by 1.75g of Boc₂And O. After stirring overnight at room temperature, the reaction medium is diluted with 150ml of DCM, water, 5% KHSO₄/K₂SO₄The solution, water, saturated NaCl solution wash. After drying and evaporation of DCM, the resulting solid was dissolved in a minimum amount of diethyl ether and heptane was added until complete precipitation. A solid was obtained. And m is 1.90 g.

NMR：1.30ppm：s：9H；3.40-3.55ppm：mt：2H；6.55ppm：t：1H；7.00ppm：t：1H；7.15-7.30ppm：mt：2H；7.55ppm：d：1H.

And 8:

to a solution of 0.60g of the product obtained in step 7 in 25ml of THF was added 1.96g of zinc powder, followed by heating at-3 deg.CNext, 2ml of AcOH was added over 25 minutes. When the addition is complete, the reaction medium is allowed to return to room temperature. After 15 minutes, the reaction medium is filtered, the filtrate is diluted with 150ml of ethyl acetate and 30ml of water, 15% Na is added₂CO₃The solution was adjusted to pH 9. After decantation, the organic phase is separated and washed with saturated NaHCO₃The solution, water, then saturated NaCl solution washing. The organic phase is separated, dried and then concentrated under reduced pressure. 0.53g of a viscous yellow oil is obtained.

RMN：1,35ppm：s：9H；3,30ppm：mt：2H；4,80ppm：s：2H；6,05ppm：t：1H；6,10-6,25ppm：mt：2H；6,50ppm：t：1H；7,10ppm：t：1H..

And step 9:

coupling under standard conditions as previously described gave compound 35.

Example 11 Compound N ° 45

To a solution of 1g of Compound 12 in 15ml of methanol and 2ml of DMF was added 1.035ml of DIPEA followed by 0.675g of formamidinylsulfonic acid (H)₂N-C(＝NH)-SO₃H) In that respect After stirring overnight at 25 ℃, the reaction medium is supplemented with water and the precipitate formed is filtered off, washed with water and then dried under reduced pressure. The crude product was purified by flash chromatography on silica gel with a gradient of 10-50% MeOH in DCM. 170mg of solid are obtained in mol/mol H₂SO₄It is converted into salt. MS: MH⁺＝596

Example 12: compound N degree 39

Preparation 39.1

To a solution of 555mg of compound 9 (example 4) in 10ml of DCM at 5 ℃ was added 0.11ml of pyridine followed by 0.20ml of trifluoromethanesulfonic anhydride diluted in 2ml of DCM over 15 minutes. After 45 minutes, the reaction medium is diluted with 50ml of DCM, successively with ice-water, 5% KHSO₄/K₂SO₄The solution, water, saturated NaCl solution wash. Then theThe organic phase was dried and concentrated under reduced pressure. 593mg of solid were recovered.

RMN¹H：1,40ppm：s：9H；4,65ppm：se：2H；6,50ppm：t：1H；6,90ppm：d：1H；7,40ppm：de：1H；7,50-7,70ppm：m：3H；8,00ppm：se：1H；8,05ppm：s：1H；8,20ppm：se：1H；9,00ppm：s：1H；10,15ppm：s：1H；10,70ppm：s：1H.

Preparation 39.2

To a solution of 579mg of the compound obtained in step 39.1 in 10ml of DCM was added 0.17ml of morpholine. The reaction medium is stirred at room temperature for 3 hours and 30 minutes and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with 20% AcOEt in DCM. 300mg of a yellow powder are obtained. MS: MH⁺＝624。

Example 13: compound N degree 40-43

Compounds 40 to 43 were prepared in the same manner as compound 39 mentioned in example 12 using the compound obtained in step 39.1 and replacing morpholine in step 39.2 with tert-butylamine, 1-Boc-piperazine, cyclopropylamine, cis-2, 6-dimethylpiperidine, respectively.

Example 14: compound N DEG 44

Compound 41 from example 13 was deprotected using TFA using the method described previously to give compound N ° 44.

Example 15: the compound has N degree of 46-48

Compound 12 is reacted with an activating acid such as an anhydride, acid chloride, acid + a coupling agent such as DCCI, BOP.

Thus, compound 12 is reacted with acetic anhydride, benzoyl chloride and cyclopropanecarbonyl chloride, respectively, to yield compounds 46-48.

Example 16: compound N ° 49

A solution of 444mg of compound 12 in 12ml of acetonitrile is cooled to 5 ℃. 0.14ml triethylamine was added followed by 0.075ml methanesulfonyl chloride. After stirring for 40 minutes at 25 ℃, the reaction medium is dissolved in AcOEt. The organic phase is washed with water and then with saturated NaCl solution, dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with a gradient of 0-5% methanol in chloroform. 220mg of solid are obtained. MS: MH⁺＝632。

Example 17: compound N50 DEG C

To a solution of 284mg of Compound 4 (example 2) in 5ml of DMF were added 40mg of tert-butylamine, 71mg of diisopropylamine and 176mg of O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU). The reaction medium is stirred for 1 hour at 25 ℃ and then diluted with AcOEt. Organic phase successively using water and saturated NaHCO₃The solution, water and saturated NaCl solution were washed. The organic phase was dried, evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of 0-5% methanol in DCM. 196mg of a yellow solid are obtained. MS: MH⁺＝624。

Example 18: compounds 51 to 54

Compounds 51-54 were prepared in the same manner as compound 50, using compound 4 and substituting cyclopropylamine, pythonine, N-isopropyl-methylamine, and methylamine for t-butylamine, respectively.

Example 19: compound N ° 62

Preparation of 819mg of the compound described in 1 and 0.314mg of 6-amino-2, 3-dihydro-benzo [ b ] in 25ml of absolute ethanol with 0.02ml of concentrated HCl]The furan was stirred at 70 ℃ for 3 hours, which was prepared according to Eur.J.Med.chem.Chimica therapeutics, 1977, Vol.12, 231-. After cooling, the precipitate was filtered, then washed with slightly hot MeOH and Et₂And O washing. 637mg of a yellow solid which melts at 197 ℃ are obtained. MS: MH⁺＝523。

Example 20: compound N degree 69

Step 1

To a solution of 3.0g of the product obtained in step 1.4 in 25ml of DMF, 432mg of 60% NaH are added within 10 minutes. After stirring for 30 minutes, 1.40g of ethyl isocyanatoacetate are added over 10 minutes, and the reaction medium is then stirred at room temperature for 3 hours and 30 minutes. The reaction medium is extracted with AcOEt, followed successively by water and 5% KHSO₄/K₂SO₄The solution, water and saturated NaCl solution were washed. The organic phase was dried and concentrated in vacuo to give a crude product which was chromatographed on silica gel with CHCl₃Purification was carried out by elution with/AcOEt 85/15v/v to give 1.52g of the expected product.

Step 2

The product obtained in step 1 was oxidized using m-chloroperbenzoic acid according to the method described for preparation 1.6. 900mg of the expected product are obtained as a light brown solid.

Step 3

798mg of the product of step 2 were heated with 295mg of 1, 3-dihydro-2-benzofuran-5-amine at 65 ℃ for 6 hours in the presence of 15ml of EtOH and 0.06ml of concentrated HCl. The reaction medium is treated with CHCl₃Diluted with water and then saturated NaHCO was added₃Solutions ofThe pH of the aqueous phase was brought to 9. After decantation, the organic phase is separated, washed with water and then with saturated NaCl solution, dried and concentrated under reduced pressure. The product was crystallized in AcOEt. 0.67g of a yellow solid is obtained.

Step 4

0.66g of the ester obtained in step 3 and 2ml of DMF in 25ml of ethanol were treated with 1.5ml of 2N NaOH for 5 hours. The reaction medium is treated with CHCl₃Dilution was carried out, then the pH was adjusted to 4 with 1N HCl and decantation was carried out. The organic phase is separated, washed with water and then with saturated NaCl solution, dried and concentrated under reduced pressure to give 0.61g of a yellow powder.

Step 5

105mg of the product from step 4, 16mg of tert-butylamine, 28mg of DIPEA (diisopropylethylamine) and 70mg of TBTU are stirred in 2.5ml of DMF for 1h 15 min. The reaction medium is then treated with CHCl₃Extracting with water and 5% KHSO₄/K₂SO₄The solution was washed with saturated NaCl solution, then dried and evaporated under reduced pressure. The crude product was chromatographed on silica gel with CHCl₃Purification was carried out with elution in/MeOH (94/6 v/v). 90mg of the expected product are obtained as a yellow solid. MS: MH⁺＝580。

Example 21: compounds 31 and 32

Enantiomers of compound 12 prepared in example 6 were separated by chiral stationary phase chromatography as follows:

technique of	Berger Prep SFC
		Detection of	UV 230nm
Stationary phase	Chiralpack AD-H 250×21mm(5μm)
		Mobile phase	60％/40％CO2/(ethanol + 0.5% isopropylamine)
Flow rate	50 ml/min
		Pressure of	100 bar
Number of injections	Piling, injecting 350 times, 28mg each time

Using 10g of the racemic mixture, 4.147g of the dextrorotatory enantiomer (compound 31) and 4.077g of the levorotatory enantiomer (compound 32) are obtained after separation.

Tables 3 and 4 below illustrate the chemical structures and physical properties of certain embodiments of the present invention. In these tables, Me, Et, iPr and tBu represent methyl, ethyl, isopropyl and tert-butyl, respectively, and Boc represents tert-butoxycarbonyl. Unless otherwise indicated, products containing asymmetric carbon atoms were obtained in racemic form.

TABLE 3

TABLE 4

Compound 34 was separated into its two enantiomers using chiral chromatography. Dextro enantiomer: [ alpha ] to]_D+72.1 °; t is 25 ℃; c ═ 0.5 (MeOH). Levorotatory enantiomer: [ alpha ] to]_D＝-73.0°；t＝25℃；C＝0.5(MeOH)。

The preparation method described in the present invention was applied using the general combinatorial chemistry techniques, and a database of the products of the present invention was also prepared. The structures of the prepared products and their characterization results are presented here.

LC/MS analysis was carried out using an LCT type Micromass apparatus in combination with an HP1100 type apparatus. The compound abundance was measured using a G1315A diode array detector at the wavelength band 200-600nm, and using a type 65 Sedex Light Scattering Evaporation Detector (LSED). Mass spectra in the range of 180-800(m/z) were recorded. These data were analyzed by the Micromass MassLynx software. These separations were carried out using a Hypersil BDS C18 column (50X 4.6mm), particle size 3 μm. Elution was performed using a 5-90% nitrile gradient containing 0.05% (v/v) trifluoroacetic acid (TFA) in an aqueous solution containing 0.05% (v/v) TFA at a flow rate of 1 ml/min for 3.5 min. The total time of the process (including column re-equilibration) was 7 minutes.

TABLE 5

Compound (I)	R1	Ar2	LC/MS (Retention time (min): MH+；MH-)
				1	Phenyl radical	2, 6-dichlorophenyl	4.42；616；614
2	t-butyl radical	3, 5-Dimethoxyphenyl	4.24；588；586
				3	Ethyl radical	2, 6-dichlorophenyl	3.77；568；566
4	t-butyl radical	3, 4-Dimethoxyphenyl	3.93；588；586
				5	t-butyl radical	Phenyl radical	3.80；528；526
6	t-butyl radical	2-methoxyphenyl radical	4.06；558；556
				7	t-butyl radical	2, 6-dibromophenyl	4.32；685；684
8	t-butyl radical	2-bromo-6-chlorophenyl	4.29；640；638
				9	Ethyl radical	2, 6-dibromophenyl	3.83；658；656
10	Phenyl radical	2-bromo-6-chlorophenyl	4.46；660；658
				11	Phenyl radical	2, 6-dibromophenyl	4.49；-；704

TABLE 6

Compound (I)	R1	Ar2	LC/MS (Retention time (min): MH+)
				1	Phenyl radical	2, 6-dichlorophenyl	4.75；543.28
2	t-butyl radical	3, 5-Dimethoxyphenyl	4.52；515.42
				3	Ethyl radical	2, 6-dichlorophenyl	4.95；495.30
4	t-butyl radical	3, 4-Dimethoxyphenyl	4.21；515.43
				5	t-butyl radical	Phenyl radical	4.42；455.41
6	t-butyl radical	2-methoxyphenyl radical	4.34；485.41
				7	t-butyl radical	2, 6-dibromophenyl	4.63；611.25
8	t-butyl radical	2-bromo-6-chlorophenyl	4.72；567.09
				9	Ethyl radical	2, 6-dibromophenyl	4.14；582.96
10	Phenyl radical	2-bromo-6-chlorophenyl	4.88；587.06
				11	Phenyl radical	2, 6-dibromophenyl	4.91；630.97

The compounds of the present invention are subjected to pharmacological tests capable of determining their anticancer activity.

In vitro assays of compounds of formula (I) of the invention were performed on a panel of human tumor lines derived from:

-breast cancer: MDA-MB231 (American type culture Collection, Rockville, Maryland, USA, ATCC-HTB26), MDA-A1 or MDA-ADR (so-called multidrug resistance MDR, described by E.Collomb et al, "blood cell count", Cytometry, 12 (1): 15-25, 1991), and MCF7(ATCC-HTB22),

-prostate cancer: DU145(ATCC-HTB81) and PC3(ATCC-CRL1435),

-colon cancer: HCT116(ATCC-CCL247) and HCT15(ATCC-CCL225),

-lung cancer: h460 (described by Carmichael in Cancer Research 47 (4): 936-942, 1987 and proposed by the national Cancer institute of America, Frederick center for Cancer Research and development, Frederick, Maryland, USA),

glioblastoma (SF268, Westphal in "Communications of biochemistry & Biophysical Research" 132 (1): 284-289, 1985 and proposed by the American national cancer institute, Frederick cancer Research and development center, Frederick, Maryland, USA),

leukemia (CMLT1, Blood, Kuriyama et al (Blood), 74: 1989, 1381-jar 1387, Soda et al, J.British Journal of Haematology, 59: 1985, 671-jar 679 and Drexler, Leukemia Research, Leukemia Research, 18: 1994, 919-jar 927, DSMZ, Mascheroder Weg 1b, 38124 Brunswick, Germany).

Cell proliferation and viability were determined by experiments using 3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T et al Oncology, 2003, 64(4), 399-. In this assay, the mitochondrial capacity of viable cells to convert their MTS to a colored compound after 72 hours of culture of a compound of formula (I) of the invention was determined. The compounds of the invention resulted in a 50% decrease in cell proliferation and viability (CI) based on tumor lines and test compounds₅₀) The concentration of (B) is 1nM to 10. mu.M.

It is therefore evident that, according to the present invention, the compounds of formula (I) cause tumor cell proliferation and reduced viability. Thus, it appears that the compounds of the present invention have anti-cancer activity and activity in the treatment of other proliferative diseases, such as for example psoriasis, restenosis, arteriosclerosis, AIDS, as well as therapeutic activity in diseases caused by vascular smooth muscle cell proliferation and in rheumatoid polyarthritis.

Thus, according to a further aspect, the present invention is directed to pharmaceutical products comprising a compound of formula (I), or an addition salt of the compound with a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I).

These medicaments have therapeutic applications, in particular in the treatment or prevention of diseases which are caused or exacerbated by the proliferation of cells, in particular tumour cells.

As inhibitors of tumor cell proliferation, these compounds are useful in the prevention and treatment of leukemia, primary and metastatic solid tumors, carcinomas (carcinomes) and cancers (carcers), in particular: breast cancer; lung cancer; small bowel, colon and rectal cancers; cancers of the respiratory tract, oropharynx, and hypopharynx; esophageal cancer; liver cancer, gastric cancer, bile duct cancer, gallbladder cancer, pancreatic cancer; urethral cancers including kidney, urothelium and bladder; female genital tract cancers including uterine cancer, cervical cancer, ovarian cancer, choriocarcinoma (choriocarcinoma) and choriocarcinoma (trophoblastoma); cancer of the male genital tract, including prostate cancer, seminal vesicle cancer, testicular cancer, germ cell tumors; endocrine adenocarcinomas, including thyroid, pituitary, and adrenal carcinomas; skin cancer including hemangioma, melanoma, sarcoma including Kaposi's sarcoma; brain tumors, neural tumors, eye tumors, meningeal tumors including astrocytomas, gliomas, glioblastoma, retinoblastoma, schwannomas, neuroblastoma, schwannomas, meningiomas, hematogenic malignancies; leukemias (acute lymphocytic leukemia (ALL), Acute Myelocytic Leukemia (AML), Chronic Myelocytic Leukemia (CML), Chronic Lymphocytic Leukemia (CLL)), greenish leukemia, plasmacytoma, T-cell or B-cell leukemia, non-Hodgkins or Hodgkins lymphoma, myelomas, and various malignancies.

According to other aspects, the invention relates to pharmaceutical compositions containing as active ingredient a compound of the invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient.

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

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (topoque), intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or a possible salt, solvate or hydrate thereof, is mixed with usual pharmaceutical excipients and administered in unit administration form (unitair d' administration) to animals or humans for the prevention or treatment of the above-mentioned disorders or diseases.

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

The unit dosage forms of tablets as compounds of the invention may contain the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

6.0mg of croscarmellose sodium

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

The above-mentioned compound of formula (I) is administered in a dose of 0.002-2000mg per day, preferably 0.1-300mg/kg per day, per kg body weight of the mammal to be treated. For use in humans, the dose may preferably be 0.02 to 10000mg, more particularly 1 to 3000mg per day, depending on the age of the subject to be treated and the type of treatment (prophylaxis or therapy).

There may be cases where the dosage is either high or low; such dosages are not outside the scope of the present invention. According to the usual practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

According to another aspect of the invention, the invention also relates to a method of treatment of the above-mentioned diseases, which comprises administering to a patient an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

According to the invention, the compound(s) of formula (I) may be administered together with one (or more) antitumor active ingredients, especially anticancer compounds, for example alkylating agents such as alkylsulfonates (busulfan), dacarbazine, procarbazine, mechlorethamine (chlormethine), melphalan, chloronebtin, cyclophosphamide, ifosfamide; nitrosoureas, such as carmustine, lomustine, methyllomustine, streptozotocin; antineoplastic alkaloids, such as vincristine, vinblastine; taxanes, such as paclitaxel or docetaxel; anti-tumor antibiotics, such as actinomycin C; intercalators, anti-tumor metabolism antagonists, folic acid antagonists, methotrexate; a purine synthesis inhibitor; purine analogs, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine, pyrimidine analogs such as fluorouracil, gemcitabine, cytarabine, and cytosine arabinoside; brequinar; topoisomerase inhibitors, such as camptothecin or etoposide; anti-cancer hormone agonists and antagonists, such as tamoxifen; kinase inhibition, imatinib; a growth factor inhibitor; anti-inflammatory agents, such as xylan polysulfate, corticosteroids, prednisone, dexamethasone, anti-topoisomerase enzymes, such as etoposide, antracyclins, including doxorubicin, bleomycin, mitomycin and mithramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; interferon alpha, triphenylthiotepa, altretamine; an anti-angiogenic agent; salicyline polyamine; an adjuvant for immunotherapy; a vaccine.

According to the invention, the compounds of formula (I) can also be administered together with one or more active ingredients effective against one of the above-mentioned diseases, such as antiemetics, analgesics, anti-inflammatory agents, anti-cachexia agents (anti-cachexy agents).

The products of the invention are useful for the manufacture of medicaments for use in the treatment of pathological conditions, in particular cancer.

The invention also relates to pharmaceutical compositions containing the compounds of the invention, in combination with pharmaceutically acceptable excipients, according to the chosen mode of administration. The pharmaceutical composition may be in solid, liquid or liposome form.

Among these solid compositions, powders, capsules, and tablets can be cited. In oral forms, solid forms that protect against gastric acidic media may also be included. Carriers for solid forms are composed in particular of mineral carriers, such as phosphates or carbonates, or of organic carriers, such as lactose, cellulose, starch or polymers. These liquid forms consist of solutions, suspensions or dispersions. As dispersants they comprise either water or organic solvents (ethanol, NMP, etc.) or mixtures of surfactants and solvents or complexing agents and solvents.

These liquid forms are preferably injectable and therefore should be an acceptable formulation (formulation) for this use.

Acceptable modes of administration by injection include intravenous, intraperitoneal, intramuscular, and subcutaneous modes of administration; intravenous injection is preferred.

The dosage of the compound of the present invention to be administered is determined by a physician in view of the mode of administration to the patient and the condition of the patient.

The compounds of the present invention may be administered alone or in admixture with other anti-cancer agents. Among these possible combinations, mention may be made of:

● alkylating agents, especially cyclophosphamide, melphalan, ifosfamide, chloronebatin, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, streptozotocin, dacarbazine, temozolomide, procarbazine and hexamethylmelamine;

● platinum derivatives, such as cisplatin, carboplatin, or oxarill;

● antibiotic agents, especially bleomycin, mitomycin and actinomycin D;

● antimicrotubule agents, especially vinblastine, vincristine, vinblastine amide, catharanthine or taxoids (taxol and docetaxel);

● anthracyclins, such as doxorubicin, daunorubicin, epirubicin, mitoxantrone or losoxantrone;

● group I and II topoisomerases such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomodex;

● Fluoropyrimidines such as 5-fluorouracil, UFT or floxuridine;

● cytosine nucleoside analogs, such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine;

● adenosine congeners, such as pentostatin, cytarabine or fludarabine phosphate;

● methotrexate and folinic acid;

● various enzymes and compounds, such as L-asparaginase, hydroxyurea, trans-retinoic acid,

Suramin, dexrazoxane, amifostine, herceptin, and estrogen or androgen;

● anti-vascular agents, such as combretastatin or colchicine derivatives and prodrugs thereof.

It is also possible to use the compounds of the invention in combination with radiotherapy. These treatments may be performed simultaneously, separately or sequentially. The doctor adjusts his therapy according to the patient to be treated.

Claims (16)

1. A compound of the formula (I):

in the formula:

-R₁is selected from (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl radical, CH₂COR₄Phenyl or substituted by hydroxy and/or halogen and/or (C)₁-C₆) Alkyl-substituted phenyl;

-R₄represents a hydroxyl group, (C)₁-C₄) Alkoxy, amino, (C)₁-C₄) Alkylamino or di (C)₁-C₄) An alkylamino group;

-Ar₁represents a group selected from:

-R₅represents cyano, hydroxy (C)₁-C₄) Alkyl, (C)₁-C₆) Alkoxy (C)₁-C₄) Alkyl or (CH)₂)_nNR₇R₈、CO₂R₇、CONHNR₇R₈、CONR₇R₈、CONR₈OR₉、(CH₂)_nNR₇COR₈、(CH₂)_nNR₇COOR₈A group;

-R₆represents a hydrogen atom, (C)₁-C₄) Alkyl or R₅One of the values of (1);

-or R₅And R₆As previously defined, they are joined together to form a 4-7 mer ring, each mer containing 0-2 heteroatoms selected from N and O, said 4-7 mer ring being optionally substituted with one or more substituents independently selected from halogen, (C) and₁-C₄) Alkyl, halo (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl group, (CH)₂)_mNR₇R₈Or a tert-butoxycarbonyl group;

-R₇and R₈Independently of one another, represent a radical selected from H, phenyl, (C)₁-C₄) Alkyl, (C)₁-C₄) alkyl-OH, (C)₃-C₇) Cycloalkyl, - (C)₃-C₇) cycloalkyl-NH₂、-(C₁-C₄) Alkyl radical- (C)₃-C₇) A cycloalkyl group, a,C(＝NH)NH₂、SO₂(C₁-C₆) Alkyl, SO₂-substituents of phenyl, R₈And may also represent a tert-butoxycarbonyl or benzyloxycarbonyl group;

-or R₇And R₈Together with the nitrogen atom they carry form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical, said radical being unsubstituted or substituted by (C)₁-C₆) Alkyl, (C)₁-C₄) alkyl-OH, COO (C)₁-C₆) Alkyl, F group substituted one or more times;

-R₉represents a hydrogen atom or (C)₁-C₄) An alkyl group;

-Ar₂represents unsubstituted phenyl or phenyl substituted 1 to 5 times by similar or different substituents selected from halogen atoms, (C)₁-C₄) Alkyl, trifluoromethyl or (C)₁-C₄) An alkoxy group;

-n represents 1, 2 or 3;

-m represents 0, 1, 2 or 3.

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

-R₁represents tert-butyl, ethyl or phenyl;

-and/or Ar₁Represents a group selected from:

-and/or R₅Is represented by (CH)₂)_nNR₇R₈、CONHNR₇R₈、CONR₇R₈Hydroxy (C)₁-C₄) Alkyl or (CH)₂)_nNR₇COR₈；

-and/or R₆Represents a hydrogen atom, a methyl group, or (CH)₂)_nNR₇R₈A group or a hydroxymethyl group;

-and/or Ar₂Represents aryl substituted by 1 or 2 substituents independently selected from halogen, (C)₁-C₄) Alkyl or (C)₁-C₄) An alkoxy group;

-n、R₇and R₈As defined above for compounds of formula (I);

the compounds are in the form of bases or addition salts with acids, and may also be in the form of hydrates or solvates.

3. A compound according to any preceding claim, characterised in that R is₅Is selected from (CH)₂)_nNR₇R₈、CONR₇R₈And (CH)₂)_nNR₇COR₈。

4. Compound according to any one of the preceding claims, characterized in that it is in the form:

achiral; or

Racemizing; or

Enriched in one stereoisomer; or

Is enriched in one enantiomer;

it is also characterized in that it is optionally solvated or hydrated and in that it is optionally salified.

5. Synthetic intermediate for the preparation of the product according to any one of claims 1 to 4, characterized in that it corresponds to the formula:

in the formula R₁And Ar₂As defined in claims 1-4.

6. Synthetic intermediate for the preparation of the product according to any one of claims 1 to 5, characterized in that it corresponds to the formula:

in the formula R₁And Ar₂As defined in claims 1-6.

7. A synthetic intermediate for the preparation of a product according to any one of claims 1 to 6, characterized in that it corresponds to the formula:

in the formula Ar₂As defined in any one of claims 1 to 3.

8. Synthetic intermediate according to any of claims 5 to 7, characterized in that Ar is₂Selected from phenyl, 2-methoxyphenyl, 2, 6-dichlorophenyl, 3, 5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 2, 6-dibromophenyl, 2-bromo-6-chlorophenyl, 2, 4-dichlorophenyl and 3, 5-dichlorophenyl.

9. Synthetic intermediate according to claim 5 or 6, characterized in that R₁Selected from ethyl, tert-butyl and phenyl.

10. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that a compound of formula:

in the formula R₁And Ar₂As defined in (I) above, and in the formula (II),

and Ar'₁NH₂(III) reaction of an amineAr 'in the formula'₁Denotes Ar as defined in (I)₁Or Ar₁A precursor of (a); ar 'of the group of the compound thus obtained'₁Conversion to the group Ar₁。

11. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that the following compounds are reacted:

(i) a compound of the formula:

in the formula R₁₀Is a leaving group as follows: (a) halogen, especially Cl or Br, or (b) alkyl-S (O)_m-, wherein m is 0, 1, or 2; in the formula R₁₁Is NHC (═ R)₁₂)-NH-R₁Wherein R is₁₂O or S; and

(ii) ar 'of formula'₁NH₂(III) reaction of an amine of formula (III) Ar'₁Represents Ar as defined under (I)₁Or Ar₁A precursor of (a); if necessary, the radical Ar 'of the compound is thus obtained'₁Conversion to the group Ar₁；

Wherein the content of the first and second substances,

a)R₁₀is halogen or alkyl-S (O)_mWhen m is 2, the reaction is carried out in a polar solvent at a temperature ranging from room temperature to the reflux temperature of the solvent:

(i) such as tetrahydrofuran, dimethyl sulfoxide or ethanol, optionally in the presence of trace acids,

such as in the presence of hydrochloric acid; or

(ii) In dimethyl sulfoxide, in the presence of a strong base, such as tBuOK;

b)R₁₀is alkyl-S (O)_m-, where m is 0 or 1, with Ar 'in the molten state at 200℃'₁NH₂(III) carrying out the reaction;

ar 'of Compound (III), if necessary'₁The amine functions present in the radical being salified or protected beforehand。

12. Pharmaceutical product, characterized in that it comprises a compound of formula (I) according to claim 1 or 2, or an addition salt of such a compound with a pharmaceutically acceptable acid, or a hydrate or solvate of said compound of formula (I).

13. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate or solvate of such a compound, and at least one pharmaceutically acceptable excipient.

14. Use of a compound of formula (I) according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment and prevention of diseases caused or exacerbated by cell proliferation.

15. Use according to claim 14 for the prevention and treatment of leukemia, primary and metastatic solid tumors, cancer and carcinomas.

16. Pharmaceutical composition according to claim 13, characterized in that it also contains one or more other active anticancer ingredients.