KR100442222B1 - Bicyclic nitrogen heterocycles - Google Patents

Abstract

The amino-substituted dihydro pyrimido [4,5-d] pyrimidinones of formula (I) and pharmaceutically acceptable salts thereof are protein kinase inhibitors. They can be used for the treatment or prevention of inflammation, immunological diseases, oncological diseases, bronchial lung diseases, skin and cardiovascular, treatment of asthma, central nervous system disease or diabetic complications, or prevention of transplant rejection after transplant surgery:

Formula I

Where

R ¹ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl;

R ² is lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl;

R ³ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl, lower cycloalkenyl or lower cycloalkyl-lower alkyl.

Description

Bicyclic nitrogen heterocycle {BICYCLIC NITROGEN HETEROCYCLES}

The present invention relates to a bicyclic nitrogen heterocycle. More specifically, the present invention relates to amino-substituted dihydropyrimido [4,5-d] pyrimidinone derivatives, methods for their preparation and pharmaceuticals containing them.

The amino-substituted dihydropyrimido [4,5-d] pyrimidinone derivatives provided by the present invention are compounds of formula I and pharmaceutically acceptable salts of basic compounds of formula I and acids, or of Pharmaceutically acceptable salts of acidic compounds and bases are:

Where

R ¹ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl;

R ² is lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl;

R ³ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl, lower cycloalkenyl or lower cycloalkyl-lower alkyl.

Compounds of formula (I) and the aforementioned salts thereof are inhibitors of protein kinases, in particular T-cell tyrosine kinase p56 ^lck . Thus, they can be used for the treatment or prevention of inflammation, immunological diseases, oncological diseases, bronchial lung diseases, skin and cardiovascular diseases, treatment of asthma, central nervous system diseases or diabetes complications, or prevention of transplant rejection after transplant surgery.

The term "lower alkyl" as used herein, alone or in combination such as "aryl-lower alkyl", "heteroaryl-lower alkyl" and "lower cycloalkyl-lower alkyl", includes methyl, ethyl, n-propyl, Straight or branched chain alkyl groups containing 1 to 7, preferably 1 to 4 carbon atoms, such as isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl to be.

The term "lower alkoxy" refers to lower alkyl groups as defined above bonded to an oxygen atom such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and the like.

The term "lower cycloalkyl", alone or in combination such as "lower cycloalkyl-lower alkyl", is a cycloalkyl group containing 3 to 7, preferably 4 to 6 carbon atoms, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl or cycloheptyl.

The term "lower cycloalkenyl" is a cycloalkenyl group containing 4 to 7 carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

The term "aryl", alone or in combination such as "aryl-lower alkyl", refers to halogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, trifluoromethyl, hydroxy, hydroxy lower-alkyl, carboxylic acid, By carboxylic esters, nitro, amino, phenyl and the like, in particular by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, amino and phenyl (the substituents may be the same or different), and / or Formula -Z-NR ⁴ R ⁵ or -Z-OR ⁶ wherein Z is a spacer; R ⁴ and R ⁵ are each hydrogen or lower alkyl or are selected from nitrogen, sulfur and oxygen together with the nitrogen atom to which they are attached 4-, 5- or 6-membered saturated or partially fired, containing one or more hetero atoms and optionally substituted by lower alkyl, lower alkoxy and / or oxo and / or optionally benz-condensed Encrypted, or a 5-or represents an aromatic heterocyclic group of the 6-membered; R ⁶ is hydrogen or lower-phenyl or naphthyl group which may be mono-substituted or multi-substituted by a alkyl, preferably hydrogen). Examples of spacing groups are-(CH ₂ ) _m- , where m is 1,2,3 or 4 and -O (CH ₂ ) _n -where n is 2,3 or 4 . The carbon atoms of the-(CH ₂ ) _m -chain may be optionally monosubstituted or disubstituted by lower alkyl, hydroxy lower alkyl or lower alkyloxy lower alkyl (these substituents may be the same or different). Examples of heterocycle groups formed by R ⁴ and R ⁵ with bonded nitrogen atoms are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and indolyl. Thus, the term "aryl" refers to phenyl, 1-naphthyl, 2-hydroxyphenyl, 3-bromophenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3- Groups, such as (2-aminoethyl) -phenyl, 4- (2-hydroxyethyl) -phenyl, 4- (2-diethylaminoethoxy) -phenyl, 3- (2-phthalimidoethyl) -phenyl do.

The term “heteroaryl”, alone or in combination such as “heteroaryl-lower alkyl,” includes one or more hetero atoms selected from N, S and O and benz-condensed and / or the same as “aryl” described above. 5- or 6-membered heteroaromatic group which may be substituted. Examples of typical heteroaryl groups include thienyl, furyl, pyridyl, pyrimidinyl, quinolyl, indolyl, benzofuranyl, imidazole, 1,2,3-triazole, 1,2,4-triazole, Tetrazole, thiazole, pyridine-N-oxide and the like.

The term "halogen" means fluorine, chlorine, bromine or iodo.

Preferred groups of compounds provided by the present invention include the general formula (Ia):

Where

R ¹⁰ is lower alkyl, aryl or aryl-lower alkyl;

R ²⁰ is aryl;

R ³⁰ is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

Preferred compounds of formula (Ia) have the general formula (Iai):

Where

R ¹⁰¹ is aryl;

R ²⁰ and R ³⁰ are each as defined above.

Preferred R ¹⁰¹ is phenyl. Preferred R ²⁰ is halophenyl, in particular 2,6-dichlorophenyl. Preferred R ³⁰ is phenyl substituted by a group of the general formula -Z-NR ⁴ R ⁵ as defined above.

Another preferred group of compounds provided by the present invention include formula (Ib):

Where

R ¹¹ is lower alkyl;

R ²¹ is aryl;

R ³¹ is heteroaryl-lower alkyl.

Preferred R ¹¹ is isopropyl and preferred R ²¹ is halophenyl.

1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidine-2 ( 1H) -one is a particularly preferred compound of formula (I).

Other exemplary compounds of the invention are as follows:

3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] Pyrimidin-2 (1H) -one,

3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-phenylpyrimido [4,5-d] Pyrimidin-2 (1H) -one,

1-benzyl-3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydropyrimido [4,5-d] Pyrimidin-2 (1H) -one,

3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-[(3-pyridyl) -methyl] Pyrimido [4,5-d] pyrimidin-2 (1H) -one,

3- (2,6-dichlorophenyl) -3,4-dihydro-1-phenyl-7-[(4-pyridyl) amino] pyrimido [4,5-d] pyrimidine-2 (1H)- On,

7- [4- [2- (diethylamino) ethoxy] anilino] -3- (2,6-difluorophenyl) -3,4-dihydro-1-methylpyrimido [4,5- d] pyrimidin-2 (1H) -one,

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] Pyrimidin-2 (1H) -one and

3- (2,6-dichlorophenyl) -1- [2-cyclohexene-1 (RS) -yl] -7- [4- [2- (diethylamino) ethoxy] -anilino] -3, 4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one.

Other preferred compounds are as follows:

1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H )-On,

1- [3- (2-aminoethyl) phenyl] -7-anilino-3,4-dihydro-3- (2,6-dimethylphenyl) -pyrimido [4,5-d] pyrimidine-2 (1H) -on,

3- (2-bromophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl ] Pyrimido [4,5-d] pyrimidin-2 (1H) -one,

1- [3-[((2-amino-1, 1-dimethyl) ethyl) phenyl] -7-anilino-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5 -d] pyrimidin-2 (1H) -one,

1- [3- (2-aminoethyl) phenyl] -3- (2-bromophenyl) -7- (4-methoxyanilino) -3,4-dihydropyrimido [4,5-d] Pyrimidin-2 (1H) -one,

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -pyrimido [4,5-d] pyrimidine-2 (1H )-On,

1- [4- (aminomethyl) phenyl] -7-anilino-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H)- On,

7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- [2- (methylamino) ethyl] phenyl] pyrimido [4,5-d] pyrimidine -2 (1H) -on,

7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- [2- (dimethylamino) ethyl] phenyl] pyrimido [4,5-d] pyrimidine -2 (1H) -on,

1- [3- (2-aminoethyl) phenyl] -7-anilino-3 (2,4-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H )-On,

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- [2- (methylamino) ethyl] phenyl] pyrimido [4,5-d] pyrimidine -2 (1H) -on,

1- [4- (2-aminoethyl) phenyl] -7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidine-2 ( 1H) -on,

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2-hydroxyethyl) ) Phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one,

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2- (dimethylamino) Ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one and

1- [3- (1-Aminomethyl-1-ethyl-propyl) -phenyl] -3- (2,6-dichloro-phenyl) -7-phenylamino-3,4-dihydro-pyrimido [4, 5-d] pyrimidin-2 (1H) -one.

According to the method provided by the present invention, the above-mentioned amino-substituted dihydropyrimido [4,5-d] pyrimidinone derivatives

(a) reacting a compound of formula (II) with an amine of formula (III) and, if necessary, converting the protected hydroxy or protected amino or protected carboxylic acid group present in the reaction product to a free hydroxy or free amino or free carboxylic acid group Letting, or

(b) cleaving an aryl-methyl group from a compound of formula (I) wherein R ¹ is aryl-methyl for preparing a compound of formula (I) wherein R ¹ is hydrogen; and

(c) if necessary, converting the obtained basic compound of formula (I) to a pharmaceutically acceptable salt using an acid or converting the acidic compound of formula (I) to a pharmaceutically acceptable salt using a base Prepared by the converting step:

[Wherein,

R ² and R ³ are each as defined above, provided that hydroxy, amino or carboxylic acid groups may be present in protected form;

L is benzylsulfonyl or lower alkanesulfonyl.]

[Wherein,

R ¹ is as defined above, provided that hydroxy, amino or carboxylic acid groups may be present in protected form.]

The protected hydroxy group or protected amino group or protected carboxylic acid group present on the starting material of formula II or III, ie, on the aryl or heteroaryl substituents R ¹ , R ² and / or R ³ is any commonly protected hydroxy It may be a hydroxyl group or a protected amino group or a protected carboxylic acid group. Thus, for example, the hydroxy group can be protected in the form of an ether such as methyl ether, or an ester such as ethyl ester. An example of a protected amino group is phthalimido. Examples of protected carboxylic acid groups are esters such as methyl esters.

The reaction of the compound of formula II according to step (a) with the amine of formula III can be carried out in the presence or absence of a solvent. When using a solvent, the solvent is usually halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, ring-opening ethers such as diethyl ether or diisopropyl ether, cyclic ethers such as tetrahydrofuran, optionally halogenated Aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, or formamides such as dimethylformamide. Suitably, the reaction is carried out in the temperature range of about 0 ° C to about 200 ° C, preferably about 100 ° C to about 200 ° C.

The conversion of a protected hydroxy group or protected amino group or protected carboxylic acid group present in the product obtained by reacting a compound of formula II with an amine of formula III can be carried out in a manner known per se. Thus, for example, ethers such as methyl ether can be treated with hydrobromic acid to convert to hydroxyl groups and esters such as ethyl esters can be converted to hydroxyl groups using alkali metal aluminum hydrides such as lithium aluminum hydride. Again, for example, phthalimido groups can be converted to amino groups by treatment with hydrazine hydrate. Esters such as methyl esters can be converted to carboxylic acids, for example by reaction with alkali metal hydroxides.

From the compound of formula (I), wherein R ¹ represents aryl-methyl according to step (b), the process of cleaving an aryl-methyl group, such as lower alkoxybenzyl, such as 4-methoxy-benzyl, uses a method known per se Can be done. For example, trifluoroacetic acid can be used to cleave typically at high temperatures, preferably at the reflux temperature of the reaction mixture.

Compounds of formula (I) which are basic are inorganic acids such as hydrochloric acid, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or organic acids such as formic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, malic acid, maleic acid, succinic acid, Tartaric acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid and the like can be used to form salts.

Acidic compounds of formula I can form salts using bases such as metals or amines such as alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are ethylenediamine, monoethanolamine, diethanolamine and the like. According to step (c), these salts can be formed and isolated in a manner known per se. Preference is given to salts of the basic compounds of formula (I) with acids.

Starting materials of formula (II) are novel and are also an object of the present invention. These can be prepared as shown in the following Scheme I, where R ² and R ³ have the above clues; R ⁷ is lower alkyl or benzyl:

According to Scheme I, in the first step the compound of formula IV is reacted with a compound of formula V to produce a compound of formula VI. This reaction is usually carried out in a solvent which is inert under the reaction conditions, preferably in halogenated aliphatic hydrocarbons, in particular dichloromethane, optionally halogenated aromatic hydrocarbons, ring-opened or cyclic ethers, formamide or lower alkanols. Suitably, the reaction is carried out at about -20 ° C to about 120 ° C.

The next step involves reducing the compound of formula VI to produce an alcohol of formula VII. This reduction is carried out in a known manner using lithium aluminum hydride, in a known manner, such as in a reducing ring or in a ring-opening or cyclic ether, in particular tetrahydrofuran, in a known manner, for example, from about −20 ° C. to about 70 ° C., preferably about 0 ° C. To about room temperature.

In the next step, the alcohol of formula VII is oxidized to produce the carboxaldehyde of formula VIII. This oxidation is conveniently carried out using manganese dioxide in a known manner in solvents which are inert under oxidizing conditions, preferably halogenated aliphatic hydrocarbons, in particular dichloromethane, or optionally halogenated aromatic hydrocarbons. Suitably, the oxidation is carried out at about 0 ° C to about 60 ° C.

In the next step, the carboxaldehyde of formula (VIII) and the amine of formula (IX) react to form a compound of formula (X). This reaction can be carried out while azeotropically removing the water formed during the reaction in the presence of an acid such as an aromatic sulfonic acid, preferably 4-toluenesulfonic acid. This reaction is conveniently carried out in a solvent which is inert under the reaction conditions, preferably optionally halogenated aromatic hydrocarbons, especially toluene, and at temperatures of about 70 ° C. to about 150 ° C., in particular at the reflux temperature of the solvent.

The next step involves reducing the compound of formula X to produce a compound of formula XI. This reduction is carried out in a known manner with sodium borohydride, lithium aluminum hydride or sodium triacetoxyborohydride. Preferably, the concentrate obtained without concentrating the compound of formula X, but rather by concentrating the reaction mixture prepared is subjected to an inert solvent, preferably a ring-opening or cyclic ether, in particular tetrahydrofuran or optionally halogenated under reducing conditions. Absorption to aromatic hydrocarbons or lower alkanols is followed by treatment with the reducing agents described above. The reduction is suitably carried out at about 0 ° C to about 100 ° C, preferably at about 25 ° C.

Cyclization of the compound of formula XI yields a compound of formula XII. This cyclization is, for convenience, a solvent which is inert in the presence of a tertiary organic base, preferably tri (lower alkyl) amines, especially triethylamine, and under the reaction conditions, preferably ring-opening or cyclic ethers, especially tetrahydrofuran, Among the aromatic hydrocarbons or halogenated aliphatic hydrocarbons which are halogenated, the reaction is carried out by reaction with phosgene or trichloromethyl chloroformate in a known manner. For convenience the reaction is carried out at about −20 ° C. to about 50 ° C., preferably at about 0 ° C. to about room temperature. The compound of formula XII is oxidized to 3-chloroperbenzoic acid to give the starting material of formula II. This oxidation is conveniently carried out in a known manner in a solvent which is inert under oxidizing conditions, preferably in halogenated aliphatic hydrocarbons, in particular dichloromethane, and at about −20 ° C. to about 50 ° C., preferably at about 0 ° C. to about room temperature. The compounds of formula (XII) of formula (I) or starting materials of formula (II) wherein R ³ is hydrogen may be treated with alkali metal hydrides, in particular sodium hydride, and then reacted with compounds of formula (XIII) to be N-substituted: R ^3a -L Wherein R ^3a is any value consistent with the aforementioned R ³ excluding hydrogen, aryl or heteroaryl, and L is a leaving group. The leaving group represented by L in the compound of formula XIII is for example halogen, lower alkanesulfo Acetates such as methanesulfonate, trifluoromethanesulfonate or aromatic sulfonates such as benzenesulfonate or 4-toluenesulfonate. L is preferably iodine. N-substitution is conveniently carried out in a solvent which is inert under the reaction conditions, preferably formamide, in particular dimethylformamide, ring-opened or cyclic ethers or optionally halogenated aromatic hydrocarbons. Suitably, the reaction is carried out at about 50 ° C to about 200 ° C, preferably at about 50 ° C to about 150 ° C.

In addition, compounds of formula (XII) of formula I or starting materials of formula (II) wherein R ³ is general formula-(CH ₂ ) _m -NR ⁴ R ⁵ , wherein NR ⁴ R ⁵ is phthalimide and m is Is aryl substituted with a group of formula (I), wherein R ³ is substituted with a group of the formula (XI) wherein R ³ is a group of the formula-(CH ₂ ) _m -OH, wherein m is as defined above Aryl) to phosgene and correspond to formula XII or II, wherein the reaction product (R ³ is aryl substituted by a group of the formula-(CH ₂ ) _m -Cl, wherein m is as defined above) Compound) can be prepared by treating with an alkali metal salt of phthalimide, preferably potassium salt.

In addition, compounds of formula (XII) in formula (I), starting materials of formula (II), or compounds of formula (I) wherein any one of R ¹ to R ³ include aryl substituted by Z—NR ⁴ R ⁵ are prepared by standard methods. From corresponding compounds substituted with Z-OH, such as by activation with methanesulfonate or toluenesulfonate and by reaction with amine HNR ⁴ R ⁵ or by reaction with HNR ⁴ R ⁵ under Mitsunobu conditions. It may also be prepared.

When any one of R ¹ to R ³ includes a nitrogen-containing heteroaryl group, it may proceed to the N-oxide formation process. N-oxides can be converted to the free N compound by standard methods, such as by reaction with triphenyl phosphine.

In another process for the preparation of the compound of formula VI in Scheme I wherein R ³ is hydrogen, the ethyl 4-amino-2-mercapto-pyrimidine-5-carboxylate of formula XIV is reacted with the compound of formula XV can do:

Where

R ⁷ is as defined above;

L has the same meaning as given in formula (XIII).

The reaction of the compound of formula XIV with the compound of formula XV is conveniently carried out in a solvent which is inert to the reaction conditions, preferably in ketones, in particular acetone, halogenated aliphatic hydrocarbons, optionally halogenated aromatic hydrocarbons, ring-opened or cyclic ethers or formamides. . The reaction is carried out at about -20 ° C to about 100 ° C, preferably about 20 ° C.

The compounds of formula IV, XIII, XIV and XV described above are known compounds or analogs of known compounds. Compounds of formula IV wherein R ⁷ is methyl are commercially available from Sigma-Aldrich Company Ltd., where R ⁷ is benzyl, see Peters, et al .; J. Amer. Chem. Soc., 64, 794-795, 1942. Compound XIV is commercially available from Lancaster Synthesis Ltd. Compounds of formula (XIII) and (XV) are commercially available from Sigma-Aldrich Company Limited where L is halogen such as methyl and ethyl iodide or benzyl bromide, and L is n-butyl methanesulfonate or ethyl 4-toluenesulfonate Sulfonates such as these are commercially available from Lancaster Synthesis Limited.

If the amine starting materials of the above formulas (III), (V) and (IX) are not known compounds or analogs of known compounds, they may be prepared in a similar manner to known compounds or as described in the examples below. In particular, the compounds of the formulas III, V and IX are commercially available, for example from Sigma-Aldrich Company Limited or Lancaster Synthesis Limited or Example 1, 15, 16, 27, 37, 57, 61, 63, 77, It may also be synthesized by the standard method described in 84 and 85. In general, aromatic and heteroaromatic amines can be prepared, for example, from corresponding nitrogen compounds, for example by reduction with Raney nickel, or by catalytic hydrogenation. Nitrogen compounds can be prepared by nitriding of aromatic or heteroaromatic compounds. Alkyl amines comprising aromatic or heteroaromatic groups can be prepared, for example, by reacting the corresponding compounds containing leaving groups with groups such as ammonia or azide, which can be converted to amines by known methods. Examples of such leaving groups are sulfonates or halides prepared from the corresponding alcohols. Alternatively, alkyl amines may be prepared from cyano compounds by reduction. Thus, amines can be prepared, for example, from commercially available alcohols, halides and nitriles.

Intermediates of formula (XI) in Scheme I may be prepared as shown in Scheme II, wherein R ² , R ³ and R ⁷ have the above meanings. R ⁸ is ethyl or 4-methoxybenzyl:

According to Scheme II, in the first step the compound of formula IV is reacted with sodium ethoxylated in ethanol or the sodium salt of 4-methoxy benzyl alcohol in tetrahydrofuran at a temperature of about O ° C. to room temperature To produce a compound.

In the next step, compound XVI is reduced to an alcohol of formula XVII. This reaction is carried out in a known manner with diisobutyl aluminum hydride or lithium aluminum hydride in a solvent which is inert under the reaction conditions, preferably in a halogenated aliphatic hydrocarbon, in particular dichloromethane, or in a ring-opening or cyclic ether, in particular tetrahydrofuran. To use. Suitably, the reaction is carried out at about -78 ° C to about room temperature.

Oxidation of an alcohol of formula (XVII) produces a carboxaldehyde of formula (XVIII). This oxidation is carried out using manganese dioxide in a solvent, preferably halogenated aliphatic hydrocarbons, in particular dichloromethane, or optionally halogenated aromatic hydrocarbons, which are inertly oxidized under known conditions for convenience. Suitably, the oxidation is carried out at about 0 ° C to about 60 ° C.

In the next step, the carboxaldehyde of formula XVIII and the amine of formula IX react to form a compound of formula XIX. This reaction can be carried out while azeotropically removing the water formed during the reaction in the presence of an acid such as an aromatic sulfonic acid, preferably 4-toluenesulfonic acid. For convenience the reaction is carried out at a temperature of from about 70 ° C. to about 150 ° C., in particular at the reflux temperature of the solvent in a solvent which is inert under the reaction conditions, preferably in an optionally halogenated aromatic hydrocarbon, in particular toluene.

The next step involves reducing the compound of formula XIX to produce a compound of formula XX. This reduction is carried out in a known manner using sodium borohydride, lithium aluminum hydride or sodium triacetoxy borohydride. Preferably, the concentrate obtained by concentrating the reaction mixture prepared, rather than purifying the compound of formula XIX, is concentrated under reduced conditions in an inert solvent, preferably in a ring-opening or cyclic ether, in particular tetrahydrofuran or optionally halogenated aromatic hydrocarbons or Absorption in lower alkanols is followed by treatment with the reducing agents described above. Optionally, the reaction mixture comprising compound XIX is subjected to a solution of any of the reducing agents described above in a solvent which is inert under reducing conditions, preferably in a ring-opening or cyclic ether, in particular tetrahydrofuran or optionally halogenated aromatic hydrocarbons or lower alkanols. Can be added without concentration.

In the ether cleavage step, the compound of formula XX reacts with concentrated sulfuric acid when R ⁸ is ethyl or trifluoroacetic acid when R ⁸ is 4-methoxybenzyl to produce pyridone of formula XXI. The reaction is carried out using the reagent as a solvent. The reaction takes place at about 120 ° C. for sulfuric acid and at its reflux temperature for trifluoroacetic acid.

In the next step, the compound of formula XXI is reacted with phosphorus oxychloride to produce the compound of formula XXII. This reaction is carried out at a temperature of about 100 ° C. using phosphorus oxychloride as solvent.

The chloride of formula (XXII) reacts with the compound of formula (V) to produce intermediate XI. The reaction is carried out in the presence or absence of a solvent. If a solvent is used, this is conveniently used for halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, ring-opening ethers such as diethyl ether or diisopropyl ether, cyclic ethers such as tetrahydrofuran, optionally halogenated hydrocarbons Such as benzene, toluene, xylene or chlorobenzene, or formamide such as dimethyl formamide. This reaction takes place in the presence of a base, in particular a tertiary amine such as diethylaniline. Suitably, the reaction is carried out in a temperature range of about 0 ° C to about 200 ° C, preferably about 100 ° C to about 200 ° C.

As noted above, the compounds of formula (I), pharmaceutically acceptable salts of basic compounds and acids of formula (I), and pharmaceutically acceptable salts of acidic compounds and bases of formula (I) all inhibit-modulate T-cell activity Inhibitors of T-cell tyrosine kinase p56 ^lck , which can lead to immunosuppression and reduced inflammation. Thus, the compounds of the present invention are anti-inflammatory agents that can be used to combat inflammatory conditions that cause a variety of diseases, and immunosuppressive agents that can be used to prevent transplant rejection, such as in transplantation treatment. This activity can be demonstrated using the test procedures described below.

Human recombinant p56 ^lck , 10 mM MnCl ₂ , 10 μM ATP, 0.2 mM sodium vanadate, 20 μM peptide substrate (AlaGluGluGluIleTyrGlyGluPheGluAlaLysLysLysLys, [γ- ³³ P] ATP (1000-2000 cpm / pmol) in 25 mM HEPES buffer, pH 7.5 ) And the reaction mixture (25 μl) containing 0.1% Triton X-100 was incubated at 30 ° C. for 60 minutes and then quenched by the addition of 10 μl of 2% orthophosphoric acid. (Millipore Multiscreen) Filter through a phosphocellulose cation exchange paper membrane to separate from unreacted [γ- ³³ P] ATP The bound peptide is washed with 0.5% orthophosphoric acid and the bound radioactivity is measured with a scintillation spectrometer.

Enzyme blocking at each concentration of test compound is calculated from Equation 1:

The IC ₅₀ value is the concentration of test compound that reduces the radiolabeled protein kinase-induced binding by 50% under the test conditions.

1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -one has an IC ₅₀ of 0.03 nM in the above test. Detailed examples are shown in Table 1 below:

Example Compound IC ₅₀ (nM) One 10 7 0.6 10 19 22 265 50 6 63 17 82 0.4 85 7

Compounds of formula (I), pharmaceutically acceptable salts of basic compounds and acids of formula (I) and pharmaceutically acceptable salts of acidic compounds and bases of formula (I) include, for example, inflammation, immunological diseases, oncological diseases, bronchial lungs, in particular It may be used in the form of a medicament for the treatment or prevention of diseases, skin and cardiovascular diseases, for the treatment of asthma, central nervous system diseases or diabetes complications, or for the prevention of transplant rejection after transplantation surgery. The agent can be administered orally, nasal, such as in the form of nasal spray, or rectally, such as suppositories, in the form of intestines, such as tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. Can be administered in the form. However, it may also be administered parenterally, eg in the form of injections.

The compounds of formula (I) and their pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert organic or inorganic carriers for the manufacture of a medicament. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as carriers for tablets, coated tablets, dragees and hard gelatin capsules, for example. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid and liquid polyols; However, depending on the type of active ingredient, no carrier is required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or cured oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the medicament may include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fragrances, salts for controlling osmotic pressure, buffers, masking agents or antioxidants. They may also include therapeutically valuable substances in addition to the compounds of formula (I) and their pharmaceutically acceptable salts described above.

A medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a compatible pharmaceutical carrier material is also an object of the present invention and includes one or more compounds or salts, and, if desired, one or more therapeutically valuable substances. It is a method for the preparation of a medicament comprising in the form of herbal medicine administration with a compatible pharmaceutical carrier.

As mentioned above, the compounds of formula (I) and their pharmaceutically acceptable salts thereof can be used according to the invention as therapeutically active substances, in particular as anti-inflammatory agents or for the prevention of transplant rejection after transplantation surgery. It is of course possible to vary the dosage in a wide range and to adapt to the individual needs in each particular case. Generally, when administered to adults, a typical daily dosage should be about 0.1 mg / kg to about 100 mg / kg, preferably about 0.5 mg / kg to about 5 mg / kg. The daily dose may be administered once or in divided doses and may also exceed the above mentioned upper dose limits, depending on the prescription.

Finally, in particular for the manufacture of a medicament for the treatment or prevention of inflammation, immunological diseases, oncological diseases, bronchial lung diseases, skin and cardiovascular diseases, treatment of asthma, central nervous system diseases or diabetes complications, or prevention of transplant rejection after transplant surgery. The use of the compounds of formula (I) and their pharmaceutically acceptable salts, as, is also an object of the present invention.

The following examples illustrate the invention in more detail, but the scope of the invention is not limited thereto.

Example 1

2.55 g (6.6 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 7 g (34 mmol) of 4- [2- (diethylamino) ethoxy] -aniline were heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel first with 5% methanol in dichloromethane followed by dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 150 ml of dichloromethane. The solution was washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to yield 1.18 g (35%) of crude product. Purification by crystallization from cyclohexane / ethyl acetate gave pure 3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro- 310 mg (9%) of 1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 123-124 ° C.

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido- [4,5-d] pyrimidine-2 (1H)-used as starting material One was prepared as follows:

a) A solution of 20 g (86 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 250 ml of dichloromethane is cooled to 0 ° C. and 35 ml (281 mmol) of a 33% solution of methylamine in ethanol Treatment was slow. After stirring for 30 minutes 150 ml of water were added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 19 g (97%) of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.

b) 9 g (237 mmol) of lithium aluminum hydride was stirred in 300 ml of anhydrous tetrahydrofuran and 34 g of ethyl 4-methyl-amino-2-methylthio-pyrimidine-5-carboxylate in 300 ml of anhydrous tetrahydrofuran 143 mmol) was added dropwise and left for 15 minutes. The mixture was ice cooled and 18 ml of water was added dropwise. 36 ml of 2 M sodium hydroxide solution followed by 48 ml of water was added dropwise. The resulting suspension was stirred at rt for 17 h and then filtered. The filter residue was washed twice with 100 ml of ethyl acetate each and the combined filtrates and washes were evaporated under reduced pressure. The residue was suspended in 200 ml of dichloromethane / hexanes (2: 1) and the solids were filtered and dried to give 23.5 g (86%) of 4-methylamino-2-methylthiopyrimidine-5-methanol as a yellow solid.

c) 20 g (108 mmol) of 4-methylamino-2-methylthiopyrimidine-5-methanol was stirred in 1 l of dichloromethane and treated with 87 g (1 mol) of manganese dioxide. The resulting suspension was stirred for 24 hours and then filtered through a filter. The filtered residue was washed with 100 ml of dichloromethane and the combined filtrates and washes were evaporated under reduced pressure to give 15.8 g (80%) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde as a white solid.

d) 6 g (32.8 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in 70 ml of toluene, 5.5 g (33.9 mmol) of 2,6-dichloroaniline and 4-toluene-sulfonic acid 1 A mixture of g (5.3 mmol) was heated for 17 hours with azeotropic removal of water under reflux. The mixture was concentrated to about 10 ml volume under reduced pressure and then treated with 120 ml of ethanol. The resulting suspension was heated to 75 ° C. and treated with 6.2 g (160 mmol) of sodium borohydride pellets for 15 minutes. The mixture was stirred for an additional 15 minutes and cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was stirred in a mixture of 200 ml of 2M sodium hydroxide solution and 200 ml of ethyl acetate for 1 hour. The phases were separated and the organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed using eluent with diethyl ether / hexane in a ratio of 3: 7 to 5- (2,6-dichlorophenyl) aminomethyl-4-methylamino-2-methylthio 5.2 g (48%) of pyrimidine were obtained as a white solid.

e) 12 ml of phosgene (20% solution in toluene; 23 mmol) in 100 ml of tetrahydrofuran in 5- (2,6-dichlorophenyl) aminomethyl-4-methylamino in 80 ml of tetrahydrofuran in an ice cold stirred solution A solution of 5 g (15.2 mmol) of -2-methylthiopyrimidine and 4 ml (29 mmol) of triethylamine was added dropwise. After stirring for 1 hour, the mixture was treated with 100 ml of saturated aqueous ammonium chloride solution and the phases were separated. The aqueous phase was extracted with 100 ml of tetrahydrofuran and the combined organic solutions were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 4.8 g (89%) were obtained as a white solid.

f) 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)-in 200 ml of dichloromethane 5 g (14.1 mmol) of solution was ice-cooled and treated with 10 g (28.9 mmol) of 3-chloroperbenzoic acid. The mixture was stirred at rt for 17 h, then treated with 2 ml of dimethyl sulfoxide and left for 10 min. Then 100 ml of saturated aqueous sodium bicarbonate solution were added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. Concentrate the filtrate under reduced pressure to afford 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)- 5 g (92%) were obtained as a white solid.

4- [2- (diethylamino) ethoxy] -aniline was used as starting material as follows:

i) A solution of 27.8 g (0.2 mol) of 4-nitrophenol in 500 ml of ethanol was treated with 15 g (0.22 mol) of sodium ethoxylate. After stirring for 30 minutes at room temperature the solvent was removed under reduced pressure. The remaining yellow solid was stirred in a mixture of 160 ml xylene and 30 ml water and then treated with 41.4 g (0.3 mol) of potassium carbonate and 34.4 g (0.2 mol) of 2-diethylaminoethyl chloride hydrochloride. The mixture was heated at reflux for 17 h and filtered when hot. The filter residue was washed with hot xylene and the combined filtrates and washes were evaporated under reduced pressure. The residue was distilled off under high vacuum to give 31.4 g (66%) of 4- [2- (diethylamino) ethoxy] -nitrobenzene in the liquid phase.

ii) A solution of 5 g (21 mmol) of 4- [2- (diethylamino) ethoxy] -nitrobenzene in 50 ml of ethanol was hydrogenated to 100 mg of 10% palladium on carbon at room temperature and atmospheric pressure. After 4 hours the suspension was filtered through a filter and the filtrate was evaporated under reduced pressure to give 4 g (92%) of 4- [2- (diethylamino) ethoxy] -aniline as an oil.

Example 2

100 mg (0.31 mmol) of 3- (2-chlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one and A mixture of 300 mg (1.4 mmol) of 4- [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 30 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-chlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino]- 20 mg (15%) of 3,4-dihydro-1-methyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid having a melting point of 150 to 151 ° C.

3- (2-chlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methyl-pyrimidin-2 (1H) -one, used as starting material, was used instead of 2-, 6-dichloroaniline. Chloraniline was used to prepare in a similar manner to that described in Examples 1 a) to f) above.

Example 3

100 mg (0.31 mmol) and 4- [2- 3-phenyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one A mixture of 300 mg (1.4 mmol) of (diethylamino) ethoxy] aniline was heated at 170 to 180 ° C. for 10 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by crystallization from cyclohexane / ethyl acetate to give 3-phenyl-7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [ 14 mg (10%) of 4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid having a melting point of 141 to 144 ° C.

3-phenyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] -pyrimidin-2 (1H) -one was used as starting material as follows. :

a) 350 mg (1.6 mmol) of sodium triacetoxyborohydride and then 0.1 ml (1.7 mmol) of acetic acid were added 4-methyl-amino-2-methylthiopyrimidine-5-carbox in 5 ml of 1,2-dichloroethane. To a mixture of 200 mg (1.1 mmol) and 110 mg (1.2 mmol) of aniline was added. After 2.5 hours 25 ml of saturated aqueous sodium bicarbonate solution and 20 ml of dichloromethane were added. The phases were separated and the aqueous phase was washed twice with 25 ml of dichloromethane. The combined organic solution was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using diethyl ether / hexane (1: 1) as eluent. Fractions containing the product were combined and evaporated to yield 218 mg (76%) of 5-phenyl-aminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid.

b) A mixture of 200 mg (0.77 mmol) of 5-phenylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 15 ml of dioxane was added to trichloro in 10 ml of dioxane. 150 mg (0.79 mmol) of methyl chloroformate were added dropwise to the ice cold solution. The mixture was then warmed to room temperature. After another 10 minutes, the mixture was evaporated. 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate solution were added to the residue. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated to 3-phenyl-7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 ( 162 mg (74%) of 1H) -one were obtained as a white solid.

c) 160 mg (0.56 mmol) of 3-phenyl-7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one in 20 ml of dichloromethane The solution of was treated with 400 mg (1.16 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 3 hours 30 ml of saturated aqueous sodium bicarbonate solution and 20 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3-phenyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 165 mg (93%) were obtained as a white solid.

Example 4

3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2- (1H) -one 100 mg (0.31 mmol) and 4- [ A mixture of 400 mg (1.9 mmol) of 2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered and dried to give 3-cyclohexyl-7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4, 25 mg (18%) of 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 90 to 92 ° C.

3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido- [4,5-d] pyrimidin-2 (1H) -one used as starting material was prepared as follows: Was:

a) a mixture of 200 mg (1.1 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde and 200 mg (2.02 mmol) of cyclohexylamine in 10 ml of methanol in excess of 500 mg of 4A It was left to itself for 3 days. The solution was decanted from the molecular sieve and 100 mg (2.7 mmol) of sodium borohydride was added thereto in small portions. After 30 minutes the mixture was evaporated and 60 ml of ethyl acetate and 60 ml of 2 M aqueous sodium hydroxide were added to the residue. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 245 mg (85%) of 5-cyclohexylaminomethyl-4-methylamino-2-methylthiopyrimidine as a colorless oil.

b) A mixture of 210 mg (0.79 mmol) of 5-cyclohexylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml of triethylamine in 10 ml of tetrahydrofuran was added to a phosgene (toluene) in 5 ml of tetrahydrofuran. 20% solution in) was added dropwise to 0.5 ml (0.96 mmol) of an ice cold solution. After 1 hour 15 ml of aqueous ammonium chloride solution and 10 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using diethyl ether / hexane (3: 2) as eluent. Fractions containing product were combined and evaporated to 120 mg (52) of 3-cyclohexyl-7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one %) Was obtained as a white solid.

c) 100 mg (0.34 mmol) of 3-cyclohexyl-7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one in 10 ml of dichloromethane ) Was treated with 250 ml (0.74 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 3 hours 30 ml of saturated aqueous sodium bicarbonate solution and 20 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3-cyclohexyl-7-methylsulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)- 165 mg (93%) were obtained as a white solid.

Example 5

250 ml (0.83 mmol) of 3-tert-butyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one and 4- A mixture of 600 mg (2.9 mmol) of (2- (diethylamino) ethoxy) aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 30 ml of dichloromethane. The solution was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered and dried to afford 3-tert-butyl-7- [4- [2- (diethylamino) -ethoxy] anilino] -3,4-dihydro-1-methylpyrimido 70 mg (21%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as an off-white solid with a melting point of 130 ° C.

The tert-butyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material was Prepared as follows:

a) A mixture of 200 mg (1.1 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde and 0.23 ml (2.18 mmol) of tert-butylamine in 10 ml of methanol was added 500 mg of Form 4A. It was left to itself for 3 days. The solution was decanted from the molecular sieve and 100 mg (2.7 mmol) of sodium borohydride were added in portions thereto. After 30 minutes the mixture was evaporated and 20 ml of ethyl acetate and 20 ml of 2M aqueous sodium hydroxide were added to the residue. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 240 mg (92%) of 5-tert-butylaminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid.

b) a mixture of 240 mg (1 mmol) of 5-tert-butylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.28 ml of triethylamine in 5 ml of tetrahydrofuran was added phosgene in 5 ml of tetrahydrofuran ( 1 ml (1.92 mmol) of an ice cold solution) was added dropwise to a 20% solution in toluene. After one hour 30 ml of saturated aqueous ammonium chloride solution and 20 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase is dried over magnesium sulfate, filtered and then evaporated to tert-butyl-7-methylthio-3,4-dihydro-1-methyl-pyrimido [4,5-d] pyrimidine-2 ( 220 mg (83%) of 1H) -one were obtained as a white solid.

c) 220 mg of tert-butyl-7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one in 20 ml of dichloromethane ( 0.83 mmol) was treated with 570 mg (1.66 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 0.2 ml of saturated aqueous sodium bicarbonate solution were added and the phases were separated. The organic phase was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to tert-butyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5 -d] 250 mg (100%) of pyrimidin-2 (1H) -one were obtained as a white solid.

Example 6

3-cyclopentyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 200 mg (0.65 mmol) and 4- [2 A mixture of 300 mg (1.4 mmol) of-(diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 30 ml of dichloromethane. The solution was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by reverse phase high performance liquid chromatography (HPLC). Mobile phase was water / 0.1% trifluoroacetic acid (A) and acetonitrile / 0.07% trifluoroacetic acid (B); Gradient was 5% to 95% B for 20 minutes; The product was detected using an ultraviolet detector at 215 nm wavelength. The fraction containing the product was lyophilized to yield 3-cyclopentyl-7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5- d] 20 mg (7%) of pyrimidin-2 (1H) -one trifluoroacetate was obtained as a white solid at melting point 89 ° C.

3-cyclopentyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one as the starting material was tert-butylamine Instead, cyclopentylamine was used to prepare in a manner similar to that described in Examples 5 a) to c).

Example 7

120 mg (0.27 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) one And a mixture of 370 mg (1.8 mmol) of 4- [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 40 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue solid was purified by crystallization from cyclohexane / ethyl acetate to give 3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-di 10 mg (6%) of hydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as an off-white solid at melting points 162 to 163 ° C.

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido- [4,5-d] pyrimidine-2 (1H)-used as starting material One was prepared as follows:

a) A mixture of 4 g (17.2 mmol) and 5 g (54 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 40 ml of dioxane was stirred at room temperature for 24 hours. The mixture was then evaporated and 100 ml of ethyl acetate and 50 ml of 2 M hydrochloric acid aqueous solution were added to the residue. The phases were separated and the organic phase was washed with 50 ml of aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The resulting solid was purified by crystallization from an aqueous ethanol solution to give 3.5 g (64%) of ethyl 4-phenylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.

b) Ice-cooled a solution of 3.5 g (11.1 mmol) of ethyl 4-phenylamino-2-methylthiopyrimidine-5-carboxylate in 50 ml of tetrahydrofuran, followed by 12 ml of 1 M lithium aluminum hydride in tetrahydrofuran ( 12 mmol) was added dropwise. Cooling was removed and the mixture was stirred at rt for 3 h. The mixture was then ice cooled and treated with careful dropwise addition of 0.5 ml of water, 2 M aqueous sodium hydroxide solution and then 1 ml of water. The resulting suspension was filtered through a filter. The filtrate was evaporated to give 2.7 g (98%) of 4-phenylamino-2-methylthiopyrimidine-5-methanol as a yellow oil.

c) 2.7 g (10.9 mmol) of 4-phenylamino-2-methylthiopyrimidine-5-methanol was stirred in 50 ml of dichloromethane and treated with 9.6 g (111 mmol) of manganese dioxide. The suspension was stirred for 18 hours and then filtered through a filter. The filtrate was evaporated and the residue was chromatographed on silica gel using diethyl ether / hexane (1: 1) as eluent. Fractions containing the product were combined and evaporated to give 1.8 g (67%) of 4-phenylamino-2-methylthiopyrimidine-5-carboxaldehyde as a white solid.

d) 700 mg (2.9 mmol) of 4-phenylamino-2-methylthiopyrimidine-5-carboxaldehyde, 490 mg (3.0 mmol) of 2,6-dichloroaniline and 100 mg of 4-toluenesulfonic acid in 50 ml of toluene (0.5 mmol) was heated for 18 hours with azeotropic removal of water under reflux. The mixture was cooled and evaporated. 50 ml of methanol and 400 mg (11.7 mmol) of sodium borohydride were added and the mixture was heated at reflux for 20 minutes, cooled and evaporated. The residue was stirred in a mixture of 50 ml of 2 M aqueous sodium hydroxide solution and 50 ml of ethyl acetate, and then the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue on silica gel with diethyl ether / hexane (2: 3) as eluent gave 410 mg (36) of 5- (2,6-dichlorophenyl) aminomethyl-4-phenylamino-2-methylthiopyrimidine. %) Was obtained as a white solid.

e) 0.25 ml (0.48 ml) of an ice cold stirred solution of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was added 5- (2,6-dichlorophenyl) aminomethyl-4-phenylamino- in 10 ml of tetrahydrofuran. Treatment was added dropwise with a solution of 100 mg (0.26 mmol) of 2-methylthiopyrimidine and 0.1 ml (0.7 mmol) of triethylamine. The mixture was stirred at rt for 3 days. 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution are added and the phases are separated and the organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7-methylthio-3,4- 110 mg (100%) of dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid.

f) 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidine-2 (1H)-in 5 ml of dichloromethane 110 mg (0.26 mmol) solution was treated with 190 mg (0.55 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidine- 120 mg (100%) of 2 (1H) -one were obtained as a pale yellow oil.

Example 8

100 mg (0.25 mmol) of 3- (2,6-dichlorophenyl) -1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 120 mg (0.5 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -1-ethyl-7- [4- [2- (diethylamino) ethoxy ] 30 mg (22%) of anilino] -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as an orange solid at a melting point of 85 ° C.

3- (2,6-dichlorophenyl) -1-ethyl-7-methanesulfonyl-3,4-dihydro-pyrimido- [4,5-d] pyrimidine-2 (1H) used as starting material The -one was prepared as follows:

a) A mixture of 49 g (246 mmol) of 4-amino-5-carbethoxypyrimidine-2-thiol and 42 g (304 mmol) of potassium carbonate in 400 ml of acetone is added to 50 g (352 mmol) of iodomethane. Treated. After stirring for 3 hours 500 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 300 ml of dichloromethane each. The combined organic phases were washed with 100 ml brine, dried over magnesium sulfate, filtered and evaporated to give 45.2 g (86%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a pale yellow solid.

b) A solution of 45 g (211 mmol) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate in 300 ml of tetrahydrofuran was stirred with 13 g (338 mmol) of lithium aluminum hydride. Treatment was added dropwise. Fifteen minutes after the addition was completed, the mixture was ice cooled and carefully treated dropwise with 25 ml of water. After stirring for 2 hours at room temperature the mixture was filtered through a filter and the filtrate was evaporated. The residue was triturated in 500 ml of dichloromethane / hexanes (1: 1), collected by filtration and dried to give 28 g (78%) of 4-amino-2-methylthiopyrimidine-5-methanol as a white solid.

c) 28 g (164 mmol) of 4-amino-2-methylthiopyrimidine-5-methanol were stirred in 500 ml of dichloromethane and treated with 150 g (1.7 mol) of manganese dioxide. The suspension was stirred for 24 hours and then filtered through a filter. The filtrate was evaporated to give 20.2 g (73%) of 4-amino-2-methylthiopyrimidine-5-carboxaldehyde as a pale yellow solid.

d) 10 g (59.2 mmol) of 4-amino-2-methylthiopyrimidine-5-carboxaldehyde in 200 ml of xylene, 9.7 g (59.9 mmol) of 2,6-dichloroaniline and 1 g of 4-toluenesulfonic acid ( 5.3 mmol) was heated for 24 hours with azeotropic removal of water under reflux. The mixture was cooled and evaporated. 50 ml of acetic acid and 20 ml of toluene were added to the residue. The mixture was ice cooled and treated with 5 g (147 mmol) of sodium borohydride for more than 30 minutes in small portions. After one hour the mixture was evaporated and the residue was stirred in a mixture of 100 ml of ethyl acetate and 100 ml of 2M aqueous sodium hydroxide solution for one hour. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from an ethanol aqueous solution to give 2.4 g (13%) of 5- (2,6-dichlorophenyl) aminomethyl-4-amino-2-methylthiopyrimidine as a white solid. 5- (2,6-dichlorophenyl) aminomethyl-4-amino-2-methylthiopyrimidine 2.1 by evaporation of the mother liquor and flash chromatography on silica gel using diethyl ether / hexane (1: 1) as eluent. g (11%) was obtained as a white solid.

e) 5.8 ml (11.2 mmol) ice-cooled stirred solution of phosgene (20% in toluene) in 80 ml of tetrahydrofuran was added 5- (2,6-dichlorophenyl) aminomethyl-4-amino-2 in 80 ml of tetrahydrofuran. Treated dropwise with a solution of 1.76 g (5.6 mmol) of methylthiopyrimidine and 1.6 ml (11.2 mmol) of triethylamine. The mixture was stirred for 1 hour. 50 ml of tetrahydrofuran and 50 ml of saturated aqueous ammonium chloride solution were added. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydropyrimido [4,5 -d] 1.7 g (89%) of pyrimidin-2 (1H) -one were obtained as a white solid.

f) 220 mg of 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 10 ml of dichloromethane 0.64 mmol) was treated with 440 mg (1.28 mmol) of 3-chloroperbenzoic acid (50% w / w water) and stirred for 18 hours. 0.2 ml of dimethyl sulfoxide was added. After 15 minutes, 15 ml of saturated aqueous sodium bicarbonate solution was added. After phase separation, the organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4 250 mg (100%) of, 5-d] pyrimidin-2 (1H) -one were obtained as a white solid.

g) 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one 100 in 6 ml of dimethylformamide mg (0.27 ml) ice-cold solution was treated with 11 mg (0.27 mmol) of sodium hydride (60% w / w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of iodoethane and then heated to 90 ° C. for 2 hours. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido 100 mg (92%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid.

Example 9

100 mg (0.22 mmol) of 1-benzyl-3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 120 mg (0.5 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1-benzyl-3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) 30 mg (23%) of oxy] -anilino] -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid having a melting point of 106 ° C.

1-benzyl-3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material Was prepared as follows:

100 mg of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 6 ml of dimethylformamide ( 0.27 mmol) of ice-cold solution was treated with 11 mg (0.27 mmol) of sodium hydride (60% w / w). After 30 minutes the mixture was treated with 0.04 ml (0.3 mmol) of benzyl bromide and then heated at 90 ° C. for 2 hours. The mixture was evaporated and 30 ml of dichloromethane and 30 ml of water were added to the residue. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to 1-benzyl-3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido 100 mg (80%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid.

Example 10

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-[(3-pyridyl) methyl] pyrimido [4,5-d] pyrimidine-2 (1H ) A mixture of 60 mg (0.13 mmol) and 150 mg (0.72 mmol) of 4- [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by reverse phase HPLC. Mobile phases were water / 0.1% trifluoroacetic acid (A) and acetonitrile / 0.07% trifluoroacetic acid (B). The gradient was 5% to 95% B for 20 minutes and the product was detected using an ultraviolet detector at wavelength 215 nm. The fraction containing the product was lyophilized to give 3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-[( 16 mg (17%) of 3-pyridyl) -methyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one trifluoroacetate were obtained as a white solid at a melting point of 64 ° C.

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-[(3-pyridyl) -methyl] pyrimido [4,5-d] used as starting material Pyrimidin-2 (1H) -one was prepared as follows:

100 mg of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 6 ml of dimethylformamide ( 0.27 mmol) Ice-cooled solution was treated with 22 mg (0.54 mmol) of sodium hydride (60% w / w). After 30 minutes the mixture was treated with 50 mg (0.3 mmol) of picolyl chloride hydrochloride and then heated at 90 ° C. for 2 hours and at 100 ° C. for an additional hour. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-[(3 60 mg (48%) of -pyridyl) methyl] -pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid.

Example 11

3- (2,6-dichlorophenyl) 7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 110 mg (0.29 mmol) And 0.31 ml (2.9 mmol) of benzylamine were heated at 180 ° C. for 10 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed sequentially with 20 ml of 5% aqueous sodium bicarbonate solution and 20 ml brine, dried over magnesium sulfate, filtered and evaporated to 7-benzylamino-3- (2,6-dichlorophenyl) -3,4- 93 mg (79%) of dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 195-198 ° C.

Example 12

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 0.25 ml (2.6 mmol) of 4-fluoroaniline were heated at 180 ° C. for 30 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 20 ml brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using ethyl acetate / hexanes (2: 3) as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -7- (4-fluoroanilino) -3,4-dihydro-1-methylpyrimido [4,5-d] 40 mg (37%) of -pyrimidin-2 (1H) -one were obtained as a pale gray solid having a melting point of 208 to 211 ° C.

Example 13

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimido-2 (1H) -one ) And 0.24 ml (2.6 mmol) of aniline were heated at 180 ° C. for 30 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 20 ml brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using ethyl acetate / hexanes (1: 1) as eluent. Fractions containing product were combined and evaporated to 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H) 42 mg (40%) of -on were obtained as a pale purple solid with a melting point of 222 to 224 ° C.

Example 14

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 0.32 ml (2.6 mmol) of 4-methoxyaniline were heated at 60 ° C. for 4 hours and then cooled. 10 ml of 2M aqueous hydrochloric acid was added to the residue. The precipitated yellow solid was filtered off, washed successively with 2M aqueous hydrochloric acid, water and diethyl ether and dried to give 3- (2,6-dichlorophenyl) -3,4-dihydro-7- (4-methoxyanilino 45 mg (40%) of) -1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid at a melting point of 175 ° C. (decomposition).

Example 15

200 mg (0.52 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 140 mg (0.8 mmol) of 4- [2- (dimethylamino) ethoxy] aniline were heated at 160 ° C. for 2 hours and then cooled. The residue was chromatographed on silica gel first with dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) and then with dichloromethane / methanol / acetic acid / water (90: 18: 3: 2). Fractions containing product were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7- [4- [ Melting point of 35 mg (23%) of 2- (dimethylamino) ethoxy] anilino] -3,4-dihydro-1-methyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one Obtained as a white solid at 173-174 ° C.

4- [2- (dimethylamino) ethoxy] aniline used as starting material was prepared as follows:

a) A suspension of 5 g (36 mmol) of 4-nitrophenol in 250 ml of xylene was treated with a solution of 1.63 g (41 mmol) of sodium hydroxide in 20 ml of water and the mixture was stirred at room temperature for 30 minutes. The mixture was then treated with 7.5 g (54 mmol) of potassium carbonate and 5.11 g (36 mmol) of dimethylaminoethyl chloride hydrochloride. The mixture was heated at reflux for 2 hours and for another 24 hours with azeotropic removal of water. The mixture was filtered when hot and the solid was washed with hot xylene. The combined filtrate and washings were evaporated and the residue was distilled under high vacuum to yield 1.28 g (20%) of 4- [2- (dimethylamino) ethoxy] nitrobenzene in an orange liquid.

b) A solution of 880 mg (3.7 mmol) of 4- [2- (dimethylamino) ethoxy] nitrobenzene in 10 ml of ethanol was hydrogenated over 88 mg of palladium on 10% activated carbon at atmospheric pressure for 3 hours. The suspension was filtered through a filter and the filtrate was evaporated to yield 680 mg (100%) of 4- [2- (dimethylamino) ethoxy] aniline in an orange liquid.

Example 16

a) 200 mg of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 0.52 mmol) and 800 mg (4.47 mmol) of ethyl 4-aminophenylacetate were heated at 185 ° C. for 45 minutes. The residue was partitioned between 10 ml of ethyl acetate and 10 ml of 2M hydrochloric acid and the insoluble milky solid was collected by filtration, washed with 20 ml of water and 20 ml of ethyl acetate and dried under high vacuum. Ethyl 2- [4-[[3- (2,6-dichlorophenyl) -1,2,3,4-tetrahydro-1-methyl-2-oxopyrimido [4,5- at melting point 211 to 212 ° C. d] 95 mg (38%) of pyrimidin-7-yl] amino] phenyl] acetate were isolated.

b) A 1.0 M solution of lithium aluminum hydride in anhydrous tetrahydrofuran (91 μl; 91 μmol) was added ethyl 2- [4-[[3- (2,6-dichlorophenyl)-in 4 ml of anhydrous tetrahydrofuran at 0 ° C. 1,2,3,4-tetrahydro-1-methyl-2-oxopyrimido [4,5-d] pyrimidin-7-yl] amino] phenyl] acetate in 40 mg (82 μmol) of a stirred solution The mixture was added dropwise and the mixture was stirred for an additional 90 minutes. The reaction was quenched with 10 ml 2M sodium hydroxide and the mixture was extracted twice with 10 ml ethyl acetate each. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexanes (2: 1) as eluent. Fractions containing product were evaporated to afford 3- (2,6-dichlorophenyl) -3,4-dihydro-7- [4- (2-hydroxyethyl) anilino] -1-methylpyrimido [4,5 -d] 25 mg (68%) of pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 148-151 ° C.

Ethyl 4-aminophenylacetate used as starting material was prepared as follows:

A solution of 1 g (4.78 mmol) of ethyl-4-nitrophenylacetate in 10 ml of anhydrous methanol was treated with 100 mg of 10% palladium on carbon and then hydrogenated at room temperature and atmospheric pressure for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to yield 830 mg (97%) of ethyl 4-aminophenylacetate as a flowing yellow oil.

Example 17

3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido- [4,5-d] pyrimidin-2 (1H) -one 100 mg (0.26 mmol) and 400 μl (3.4 mmol) of phenethylamine were heated at 180 ° C. for 4 hours and then cooled to room temperature. The mixture was dissolved in 10 ml of ethyl acetate and washed sequentially with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution. The ethyl acetate phase was separated, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel using 5% methanol / dichloromethane as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -3,4-dihydro-1-methyl-7- (2-phenylethylamino) pyrimido [4,5-d] pyrimidine 35 mg of -2 (1H) -one were obtained as a pale yellow solid at a melting point of 148-151 ° C.

Example 18

2.2 g (5.7 mmol) of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 4.8 g (28.5 mmol) of 2,4-dimethoxybenzylamine were heated at 55 ° C. for 2 hours and then left to cool. The mixture was dissolved in 100 ml of dichloromethane and washed sequentially with 30 ml of 2M hydrochloric acid, 30 ml of saturated aqueous sodium bicarbonate solution and 30 ml of brine. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate / hexanes (1: 1) and 3- (2,6-dichlorophenyl) -3,4-dihydro-7- (2,4-dimethoxybenzylamino) -1-methylpyrimido [4,5-d] -pyrimidin-2 (1H) -one was collected by filtration as a white solid and dried under high vacuum at 40 ° C. Yield was 2.35 g (87%) after drying and melting point was 152-154 ° C.

Example 19

3- (2,6-dichlorophenyl) -3,4-dihydro-7- (2,4-dimethoxybenzylamino) -1-methylpyrimido [4,5-d] pyrimidine in 2 ml of dichloromethane A 200 mg (0.42 mmol) solution of -2 (1H) -one was treated with 2 ml of trifluoroacetic acid and the mixture was stirred at room temperature under a stream of nitrogen for 5 hours. The solvent was evaporated and the residue was triturated with saturated aqueous sodium bicarbonate solution and the product was collected by filtration and suction dried. The dried product was suspended in dichloromethane and further purified by filtration through polytetrafluoroethylene membrane. The filtrate was evaporated and the residue was dried to give 7-amino-3- (2,6-dichlorophenyl) -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)- 115 mg (84%) on were obtained as a white solid with a melting point of 176-184 ° C.

Example 20

3- (2,6-dichlorophenyl) -7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2-one in 2 ml of dichloromethane A solution of 100 mg (0.22 mmol) and 300 μl (2.4 mmol) of cyclohexylamine was stirred overnight at room temperature. The mixture was diluted with 10 ml of dichloromethane and washed with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 99 mg (96%) of 3- (2,6-dichlorophenyl) -7-cyclohexylamino-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) Was isolated as white foam at melting point 258-259 ° C.

Example 21

3- (2,6-dichlorophenyl) -7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2-one in tetrahydrofuran A solution of 100 mg (0.22 mmol) and 2 ml of methylamine was stirred for 48 hours at room temperature. The mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 30 mg (34%) of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methylamino-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one Was isolated as a white solid at melting points 211-213 ° C.

Example 22

3- (2,6-dichlorophenyl) -7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2-one in 2 ml of dichloromethane A solution of 100 mg (0.22 mmol) and 200 mg (2.12 mmol) of 4-aminopyridine was stirred overnight at room temperature. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 10% methanol / dichloromethane as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -3,4-dihydro-1-phenyl-7-[(4-pyridyl) amino] pyrimido [4,5-d 16 mg (15%) of pyrimidin-2 (1H) -one were obtained as an off-white solid that decomposed at 289 ° C.

Example 23

3- (2,6-dichlorophenyl) -7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2-one in 2 ml of dichloromethane A solution of 100 mg (0.22 mmol) and 285 μL (2.2 mmol) of cyclohexylmethylamine was stirred overnight at room temperature. The mixture was diluted with 10 ml of dichloromethane and washed with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 3- (2,6-dichlorophenyl) -7- (cyclohexylmethylamino) -3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one 100 mg (94%) was isolated as white foam having a melting point of 229 to 233 ° C.

Example 24

100 mg (0.22 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido [4,5-d] pyrimidin-2-one ) And 320 mg (2.2 mmol) of 1-aminonaphthalene were heated at 130 ° C. for 4 hours. The mixture was left to cool and then partitioned between 10 ml of ethyl acetate and 2M hydrochloric acid. Insoluble 1-aminonaphthalene hydrochloride was removed by filtration. The ethyl acetate phase was separated and washed with 10 ml saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexanes (1: 1) as eluent. Fractions containing product were evaporated to evaporate 3- (2,6-dichlorophenyl) -3,4-dihydro-7- (1-naphthylamino) -1-phenylpyrimido [4,5-d] pyrimidine 46 mg (40%) of -2 (1H) -one were obtained as a pale pink solid at melting point 213-214 ° C.

Example 25

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And a mixture of 136 mg (1 mmol) of p-xylenediamine were heated at 70 ° C. for 20 minutes. The product was purified by flash column chromatography on silica gel using dichloromethane / methanol / water / acetic acid (98: 18: 3: 2) as eluent. Fractions containing product were combined and evaporated. The residue was dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7- [4- (aminoethyl) benzylamino] -3- (2,6-dichlorophenyl) 35 mg (30%) of -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as white solids having a melting point of 151 to 152 ° C.

Example 26

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 140 mg (1 mmol) of 2- (4-aminophenyl) ethylamine were heated at 70 ° C. for 20 minutes. The product was purified by flash column chromatography using 5% methanol in dichloromethane as eluent. Fractions containing product were combined and evaporated. The residue was recrystallized from ethyl acetate to give 7- [2- (4-aminophenyl) ethylamino] -3- (2,6-dichlorophenyl) -3,4-dihydro-1-methylpyrimido [4,5- d] 3 mg (3%) of pyrimidin-2 (1H) -one were isolated as a yellow solid at melting point 174-175 ° C.

Example 27

100 mg (0.26 mmol) of 3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 238 mg (1.07 mmol) of 4- (2-diethylaminoethoxy) benzylamine were heated at 170 ° C. for 30 minutes. The product was purified by flash column chromatography using dichloromethane / methanol / water / acetic acid (120: 14: 3: 2) as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] benzylamino] -3,4-dihydro-1-methyl 40 mg (29%) of pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 137-138 ° C.

4- (2-diethylaminoethoxy) benzylamine used as starting material was prepared as follows:

a) A solution of 8.04 g (67 mmol) of 4-cyanophenol in 100 ml of xylene was treated with a solution of 2.99 g (74 mmol) of sodium hydroxide in 20 ml of water and the mixture was stirred for 30 minutes. To this mixture was added 13.88 g (100 mmol) of potassium carbonate and 12.83 g (75 mmol) of 2-diethylaminoethyl chloride hydrochloride. The reaction mixture was then heated to reflux for 3 hours, then left to cool, washed twice with 50 ml of water each, dried over magnesium sulfate, filtered and evaporated to give 10.93 g of 4- (2-diethylaminoethoxy) benzonitrile ( 74%) was obtained as a colorless flowing liquid.

b) A lithium aluminum hydride (5 ml; 5 mmol) 1M solution was added dropwise at 0 ° C. to a stirred solution of 1.01 g (5 mmol) of 4- (2-diethylaminoethoxy) benzonitrile in 5 ml of anhydrous tetrahydrofuran. . The mixture was warmed to rt and stirred overnight. The reaction was quenched by careful addition of 5 ml saturated solution of Rochelle's salt and evaporated. The residue was partitioned between 25 ml of diethyl ether and 25 ml of water and the organic phase was separated, dried over magnesium sulfate and evaporated. The crude product was purified by flash column chromatography on silica gel using dichloromethane / methanol / water / acetic acid (60: 18: 2: 3) as eluent. Fractions containing the product were combined and evaporated to yield 785 mg (71%) of 4- (2-diethylaminoethoxy) benzylamine as colorless oil. [Mass spectrum (ESI) MH ⁺ = 223].

Example 28

65 mg (0.19 mmol) of 3- (2,6-dimethylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And a mixture of 180 mg (0.87 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 20 ml of dichloromethane, washed three times with 20 ml each of saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and evaporated to afford 15 mg of a pink oil which was purified by HPLC. Mobile phase was water / 0.1% trifluoroacetic acid (A) and acetonitrile / 0.07% trifluoroacetic acid (B); gradient was 5% to 95% B for 20 minutes; The product was detected at wavelength 215 nm using an ultraviolet detector. The fraction containing the product was lyophilized and the lyophilisate was dissolved in 20 ml of dichloromethane, washed three times with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 7- [4- [2- ( Diethylamino) ethoxy] anilino] -3,4-dihydro-1-methyl-3- (2,6-dimethylphenyl) pyrimido [4,5-d] pyrimidin-2 (1H) -one 10 mg (11%) were obtained as a white solid with a melting point of 58 ° C.

3- (2,6-dimethylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material Was prepared as follows:

a) Triacetoxyboron in a mixture of 200 mg (1.1 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde and 0.15 ml (1.2 mmol) of 2,6-dimethylaniline in 5 ml of dichloromethane 350 mg (1.6 mmol) of sodium hydride and then 0.1 ml (1.7 mmol) of acetic acid were added. After 5 hours additional 0.15 ml of 2,6-dimethylaniline was added and the mixture was stirred for 18 hours at room temperature. 20 ml of saturated aqueous sodium bicarbonate solution and 25 ml of dichloromethane were added. The phases were separated and the aqueous phase was washed twice with 25 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using diethyl ether / hexane (1: 2) as eluent. Fractions containing product were combined and evaporated to give 40 mg (13%) of 5- (2,6-dimethylphenyl) aminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid [mass spectrum (ESI) MH ⁺ 289] and 200 mg (65%) of 5- (2,6-dimethylphenyl) iminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid [Mass Spectrum (ESI) MH ⁺ = 287]. Obtained.

b) a mixture of 195 mg (0.68 mmol) of 5- (2,6-dimethylphenyl) aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.19 ml (1.4 mmol) of triethylamine in 10 ml of dioxane. To the ice-cooled solution of 0.085 ml (0.7 mmol) of trichloromethyl chloroformate in 10 ml of dioxane was added dropwise. The mixture was then left to warm to room temperature. After 10 minutes more the mixture was evaporated. 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate solution were added to the residue. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 15 ml of pyridine and heated at reflux for one hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of dichloromethane and 2M hydrochloric acid. The organic phase was washed with 20 ml of water, dried over magnesium sulfate and evaporated to 3- (2,6-dimethylphenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido- [4,5-d ] 100 mg (47%) of pyrimidin-2 (1H) -one were obtained as off-white solid. [Mass spectrum (ESI) MH ⁺ = 315].

c) 3- (2,6-dimethylphenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)-in 10 ml of dichloromethane 100 mg (0.32 mmol) of solution was treated with 220 mg (0.64 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 30 ml of saturated aqueous sodium bicarbonate solution and 20 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dimethylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine- 65 mg (59%) of 2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 347].

Example 29

250 mg (0.67 mmol) and 4- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one A mixture of 600 mg (2.9 mmol) of [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered and dried to give 3- (2,6-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydropyrimido- 70 mg (21%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as an off-white solid with a melting point of 248 ° C.

Example 30

70 mg (0.16) of 3- (2,6-dichlorophenyl) -1-isopropyl-7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one mmol) and 166 mg (0.8 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 30 ml of dichloromethane, each washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) 7- [4- [2- ( Diethylamino) ethoxy] anilino] -3,4-dihydro-1-isopropylpyrimido [4,5-d] pyrimidin-2 (1H) -one 5 mg (22%) Melting point 125 DEG C Obtained as a white solid.

3- (2,6-dichlorophenyl) -1-isopropyl-7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H)-used as starting material One was prepared as follows:

a) 100 mg of 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 6 ml of dimethylformamide (0.27 mmol) of an ice cold solution was treated with 13 mg (0.33 mmol) of sodium hydride (60% w / w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of 2-bromopropane and then heated at 90 ° C. for 2 hours, cooled and left for 3 days. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -1-isopropyl-7-methylthio-3,4-dihydropyrimido 60 mg (54%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid. [Mass spectrum (ESI) MH ⁺ = 383].

b) 3- (2,6-dichlorophenyl) -1-isopropyl-7-methylthio-3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H) in 10 ml of dichloromethane -60 mg (0.16 mmol) of a solution were treated with 108 mg (0.32 mol) of 3-chloroperbenzoic acid (50% w / w water) and stirred for 18 hours. 0.2 ml of dimethyl sulfoxide was added. After 15 minutes more, 15 ml of saturated aqueous sodium bicarbonate solution was added and the phases were separated. The organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to 3- (2,6-dichlorophenyl) -1-isopropyl-7-methanesulfonyl-3,4-dihydropyrimido [4 65 mg (100%) of, 5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 415].

Example 31

200 mg (0.6 mmol) and 4 of 3- (2-methylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one A mixture of 300 mg (1.4 mmol) of-[2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7- [4- [2- (diethylamino) ethoxy] anilino ] -3,4-dihydro-1-methyl-3- (2-methylphenyl) pyrimido [4,5-d] pyrimidin-2 (1H) -one 30 mg (11%) with a pink melting point of 132 ° C Obtained as a solid.

3- (2-methylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material Prepared as follows:

a) 300 mg (1.6 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in 50 ml of toluene, 0.20 ml (1.8 mmol) of o-toluidine and 59 mg (0.3 mmol) of 4-toluenesulfonic acid ) Was heated at reflux for 18 hours with azeotropic removal of water. The mixture was cooled and evaporated. The residue was dissolved in 40 ml of ethanol and heated at 70 ° C. 300 mg (8 mmol) of sodium borohydride were carefully added and the mixture was heated at 70 ° C. for 2 hours. Further 300 mg (0.8 mmol) of sodium borohydride were carefully added and heated for an additional hour. The mixture was cooled and evaporated. The residue was partitioned between 50 ml of 2M aqueous sodium hydroxide solution and 50 ml of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using diethyl ether / hexane (1: 1) as eluent. Fractions containing the product were combined and evaporated to give 190 mg (43%) of 5- (2-methylphenyl) aminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH ⁺ = 275].

b) 0.7 ml (1.3 mmol) ice-cooled stirred solution of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was added 5- (2-methylphenyl) aminomethyl-4-methylamino-2-methyl in 5 ml of tetrahydrofuran. Treatment was added dropwise with a solution containing 189 mg (0.69 mmol) of thiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine. The mixture was stirred for 1 hour. To the mixture was added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to 3- (2-methylphenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine- 210 mg (100%) of 2 (1H) -one were obtained as a milky solid. [Mass spectrum (ESI) MH ⁺ = 301].

c) 210 mg of 3- (2-methylphenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one in 10 ml of dichloromethane (0.7 mmol) was treated with 482 mg (1.4 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours, 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of dichloromethane were added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to 3- (2-methylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H 200 mg (86%) of) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 333].

Example 32

40 mg (0.096 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 1 ml (11 mmol) of aniline were heated and cooled at 180 ° C. for 45 minutes and partitioned between 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid. The separated organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using ethyl acetate / hexanes (1: 2) as eluent. Fractions containing the product were combined and evaporated to give a tan solid which was purified by HPLC. Mobile phase was water / 0.1% trifluoroacetic acid (A) and acetonitrile / 0.07% trifluoroacetic acid (B); Gradient was 5% to 95% B for 20 minutes; The product was detected at wavelength 215 nm using an ultraviolet detector. The fraction containing the product was lyophilized to give 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidine-2 (1H 5 mg (4%) of) -one were obtained as a white solid at a melting point of 138 ° C.

Example 33

56 mg (0.13 mmol) of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And 1 ml of 4-methoxybenzylamine were heated at 100 ° C. for 30 minutes, then cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -3,4-dihydro-7- (4-methoxybenzyl) amino-1-phenylpyrimido [4,5- 68 mg (100%) of d] -pyrimidin-2 (1H) -one were obtained as a yellow solid with a melting point of 56 ° C.

Example 34

3- (2,6-dichlorophenyl) -7- (4-methoxybenzyl) -amino-3,4-dihydro-1-phenylpyrimido [4,5-d] pyridine in 5 ml of trifluoroacetic acid A solution of 40 mg (0.96 mmol) of midin-2 (1H) -one was heated at reflux for 5 hours. The mixture was evaporated and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of 2M aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and evaporated and the residue was column chromatographed on silica gel using dichloromethane / methanol (20: 1) as eluent. Fractions containing product were combined and evaporated to 7-amino-3- (2,6-dichlorophenyl) -3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidine-2 (1) 10 mg (27%) of -on was obtained as a white solid with a melting point above 300 ° C.

Example 35

200 mg of 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 0.56 mmol) and 400 mg (1.9 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7- [4- [2- (diethylamino) ethoxy] anilino] -3- ( 30 mg (11%) of 2,6-difluorophenyl) -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as an orange solid. . [Mass spectrum (ESI) MH ⁺ = 483].

3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido- [4,5-d] pyrimidine-2 (1H used as starting material ) -One was prepared as follows:

a) 300 mg (1.6 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in 30 ml of toluene, 232 mg (1.8 mmol) of 2,6-difluoroaniline and 4-toluenesulfonic acid A mixture of 59 mg (0.3 mmol) of monohydrate was heated for 18 hours with azeotropic removal of water under reflux. The mixture was cooled and evaporated. The residue was dissolved in 20 ml tetrahydrofuran and further added dropwise to a solution of 1.6 ml (1.6 mmol) of lithium aluminum hydride (1M in tetrahydrofuran) in 20 ml of tetrahydrofuran. After 30 minutes the mixture was ice-cooled and carefully added dropwise 0.5 ml of water, 0.75 ml of 2M sodium hydroxide solution and then 1 ml of water. The resulting suspension was filtered through a filter and the filtrate was evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether / hexane (1: 1) as eluent to give 210 mg of 5- (2,6-difluorophenyl) aminomethyl-4-methylamino-2-methylthiopyrimidine. (44%) was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 297].

b) 0.7 ml (1.3 mmol) ice-cooled stirred solution of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was added 5- (2,6-difluorophenyl) aminomethyl-4-methyl in 5 ml of tetrahydrofuran. The solution was added dropwise with a solution of 210 mg (0.71 mmol) of amino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine. The mixture was stirred for 1 hour. To the mixture was added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-difluorophenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine 200 mg (87%) of -2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 323].

c) 3- (2,6-difluorophenyl) -7-methylthio-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H in 10 ml of dichloromethane A 200 mg (0.62 mmol) solution of) -one was treated with 430 mg (1.24 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyridine 200 mg (91%) of midin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 355].

Example 36

200 mg (0.52 mmol) of 3- (2,4-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And a mixture of 300 mg (1.4 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino 20 mg (8%) of ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one as an orange solid having a melting point of 172 ° C. Obtained.

3- (2,4-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido- [4,5-d] pyrimidine-2 (1H)-used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methyl using 2,4-dichloroaniline instead of 2,6-difluoroaniline Prepared in a similar manner as described in Example 35 for pyrimido [4,5-d] pyrimidin-2 (1H) -one.

Example 37

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyrimidine- 200 mg (0.52 mmol) of 2 (1H) -one and 3 ml of aniline were heated at 180 ° C. for 40 minutes and then cooled. The mixture was partitioned between 40 ml of dichloromethane and 40 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using diethyl ether / hexane (1: 1) as eluent. Fractions containing product were combined and evaporated to 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4 30 mg (29%) of, 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 142 ° C.

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5- used as starting material d] pyrimidin-2 (1H) -one was prepared as follows:

a) To a solution of 10 g (60 mmol) of 3-nitrophenylacetic acid in 120 ml of ethanol was added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate and the mixture was heated at reflux for 4 hours, cooled and left at room temperature for 18 hours. . The mixture was evaporated and the residue was partitioned between 120 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 10.3 g (82%) of ethyl 3-nitrophenylacetate as a pale yellow oil. [NMR spectrum (250 MHz) δ 1.25 (t) (3H), δ 3.68 (s) (2H), δ 4.16 (q) (2H), δ6.5-δ6.7 (m) (3H), delta 7.09 (dd) (1H)].

b) A solution of 10.3 g (49 mmol) of ethyl 3-nitrophenylacetate in 120 ml of ethanol was hydrogenated with 1 g of palladium on 10% activated carbon for 6 hours. The mixture was filtered and the filtrate was evaporated to give 9.3 g (100%) of ethyl 3-aminophenylacetate as a yellow oil. [NMR spectrum (250 MHz) δ 1.19 (t) (3H), δ 3.48 (s) (2H), δ 4.16 (q) (2H), δ 7.48 (dd) (1H), δ7.62 ( d) (1H), δ 8.12 (m) (2H)].

c) a mixture of 5 g (21.5 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate and 4 g (22.3 mmol) of ethyl 3-aminophenylacetate in 80 ml of 1,4-dioxane. Treatment with 6 ml (43 mmol) of triethylamine was followed by heating at 60 ° C. for 4 hours. The mixture was cooled and evaporated. The residue was partitioned between 120 ml of ethyl acetate and 100 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 7.4 g (92%) of 4- [3- (ethoxycarbonylmethyl) -phenyl] amino-2-methylthiopyrimidine-5-carboxylate as a white solid. Obtained as a pale orange oil which solidified. [Mass spectrum (ESI) MH ⁺ = 376].

d) To an ice-cooled solution of 1.3 g (34 mmol) of lithium aluminum hydride in 70 ml of tetrahydrofuran, ethyl 4- [3- (ethoxycarbonylmethyl) phenyl] amino-2-methylthiopyrimidine in 70 ml of tetrahydrofuran. A solution of 6.5 g (17 mmol) of -5-carboxylate was added dropwise. Cooling was removed and the mixture was stirred at rt for 2 h. The reaction was quenched by careful dropwise addition of 1.2 ml of water, 1.2 ml of 2M aqueous sodium hydroxide solution and then 3.6 ml of water. The resulting suspension was filtered through a filter and the filtrate was evaporated. The residue was column chromatographed on silica gel using dichloromethane / methanol (10: 1) as eluent. Fractions containing the product were combined and evaporated to yield 3.1 g (62%) of 5-hydroxymethyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine as a yellow oil. [Mass spectrum (ESI) MH ⁺ = 292].

e) 9 g (100 g) of manganese dioxide in a solution of 3.1 g (10.7 mmol) of 5-hydroxymethyl-4- [3- (2-hydroxyethyl) -phenyl] amino-2-methylthiopyrimidine in 250 ml of dichloromethane mmol) was added and the mixture was stirred for 24 h. The mixture was filtered through a filter and the filtrate was evaporated to yield 2.6 g (84%) of 5-formyl-4- (3- (2-hydroxyethyl) phenylamino-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH ⁺ = 290].

f) A solution of 4 g (13.8 mmol) of 5-formyl-4- [3- (2-hydroxyethyl) -phenyl] amino-2-methylthiopyrimidine in 80 ml of toluene was added with 2,6-dichloroaniline 2.4. Treated with g (15 mmol) and 0.25 g (1.3 mmol) of 4-toluenesulfonic acid monohydrate and the mixture was heated under reflux with azeotropic removal of water and then cooled. The mixture was evaporated and the residue was dissolved in 40 ml of tetrahydrofuran and added dropwise to a solution of 0.6 g (16 mmol) of lithium aluminum hydride in 40 ml of tetrahydrofuran. After one hour 0.6 ml of water, 0.6 ml of 2M aqueous sodium hydroxide solution and 1.8 ml of water were carefully added dropwise to quench the reaction. The resulting suspension was filtered through a filter and the filtrate was evaporated. The residue was column chromatographed on silica gel using dichloromethane / methanol as eluent in the gradient 50: 1 to 10: 1. Fractions containing product from the first product eluting from the column were combined and evaporated to 5- (2,6-dichloroanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthio 1 g (17%) of pyrimidine was obtained as a white solid. Mass spectrum (ESI) MH ⁺ = 435. Fractions containing product from the second product eluting from the column were combined and evaporated to 5-hydroxymethyl-4- [3- (2-hydroxyethyl) phenyl] amino-2 1.8 g (45%) of methylthiopyrimidine was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 292].

g) 1 g (2.3 mmol) of 5- (2,6-dichloroanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine in 60 ml of tetrahydrofuran The solution was treated with 0.8 ml (6 mmol) of triethylamine and the mixture was added dropwise to a 1.8 ml solution of phosgene (20% in toluene) in 40 ml of tetrahydrofuran. Cooling was removed. After 2 hours, 100 ml of saturated aqueous ammonium chloride solution were added. The mixture was separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using diethyl ether / hexane (1: 2) as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1- [3- (2-chloroethyl) phenyl] pyrimido [4, 0.5 g (50%) of 5-d] pyrimidin-2 (1H) -one was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 479].

h) 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1- [3- (2-chloroethyl) phenyl] pyrimido [4,5 in 30 ml of dimethylformamide 0.5 g (1.1 mmol) of a solution of pyrimidin-2 (1H) -one was treated with 0.2 g (1.1 mmol) of phthalimide potassium salt and the mixture was heated at 80 ° C. for 2 hours. The cooled mixture was evaporated and partitioned between 40 ml of dichloromethane and 40 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel using diethyl ether / hexane (1: 1) as eluent. Fractions containing product were combined and evaporated to 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] -pyrimido [ 0.43 g (70%) of 4,5-d] pyrimidin-2 (1H) -one was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 590].

i) 3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5 in 20 ml of dichloromethane A solution of 400 mg (0.68 mmol) of pyrimidin-2 (1H) -one was treated with 470 mg (1.36 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of dichloromethane were added and the phases were separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyridine 370 mg (88%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 622].

Example 38

3- (2,6-dichlorophenyl) -7-anilino-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] in 5 ml of ethanol A solution of 30 mg (0.05 mmol) of pyrimidin-2 (1H) -one was treated with 0.02 ml of hydrazine hydrate. After 5 h the mixture was evaporated and 10 ml of dichloromethane were added to the residue. The resulting suspension was filtered and the filtrate was evaporated. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (2-aminoethyl) -phenyl] -7-anilino-3- 12 mg (50%) of (2,6-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid at a melting point of 208 ° C.

Example 39

250 mg (0.98 mmol) and 4- [2- 3-methyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one A mixture of 560 mg (2.7 mmol) of (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was then triturated in hexane, filtered and dried to 7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1,3-dimethylpyrimido [4,5 -d] 23 mg (7%) of pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 186 ° C.

3-Methyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material is methylamine instead of cyclohexylamine 3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido- [4,5-d] pyrimidine-2 (1H) (as a 2M solution in tetrahydrofuran) Prepared in a similar manner to that described in Example 4 for) -on.

Example 40

160 mg (0.45) 3- (2-chloro-6-methylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one mmol) and 4- [2- (diethylamino) ethoxy] aniline 300 mg (1.4 mmol) were heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 30 ml of dichloromethane and washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was also purified by HPLC. Mobile phase was water / 0.1% trifluoroacetic acid (A) and acetonitrile / 0.07% trifluoroacetic acid (B); Gradient was 5% to 95% B for 20 minutes; The product was detected at wavelength 215 nm using an ultraviolet detector. The fraction containing the product was lyophilized and the lyophilisate was dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-chloro-6- Methylphenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)- On 5 mg (2%) were obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 495].

3- (2-chloro-6-methylphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)-used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1 using 2-chloro-6-methylaniline instead of 2,6-difluoroaniline Prepared in a manner similar to that described in Example 35 for -methylpyrimido [4,5-d] pyrimidin-2 (1H) -one.

Example 41

3-isopropyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) one 350 mg (1.2 mmol) and 4- [2- A mixture of 500 mg (2.4 mmol) of (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered and dried to give 7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-3-isopropyl-1-methylpyrimido [4, 40 mg (8%) of 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 154 ° C.

3-isopropyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material in place of cyclohexylamine Example 4 for 3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one using isopropylamine It was prepared in a manner similar to that described in.

Example 42

3- (2,6-dichlorophenyl) -1- [2-cyclohexene-1 (RS) -yl] -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidine A mixture of 70 mg (0.15 mmol) of 2-2 (1H) -one and 150 mg (0.7 mmol) of 4- [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue is then dissolved in 30 ml of dichloromethane, each washed twice with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl) -1- [2-cyclohexene -1 (RS) -yl] -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H 5 mg (22%) of) -one were obtained as an orange gum. [Mass spectrum (ESI) MH ⁺ = 581].

3- (2,6-dichlorophenyl) -1- [2-cyclohexene-1 (RS) -yl] -7-methanesulfonyl-3,4-dihydropyrimido [4,5 used as starting material -d] pyrimidin-2 (1H) -one was prepared as follows:

200 mg of 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 12 ml of dimethylformamide ( 0.54 mmol) of ice-cold solution was treated with 22 mg (0.54 mmol) of sodium hydride (60% w / w). After 30 minutes the mixture was treated with 0.07 ml (0.6 mmol) of 3-bromocyclohexene and then heated at reflux for 4 hours. The mixture was evaporated and 30 ml of dichloromethane and 30 ml of water were added to the residue. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to 3- (2,6-dichlorophenyl-1- [2-cyclohexene-1 (RS) -yl] -7-methane 70 mg (29%) of sulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a brown oil [Mass Spectrum (ESI) MH ⁺ = 453 ].

Example 43

200 mg (0.5 mmol) of 3- (2-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one And 208 mg (1 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -7- [4- [2- (diethyl Amino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 22 mg (8%) with milky solid at 144 ° C Obtained as

3- (2-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [2-bromoaniline was used instead of 2,6-difluoroaniline [ Prepared in a similar manner to that described in Example 35 for 4,5-d] pyrimidin-2 (1H) -one.

Example 44

200 mg (0.52 mmol) of 3- (2,5-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one ) And a mixture of 218 mg (1.04 mmol) of 4- (2- (diethylamino) ethoxy) aniline were heated at 180 ° C. for 30 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,5-dichlorophenyl) -7- [4- [2- (di Ethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 15 mg (6%) at a melting point of 138 ° C. white Obtained as a solid. [Mass spectrum (ESI) MH ⁺ = 514].

3- (2,5-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyri using 2,5-dichloroaniline instead of 2,6-difluoroaniline Prepared in a manner similar to that described in Example 35 with respect to middo [4,5-d] pyrimidin-2 (1H) -one.

Example 45

200 mg (0.5 mmol) of 3- (3-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one And 300 mg (1.4 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 35 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (3-bromophenyl) -7- [4- [2- (diethylamino 30 mg (11%) of ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one as an off-white solid with a melting point of 150 ° C Obtained.

3- (3-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido using 3-bromoaniline instead of 2,6-difluoroaniline [ Prepared in a similar manner to that described in Example 35 for 4,5-d] pyrimidin-2 (1H) -one.

Example 46

380 mg (1.1 mmol) 3- (2-methoxyphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one And a mixture of 3 ml of aniline was heated at 180 ° C. for 45 minutes, then cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed on silica gel with dichloromethane / methanol as eluent in a gradient of 99: 1 to 20: 1. Fractions containing product were combined and evaporated to yield an off-white solid, 7-anilino-3,4-dihydro-3- (2-methoxyphenyl) -1-methylpyrimido [4,5-d] pyri, at 225 ° C. Midin-2 (1H) -one was obtained.

3- (2-methoxyphenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3- (2,6-difluorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido using 2-methoxyaniline instead of 2,6-difluoroaniline [ Prepared in a similar manner to that described in Example 35 for 4,5-d] pyrimidin-2 (1H) -one.

Example 47

3- (2-methoxyphenyl) -7-anilino-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H)-in 15 ml of 48% aqueous hydrobromic acid solution Warm 50 mg (0.14 mmol) of the solution was heated at reflux for one hour. The mixture was cooled and evaporated and the residue triturated in hexanes. The resulting solid was filtered and dried to give 7-anilino-3,4-dihydro-3- (2-hydroxyphenyl) -1-methylpyrimido [4,5-d] pyrimidine-2 (1H)- 40 mg (82%) were obtained as an off-white solid with a melting point of 192 ° C.

Example 48

200 mg (0.55 mmol) of 3- (4-methoxybenzyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one And a mixture of 300 mg (1.4 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 20 minutes and then cooled. The residue was column chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered and dried to afford 7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-3- (4-methoxybenzyl) -1-methyl 20 mg (7%) of pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 112 ° C.

3- (4-methoxybenzyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H using 4-methoxybenzylamine instead of cyclohexylamine Prepared in a similar manner to that described in Example 4 for) -on.

Example 49

3- (2-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidine-2 A mixture of 300 mg (0.6 mmol) of (1H) -one and 1.5 ml of 4-methoxybenzylamine was heated at 100 ° C. for one hour. The mixture was cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M aqueous hydrochloric acid solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 10 ml of trifluoroacetic acid and then heated under reflux for 3 hours. The mixture was cooled and evaporated and the residue was partitioned between 25 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated and the residue was column chromatography on silica gel using ethyl acetate as eluent. Fractions containing product were combined and evaporated to 7-amino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4,5- d] 105 mg (40%) of pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 154 ° C.

3- (2-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d used as starting material ] Pyrimidin-2 (1H) -one was prepared as follows:

a) A solution of 2.5 g (8.65 mmol) of 5-formyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine in 120 ml of toluene was charged with 1.5 g of 2-bromoaniline ( 9.3 mmol) and 100 mg (0.5 mmol) of 4-toluenesulfonic acid monohydrate and then heated with azeotropic removal of water for 1 hour under reflux. The cooled mixture was evaporated and the residue dissolved in 4 ml of tetrahydrofuran. The resulting solution was added dropwise to a 9 ml (9 mmol) solution of lithium aluminum hydride (as a 1M solution in tetrahydrofuran) in 40 ml of tetrahydrofuran. After 1 hour, the reaction was quenched by carefully dropwise addition of 0.35 ml of water, 0.35 ml of 2M aqueous sodium hydroxide solution and 1 ml of water. The resulting suspension was filtered through a filter and the filtrate was evaporated. The residue was partitioned between 150 ml of ethyl acetate and 50 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to 3.5 g (91%) of 5- (2-bromoanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine ) Was obtained as an orange gum. [Mass spectrum (ESI) MH ⁺ = 444].

b) a solution of 3.5 g (7.9 mmol) of 5- (2-bromoanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine in 100 ml of dichloromethane Treated with 3.3 g (39 mmol) of dihydropyran and 15 mg (0.08 mmol) of 4-toluenesulfonic acid monohydrate. After 18 hours the mixture was treated with 100 mg (0.4 mmol) of pyridinium 4-toluenesulfonate. After another 3 days, 100 ml of ether and 100 ml of 50% saturated brine were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to 5- (2-bromoanilino) methyl-4- [3- (2- (tetrahydropyran-2-yl) oxyethyl] phenylamino-2-methylthio 2.6 g (62%) of pyrimidine were obtained as a yellow oil [mass spectrum (ESI) MH ⁺ = 529].

c) 5- (2-bromoanilino) methyl-4- [3- (2- (tetrahydropyran-2-yl) oxyethyl] phenylamino-2-methylthiopyrimidine 2.6 in 60 ml of tetrahydrofuran 2.6 A solution of g (4.9 mmol) was treated with 2 ml (14.4 mmol) of triethylamine and the mixture was added dropwise to an ice-cooled solution of 3 ml of phosgene (20% in toluene) in 20 ml of tetrahydrofuran. 50 ml of aqueous solution were added, the organic phase was separated, dried over magnesium sulfate, filtered and evaporated The residue was dissolved in 100 ml of methanol and 20 ml of saturated hydrochloric acid solution in ethyl acetate was added 10 minutes later the mixture was evaporated to 3- ( 2-bromophenyl) -7-methylthio-3,4-dihydro-1- (3- (2-hydroxyethyl) phenyl) -pyrimido [4,5-d] pyrimidine-2 (1H) 1.8 g (78%) of -one was obtained as an off-white solid [mass spectrum (ESI) MH ⁺ = 471].

d) 3- (2-bromophenyl) -7-methylthio-3,4-dihydro-1- (3- (2-hydroxyethyl) phenyl) -pyrimido [4,5 in 60 ml of dichloromethane -d] A solution of 1.4 g (3 mmol) of pyrimidin-2 (1H) -one was treated with 2 g (6 mmol) of 3-chloroperbenzoic acid (50% w / w water). After 18 hours 40 ml of saturated aqueous sodium bicarbonate solution were added. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -7-methanesulfonyl-3,4-dihydro-1- (3- (2-hydroxyethyl) phenyl] pyrimido 1.45 g (100%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid [mass spectrum (ESI) MH ⁺ = 503].

Example 50

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyridine in 20 ml of ethanol A solution of 200 mg (0.31 mmol) of midin-2 (1H) -one was treated with 0.3 ml of hydrazine hydrate. After 20 hours the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- 45 mg (28%) of (2-bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid at a melting point of 130 ° C.

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] used as starting material 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1 using pyrimidin-2 (1H) -one as 2-bromoaniline instead of 2,6-dichloroaniline Prepared in a similar manner to that described in Example 37 for-[3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one.

Example 51

7-anilino-3,4-dihydro-3- (2,6-dimethylphenyl) -1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] in 30 ml of ethanol A solution of 500 mg (0.86 mmol) of pyrimidin-2 (1H) -one was treated with 0.8 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with hexane and then filtered to give 1- [3- (2-aminoethyl) phenyl] -7-anilino-3,4-dihydro-3- (2,6-dimethylphenyl) -pyrimido [4 10 mg (3%) of, 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 128 ° C.

7-anilino-3,4-dihydro-3- (2,6-dimethylphenyl) -1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d used as starting material ] Pyrimidin-2 (1H) -one with 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro using 2,6-dimethylaniline instead of 2,6-dichloroaniline Prepared in a similar manner to that described in Example 37 for -1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one.

Example 52

7-anilino-3- (2-chloro-4-trifluoromethylphenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4, in 20 ml of ethanol A solution of 155 mg (0.23 mmol) of 5-d] pyrimidin-2 (1H) -one was treated with 0.3 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with hexane and filtered to give 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2-chloro-4-trifluoromethylphenyl) -3,4-dihydropyri 40 mg (32%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 102 ° C.

7-anilino-3- (2-chloro-4-trifluoromethylphenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4 used as starting material , 5-d] pyrimidin-2 (1H) -one using 2-chloro-4-trifluoromethylaniline instead of 2,6-dichloroaniline 7-anilino-3- (2,6-dichlorophenyl ) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one similar to that described in Example 37 Prepared in the manner.

Example 53

7-anilino-1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4- in 30 ml of tetrahydrofuran A solution of 1.2 g (1.7 mmol) of dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one was treated with 2.25 ml (2.25 mmol) of tetrabutylammonium fluoride (1M in tetrahydrofuran) It was. The mixture was heated at reflux for 5 hours, cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 2M aqueous hydrochloric acid solution. The organic phase was washed with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a gradient elution of dichloromethane / methanol 100: 1 to dichloromethane / methanol 100: 5. Fractions containing product were evaporated to 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4, 5-d] pyrimidin-2 (1H) -one 350 mg (42%) were obtained as a gum. [Mass spectrum (ESI) MH ⁺ = 486].

7-anilino-1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4-di used as starting material Hydropyrimido [4,5-d] pyrimidin-2 (1H) -one was prepared as follows:

a) solution of 3.4 g (11.7 mmol) of 5-formyl-4- (3- (2-hydroxyethyl) phenylamino) -2-methylthiopyrimidine of Example 37 (e) in 50 ml of dimethylformamide Was treated with 3.9 g (14 mmol) of tert-butyldiphenylchlorosilane, 2.4 g (35 mmol) of imidazole and 50 mg (0.4 mmol) of 4- (dimethylamino) pyridine. The mixture was stirred for 18 hours and then evaporated. The residue was partitioned between 150 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid solution. The organic phase was washed with 100 ml of additional 2M aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to 4- (3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenylamino) -5-formyl- 6.2 g (100%) of 2-methylthiopyrimidine was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 528].

b) 2.6 g (5 mmol) of 4- (3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenylamino) -5-formyl-2-methylthiopyrimidine in 80 ml of toluene and 2- A mixture of 0.63 ml (722 mg, 5.1 mmol) of chloro-6-methylaniline was treated with 170 mg (0.9 mmol) of 4-toluenesulfonic acid monohydrate and then heated for 2 hours with azeotropic removal of water under reflux. The mixture was cooled and evaporated. The residue was dissolved in 20 ml of tetrahydrofuran and 30 ml of tetrahydrofuran was added dropwise to a solution of 5 ml (5 mmol) of lithium aluminum hydride (1M in tetrahydrofuran). After stirring for 1 hour, the reaction was quenched by careful dropwise addition of 1.5 ml of water, 2 ml of 2M aqueous sodium hydroxide and 2.5 ml of water. The mixture was filtered through a filter and the filtrate was evaporated to afford 4- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] amino-5- (2-chloro-6-methylanilino) methyl-2 3.3 g (100%) of methylthiopyrimidine was obtained as a yellow oil and used without further purification. [Mass spectrum (ESI) MH ⁺ = 653].

c) 4- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] amino-5- (2-chloro-6-methylanilino) methyl-2-methyl in 50 ml of tetrahydrofuran A solution of 3.3 g (5 mmol) of thiopyrimidine was treated with 1.4 ml (10 mmol) of triethylamine and the resulting mixture was added to a solution of 5 ml (9.6 mmol) of phosgene (20% in toluene) in 30 ml of tetrahydrofuran. Added dropwise. The mixture was stirred at rt for 24 h and then further heated at reflux for 18 h. The mixture was cooled and evaporated. The mixture was partitioned between 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to 1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4- 1.58 g (47%) of dihydro-7-methylthio-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid. [Mass spectrum (ESI) MH ⁺ = 679].

d) 1- [3- (2-tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4-dihydro-7- in 40 ml of dichloromethane A solution of 1.58 g (2.3 mmol) of methylthio-pyrimido [4,5-d] pyrimidin-2 (1H) -one with 1.6 g (4.3 mmol) of 3-chloroperbenzoic acid (50% w / w water) Treated. After 18 hours 40 ml of saturated aqueous sodium bicarbonate solution were added. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was recrystallized from ethanol to give 1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4-dihydro-7- 1.1 g (67%) of methanesulfonyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 711].

e) 1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4-dihydro-7-methanesulfonyl- A mixture of 1.1 g (1.5 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one and 3 ml of aniline was heated at 180 ° C. for 20 minutes. The mixture was cooled and added to 50 ml of 2M aqueous hydrochloric acid solution. The resulting suspension is filtered and the solid is washed with water and dried to give 1- [3- (2- (tert-butyldiphenylsilyloxy) ethyl) phenyl] -7-anilino-3- (2-chloro-6- 1.2 g (100%) of methylphenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a tan solid. [Mass spectrum (ESI) MH ⁺ = 724].

Example 54

7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d in 10 ml of ethanol ] 250 mg (0.4 mmol) solution of pyrimidin-2 (1H) -one was treated with 0.5 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was then triturated with hexane and filtered to give 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydropyrimido [ 30 mg (15%) of 4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 192 ° C.

7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5- used as starting material d] pyrimidin-2 (1H) -one was prepared as follows:

a) 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4, in 15 ml of dichloromethane 5-d] pyrimidin-2 (1H) -one (prepared in Example 53) 200 mg (0.41 mmol) of a solution of 0.12 ml (0.82 mmol) triethylamine and 87 mg (0.5 mmol) methanesulfonic anhydride Treated with. After 18 hours the mixture was washed with 30 ml of saturated aqueous sodium bicarbonate solution, filtered and evaporated to 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2- 233 mg (100%) of methanesulfonyloxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a gum. [Mass spectrum (ESI) MH ⁺ = 564].

b) 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyrimido in 10 ml of dimethylformamide A solution of 233 mg (0.41 mmol) of [4,5-d] pyrimidin-2 (1H) -one was treated with 100 mg (0.54 mmol) of potassium phthalimide and the mixture was heated at 90 ° C. for 3 hours. The mixture was cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyridine 250 mg (99%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 615].

Example 55

7-anilino-3- (2,5-dichlorophenyl) -3,4-dihydro-1- [3-(2-phthalimidoethyl) phenyl] pyrimido [4,5-d] in 15 ml of methanol A solution of 90 mg (0.14 mmol) of pyrimidin-2 (1H) -one and 0.07 ml of hydrazine hydrate was stirred at room temperature under atmospheric pressure for 18 hours. The reaction was evaporated and the residue was purified by flash column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated again with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- ( 37 mg (52%) of 2,5-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid at a melting point of 120 to 123 ° C. . [Mass spectrum (ESI) MH ⁺ = 505].

7-anilino-3- (2,5-dichlorophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d used as starting material ] Pyrimidin-2 (1H) -one in a manner similar to that described in Example 54, 7-anilino-3- (2,5-dichlorophenyl) -3,4-dihydro-1- [3- (2 -Hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one (2,5-dichloroaniline instead of 2-chloro-6-methylaniline as in Example 53 Prepared in a similar manner).

Example 56

3- (2-Bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidine- 200 mg (0.40 mmol) of 2 (1H) -one were treated with 250 mg (1.2 mmol) of 4- [2- (diethylamino) ethoxy] aniline and the mixture was heated at 180 ° C. for 40 minutes. The mixture was cooled and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -7- [4- [2- (diethylamino 45 mg () ethoxy] anilino] -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one 18%) was obtained as a white solid with a melting point of 98 ° C.

3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5- used as starting material d] pyrimidin-2 (1H) -one was prepared as follows:

a) 5- (2-bromoanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine (instead of 2,6-dichloroaniline in 100 ml of dichloromethane) 5- (2,6-dichloroanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine of Example 37 (f) using 2-bromoaniline Prepared in a similar manner to that for 3.5 g (7.9 mmol) of a solution of 3.3 g (39 mmol) of 2,3-dihydropyran and 15 mg (0.08 mmol) of toluenesulfonic acid monohydrate and the mixture at room temperature. Stir for three days. Then 100 ml of diethyl ether and 100 ml of brine were added. The mixture was separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. Purified by flash chromatography on silica gel using diethyl ether and hexane in a 1: 1 ratio as eluent, to obtain 5- (2-bromoanilino) methyl-4- [3- (2- (tetrahydropyranyloxy) ethyl 2.6 g)) phenyl] amino-2-methylthiopyrimidine was obtained as a yellow oil. [Mass spectrum (ESI) MH ⁺ = 529].

b) 2.6 g of 5- (2-bromoanilino) methyl-4- [3- (2- (tetrahydropyranyloxy) ethyl) phenyl] amino-2-methylthiopyrimidine in 40 ml of tetrahydrofuran ( 4.9 mmol) was treated with 2 ml (14.4 mmol) of triethylamine and the resulting solution was added dropwise to an ice cold solution of phosgene (3 ml of a 20% solution in toluene, 5.8 mmol) in 40 ml of tetrahydrofuran. After one hour 50 ml of saturated ammonium chloride solution were added. The mixture was separated and the organic phase was dried over magnesium sulfate and filtered. To this solution was added 20 ml of saturated hydrogen chloride solution in ethyl acetate. After 10 minutes the solution was evaporated to 3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methylthio-pyrimido [4,5 -d] 1.8 g (78%) of pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 471].

c) 3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methylthio-pyrimido [4,5 in 60 ml of dichloromethane A solution of 1.4 g (3 mmol) of pyrimidin-2 (1H) -one was treated with 2 g (6 mmol) of 3-chloroperbenzoic acid (50% w / w water) and the mixture was stirred for 18 hours. . The mixture was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl 1.45 g (100%) of] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained. [Mass spectrum (ESI) MH ⁺ = 503].

Example 57

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3-((1,1-dimethyl-2- (tert-butyldiphenyl) in 30 ml of tetrahydrofuran A solution of 1.3 g (1.7 mmol) of silyloxy)) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) one was dissolved in 2.1 ml of tetrabutylammonium fluoride (1M in tetrahydrofuran). 2.1 mmol). The mixture was heated at reflux for 5 hours, cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid solution. The organic phase was washed with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a gradient elution of dichloromethane / methanol 100: 1 to dichloromethane / methanol 100: 5. Fractions containing product were evaporated and the residue was recrystallized from ethyl acetate to give 7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3-((1,1-dimethyl-2 500 mg (54%) of -hydroxy) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) one were obtained as a milky solid at a melting point of 178 ° C. [Mass spectrum (ESI) MH ⁺ = 545].

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3-((1,1-dimethyl-2- (tert-butyldiphenylsilyl) used as starting material Oxy)) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) one to 5-formyl-4- (3- (2-hydroxyethyl) phenylamino) -2-methylthio 5-formyl-4- (3-((1,1-dimethyl-2-hydroxy) ethyl) phenylamino) 2-methylthiopyrimidine and 2 instead of 2-chloro-6-methylaniline instead of pyrimidine 7-anilino-3- (2-chloro-6-methylphenyl) -3,4-dihydro-1- [3- (2- (tert-butyldiphenyl) of Example 53 starting from bromoaniline Prepared in a similar manner to silyloxy) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one.

5-formyl-4- (3-((1,1-dimethyl-2-hydroxy) ethyl) phenylamino) -2-methylthiopyrimidine was replaced with 3-nitrophenylacetate and ethyl (2,2-dimethyl Prepared in a similar manner to 5-formyl-4- (3- (2-hydroxyethyl) phenylamino) -2-methylthiopyrimidine of Example 37 using -2- (3-nitrophenyl)) acetate It was.

Ethyl (2,2-dimethyl-2- (3-nitrophenyl)) acetate was prepared as follows:

A solution of 5 g (24 mmol) of ethyl 3-nitrophenylacetate in 20 ml of tetrahydrofuran was added dropwise to a suspension of 2.88 g (72 mmol) of sodium hydride (60% w / w) in 80 ml of tetrahydrofuran. After 30 minutes 3.6 ml (57 mmol) of iodomethane were added dropwise and the resulting brown suspension was stirred for 1 hour. 50 ml of saturated aqueous ammonium chloride solution and then 50 ml of ethyl acetate were carefully added. The mixture was separated and the organic phase was washed with 50 ml brine, dried over magnesium sulfate, filtered and evaporated to give 5.5 g (97%) of ethyl (2,2-dimethyl-2- (3-nitrophenyl)) acetate as a brown oil. It was. [Mass spectrum (ESI) MH ⁺ = 238].

Example 58

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3-((1,1-dimethyl-2-phthalimido) ethyl) phenyl] pyridine in 10 ml of ethanol A solution of 250 mg (0.37 mmol) of middo [4,5-d] pyrimidin-2 (1H) one was treated with 0.5 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane to give 1- [3-((2-amino-1,1-dimethyl) ethyl) phenyl] -7-anilino-3- (2-bromophenyl) -3,4-dihydropyri 40 mg (20%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 188 ° C.

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3-((1,1-dimethyl-2-phthalimido) ethyl) phenyl] used as starting material Pyrimido [4,5-d] pyrimidin-2 (1H) one was prepared in a similar manner as used in Example 54 to 7-anilino-3- (2-bromophenyl) -3,4-dihydro- Prepared from 1- [3-((1,1-dimethyl-2-hydroxy) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one (prepared in Example 57) It was.

Example 59

3- (2-Bromophenyl) -7-methanesulfonyl-3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5- prepared from Example 50 d] A solution of 130 mg (0.31 mmol) of pyrimidin-2 (1H) -one was treated with 1 g (8 mmol) of 4-methoxyaniline. The mixture was heated at 120 ° C. for 2 hours. The mixture was cooled and treated with 30 ml of 2M aqueous hydrochloric acid solution. The suspended solids were filtered off, washed with water and dried. The solid was dissolved in 20 ml of ethanol and treated with 0.2 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (2-aminoethyl) phenyl] -3- (2-bromophenyl ) -7- (4-methoxyanilino) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one 35 mg (31%) at a melting point of 132-133 ° C. Obtained as a white solid.

Example 60

1- [3- (2-aminoethyl) phenyl] -3- (2-bromophenyl) -7- (4-methoxyanilino) -3,4-dihydropyrimido [ 25 mg of 4,5-d] pyrimidin-2 (1H) -one were treated with 2 ml of 40% aqueous hydrobromic acid solution and the mixture was heated at 150 ° C. for 2 hours. The mixture was cooled and evaporated. The residue was triturated in hexane to give 1- [3- (2-aminoethyl) phenyl] -3- (2-bromophenyl) -7- (4-hydroxyanilino) -3,4-dihydropyrimido [ 20 mg (80%) of 4,5-d] pyrimidin-2 (1H) -on hydrobromide were obtained as a white solid with a melting point of 210 ° C. (decomposition).

Example 61

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (phthalimidomethyl) phenyl] pyrimido [4,5-d] pyrimidine- in 10 ml of ethanol A 230 mg solution of 2 (1H) -one was treated with 0.5 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined, evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (aminomethyl) phenyl] -7-anilino-3- (2 Bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one 5 mg (2.8%) was obtained as a white solid at melting point 121 ° C.

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (phthalimidomethyl) phenyl] pyrimido [4,5-d] pyrimidine used as starting material -2 (1H) -one was prepared as follows:

a) A solution of 5 g (33 mmol) of 3-nitrobenzyl alcohol in 100 ml of dimethylformamide was charged with 10.8 g (40 mmol) of tert-butyldiphenylchlorosilane, 6.7 g (99 mmol) and 4- (dimethyl) Treatment with 100 mg (0.9 mmol) of amino) pyridine and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was partitioned between 100 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid solution. The organic phase was washed with additional 50 ml of 2M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated to give 12.9 g (100%) of 3- (tert-butyldiphenylsilyloxymethyl) nitrobenzene as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 392].

b) A solution of 12.9 g (33 mmol) of 3- (tert-butyldiphenylsilyloxymethyl) nitrobenzene in 150 ml of ethanol was treated with 1 g of palladium on 10% activated carbon and then shaken in a hydrogen stream for 18 hours. The mixture was filtered and the filtrate was evaporated to give 12 g (100%) of 3- (tert-butyldiphenylsilyloxymethyl) aniline as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 362].

c) A solution of 2.32 g (10 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 30 ml of 1,4-dioxane was added with 1.4 ml (10 mmol) of triethylamine and 3- (3 It was treated with 4.7 g (13 mmol) of tert-butyldiphenylsilyloxymethyl) aniline. The mixture was heated at 50 ° C. for 18 h and then evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 5.6 g (10 mmol) of ethyl 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -2-methylthiopyrimidine-5-carboxylate. Obtained as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 558].

d) A solution of 5.6 g (10 mmol) of 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -2-methylthiopyrimidine-5-carboxylate in 30 ml of tetrahydrofuran was added with tetrahydro 20 ml of furan was added dropwise to an ice-cooled solution of 10 ml of a lithium aluminum hydride 1M solution in tetrahydrofuran (10 mmol). After an hour, the reaction was carefully quenched by the addition of 1 ml of water, 1.5 ml of 2M aqueous sodium hydroxide solution and 2 ml of water in turn. The mixture was filtered through a hyflo filter and the solids washed thoroughly with tetrahydrofuran. The combined filtrates and washes were evaporated to yield 4.6 g (88%) of 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -5-hydroxymethyl-2-methylthiopyrimidine as a yellow oil. It was. [Mass spectrum (ESI) MH ⁺ = 516].

e) A solution of 7.7 g (15 mmol) of 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -5-hydroxymethyl-2-methylthiopyrimidine in 100 ml of dichloromethane was dissolved in manganese dioxide 13 Treated with g (150 mmol) and stirred the mixture for 18 hours. The product was purified by flash chromatography on silica gel using ethyl acetate / hexane in a 1: 2 ratio as eluent. Fractions containing product were combined and evaporated to give 3.5 g (46%) of 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -2-methylthiopyrimidine-5-carboxaldehyde as a colorless oil. Obtained. [Mass spectrum (ESI) MH ⁺ = 514].

f) A solution of 3.5 g (6.8 mmol) of 4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -2-methylthiopyrimidine-5-carboxaldehyde in 100 ml of toluene was 2-brominated. Treated with 12 g (7 mmol) of moaniline and 100 mg (0.5 mmol) of toluenesulfonic acid monohydrate. The mixture was heated at reflux with azeotropic removal of water for 2 hours, then cooled and evaporated. The residue was dissolved in 20 ml of tetrahydrofuran and then added dropwise to an ice cold solution of 7 ml of 1 M lithium aluminum hydride in tetrahydrofuran (7 mmol) to which 20 ml of tetrahydrofuran was added. After 1 hour, the reaction was carefully quenched by the addition of 1.5 ml of water, 2 ml of 2M aqueous sodium hydroxide solution and 3 ml of water in turn. The mixture was filtered through a hyflo filter and the solid was washed thoroughly with tetrahydrofuran. The combined filtrate and washings were evaporated to give 4.5 g (5-((2-bromoanilino) methyl) -4- [3- (tert-butyldiphenylsilyloxymethyl) anilino] -2-methylthiopyrimidine 100%) was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 670].

g) 4.5 g (6.8 (5-((2-bromoanilino) methyl) -4- [3- (tert-butyldiphenylsilyloxymethyl) anilino) -2-methylthiopyrimidine in 50 ml of toluene) mmol) and 1.9 ml (13.6 mmol) of triethylamine were added dropwise to a solution of 7 ml in a 20% solution of phosgene in toluene (13.6 mmol) with 50 ml of toluene added. The mixture was heated at reflux for 5 hours and then cooled. 50 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate solution were added and the mixture was separated. The organic phase is dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -1- [3- (tert-butyldiphenylsilyloxymethyl) phenyl] -3,4-dihydro-7-methyl 4.7 g (100%) of thio-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 696].

h) 3- (2-bromophenyl) -1- [3- (tert-butyldiphenylsilyloxymethyl) phenyl] -3,4-dihydro-7-methylthio-pyrimido in 100 ml of dichloromethane A solution of 4.7 g (6.8 mmol) of [4,5-d] pyrimidin-2 (1H) -one was treated with 4.6 g (13.6 mmol) of 3-chloroperbenzoic acid (50% w / w water) and the mixture was 18 Stir for hours. 60 ml of saturated aqueous sodium bicarbonate solution were added. The organic phase was dried over magnesium sulfate and evaporated. The residue was recrystallized from ethanol to give 3- (2-bromophenyl) -1- [3- (tert-butyldiphenylsilyloxymethyl) phenyl] -3,4-dihydro-7-methanesulfonyl-pyrimido 4.3 g (87%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 728].

i) 3- (2-bromophenyl) -1- [3- (tert-butyldiphenylsilyloxymethyl) phenyl] -3,4-dihydro-7-methanesulfonyl-pyrimido in 30 ml of methanol A solution of 400 mg (0.55 mmol) of [4,5-d] pyrimidin-2 (1H) -one was treated with 400 mg (11 mmol) of ammonium fluoride and the mixture was heated at reflux for 1 hour. The mixture was evaporated and the product was purified by flash chromatography on silica gel eluting with dichloromethane / methanol at a 20: 1 ratio. Fractions containing product were combined and evaporated to 3- (2-bromophenyl) -3,4-dihydro-1- [3- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4, 257 mg (96%) of 5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 490].

j) 3- (2-bromophenyl) -3,4-dihydro-1- [3- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5- in 15 ml of dichloromethane d] A solution of 257 mg (0.53 mmol) of pyrimidin-2 (1H) -one was treated with 0.15 ml (1.06 mmol) of triethylamine and 104 mg (0.6 mmol) of methanesulfonic anhydride. After 18 hours 10 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -3,4-dihydro-7-methanesulfonyl-1- [3- (methanesulfonyloxymethyl) 250 mg (83%) of phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as colorless oil. [Mass spectrum (ESI) MH ⁺ = 567].

k) 3- (2-bromophenyl) -3,4-dihydro-7- (methanesulfonyl) -1- [3- (methanesulfonyloxymethyl) phenyl] pyrimido in 10 ml of dimethylformamide 250 mg (0.44 mol) solution of 4,5-d] pyrimidin-2 (1H) -one was treated with 111 mg (0.6 mmol) of potassium phthalimide and the mixture was heated at 90 ° C. for 1 hour and then cooled Evaporated. The residue was partitioned between 30 ml of dichloromethane and 30 ml of water. Combine the organic phases, dry with magnesium sulfate, filter and evaporate to 3- (2-bromophenyl) -3,4-dihydro-7- (methanesulfonyl) -1- [3- (phthalimidomethyl) phenyl] pyri 270 mg (99%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 618].

l) 3- (2-bromophenyl) -3,4-dihydro-7-methanesulfonyl-1- [3- (phthalimidomethyl) phenyl] pyrimido [4,5-d] pyrimidine-2 270 mg (0.44 mmol) of (1H) -one were treated with 3 ml of aniline and the mixture was heated at 180 ° C. for 20 minutes and cooled. 20 ml of ethyl acetate and 20 ml of 2M aqueous hydrochloric acid were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (phthalimidomethyl) phenyl] pyrimido [4, 230 mg (83%) of 5-d] pyrimidin-2 (1H) -one were obtained as a tan solid. [Mass spectrum (ESI) MH ⁺ = 632].

Example 62

7-anilino-3- (2-bromophenyl) -1- [3-((tert-butyldiphenylsilyloxy) methyl) phenyl] -3,4-dihydro-pyri in 30 ml of tetrahydrofuran A solution of 1.5 g (2 mmol) of mido [4,5-d] pyrimidin-2 (1H) -one was treated with 2.5 ml (2.5 mmol) of tetrabutylammonium fluoride (1 M in tetrahydrofuran). The mixture was heated at reflux for 5 hours, cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid solution. The organic phase was washed with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane / methanol 100: 1 as eluent. Fractions containing product were evaporated to 7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [3- (hydroxymethyl) phenyl] pyrimido [4,5-d ] 550 mg (55%) of pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 136 ° C. [Mass spectrum (ESI) MH ⁺ = 486].

7-anilino-3- (2-bromophenyl) -1- [3-((tert-butyldiphenylsilyloxy) methyl) phenyl] -3,4-dihydro-pyrido used as starting material [4,5-d] pyrimidin-2 (1H) -one was prepared as follows:

3- (2-bromophenyl) -1- [3- (tert-butyldiphenylsilyloxymethyl) phenyl] -3,4-dihydro-7-methanesulfonyl-pyrimido [4,5-d ] Pyrimidin-2 (1H) -one (prepared in Example 61 (h)) 1.5 g (2 mmol) was treated with 3 ml of aniline and the mixture was heated at 180 ° C. for 20 minutes and cooled. The mixture was poured into 50 ml of 2M aqueous hydrochloric acid solution and the precipitated product was filtered, washed with water and dried to give 7-anilino-3- (2-bromophenyl) -1- [3-((tert-butyldiphenylsilyloxy 1.5 g (100%) of (methyl) phenyl] -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a light brown solid. [Mass spectrum (ESI) MH ⁺ = 741].

Example 63

3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidine-2 ( A mixture of 180 mg (0.37 mmol) and 0.34 ml (3.7 mmol) of 1H) -one was heated at 120 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and then triturated with 5 ml of 2M hydrochloric acid. The pale tan solid was collected by filtration and washed with water followed by diethyl ether. The crude material was purified by flash chromatography on silica gel using 3% methanol in dichloromethane as eluent. Fractions containing product were combined and evaporated to 7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -pyrimido [4,5- d] 65 mg (35%) of pyrimidin-2 (1H) -one were obtained as an off-white solid at melting point of 129-132 ° C. [Mass spectrum (ESI) MH ⁺ = 502].

3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] used as starting material Pyrimidin-2 (1H) -one was prepared as follows:

a) 5.9 g (38.7 mmol) of 4-nitrobenzyl alcohol, 17.6 ml (33.5-dihydro-2H-pyran) and 500 mg (2.6 mmol) of p-toluene sulfonic acid monohydrate in 200 ml of dichloromethane The solution was stirred at rt for 4 h. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel using ethyl acetate / hexane in a 1: 4 ratio as eluent. Fractions containing the product were combined and evaporated to yield 8.52 g (93%) of 2- (4-nitrobenzyloxy) -tetrahydropyran as light yellow oil.

b) A solution of 8.5 g (35.9 mmol) of 2- (4-nitrobenzyloxy) -tetrahydropyran in 150 ml of methanol was hydrogenated for 8 hours in the presence of 800 mg of 10% palladium on carbon at room temperature and atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give a dark yellow oil. Purification by flash column chromatography on silica gel using ethyl acetate / hexane in a 1: 2 ratio as eluent gave 4.8 g (65%) of 4- (tetrahydropyran-2-yloxymethyl) aniline as pale yellow oil. Mass Spectrum (ESI) [M−H + MeCN] ⁺ = 249.

c) 4.25 g (18.26 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate in 1,4-dioxane dried with sieving, 4- (tetrahydropyran-2-yloxymethyl) A solution of 4.73 g (22.85 mmol) and 6.4 ml (45.7 mmol) of triethylamine was heated at 60 ° C. for 4 hours. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried over MgSO ₄ and evaporated to afford a brown oil which was purified by flash chromatography on silica gel using ethyl acetate / water in a 1: 4 ratio as eluent. Fractions containing the product were combined and evaporated to yield 6.68 g (90%) of ethyl 4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine-5-carboxylate as a yellow oil. Obtained. [Mass spectrum (ESI) MH ⁺ = 404].

d) A solution of 6.6 g (16.37 mmol) of ethyl 4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine-5-carboxylate in 100 ml of anhydrous tetrahydrofuran was added. At 0 ° C. was added dropwise to 20.5 ml (20.5 mmol) of lithium aluminum hydride (1M in tetrahydrofuran) in 100 ml of anhydrous tetrahydrofuran. The reaction was warmed to room temperature for 2 hours and then raised to 65 ° C. and then quenched by the addition of 0.75 ml of water, 0.75 ml of 2M sodium hydroxide solution and 2.25 ml of water in turn. The reaction was cooled and then filtered through a filter and the filtrate was evaporated to 4.5 g (75% of 4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-5-hydroxymethyl-2-methylthiopyrimidine ) Was obtained as a yellow semisolid.

e) 4.54 g (12.57 mmol) of 4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-5-hydroxymethyl-2-methylthiopyrimidine in a similar manner to Example 7 (c) The reaction was yielded 4.02 g (89%) of 5-formyl-4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine.

f) 4.0 g (11.1 mmol) of 5-formyl-4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine in a similar manner to Example 37 (f) and 2-bromoaniline is reacted to yield 1.13 g (5- (2-bromoanilino) methyl-4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine %) Was obtained as a pale yellow gum. [Mass spectrum (ESI) MH ⁺ = 515].

g) 0.93 g of 5- (2-bromoanilino) methyl-4- [4- (tetrahydropyran-2-yloxymethyl) phenyl] amino-2-methylthiopyrimidine in 5 ml of anhydrous tetrahydrofuran ( 1.8 mmol) and 0.5 ml (3.61 mmol) of triethylamine were added dropwise to 1.9 ml (3.61 mmol) of a 20% phosgene solution in toluene dissolved in 5 ml of tetrahydrofuran at 0 ° C. under nitrogen stream. The reaction was further stirred at 0 ° C. for 60 minutes and then evaporated. The residue was partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml), the ethyl acetate layer was separated and washed with saturated aqueous sodium bicarbonate solution (10 ml), dried over magnesium sulfate, filtered and evaporated to 3- ( 2-bromophenyl) -3,4-dihydro-1- [4- (tetrahydropyran-2-yloxymethyl) phenyl] -7-methylthio-pyrimido [4,5-d] pyrimidine- 0.945 g (97%) of 2 (1H) -one was obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 541].

h) 3- (2-bromophenyl) -3,4-dihydro-1- [4- (tetrahydropyran-2-yloxymethyl) phenyl] -7- in 10 ml of saturated hydrogen chloride in ethyl acetate A solution of 0.945 g (1.75 mmol) of methylthio-pyrimido [4,5-d] pyrimidin-2 (1H) -one was stirred at room temperature for 2 hours. The reaction was diluted with 10 ml of ethyl acetate, washed with 10 ml of water and 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2-bromophenyl) -3,4-dihydro-1 0.68 g (85%) of-[4- (hydroxymethyl) phenyl] -7-methylthio-pyrimido [4,5-d] pyrimidin-2 (1H) -one was obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 457].

i) 3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -7-methylthio-pyrimido [4,5-d] pyrimidine-2 0.68 g (1.49 mmol) of (1H) -one was reacted with 3-chloroperbenzoic acid in a manner similar to Example 7 (f) to 3- (2-bromophenyl) -3,4-dihydro-1- [ 0.36 g (49%) of 4- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a milky foam. [Mass spectrum (ESI) MH ⁺ = 491].

Example 64

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [4- (phthalimidomethyl) phenyl] pyrimido [4,5-d] pyrimidine- in 5 ml of ethanol A solution of 160 mg (0.253 mmol) of 2 (1H) -one and 0.5 ml of hydrazine hydrate was stirred at room temperature under a stream of nitrogen for 4 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated again with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [4- (aminomethyl) phenyl] -7-anilino-3- (2 -Bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one 55 mg (43%) were obtained as a white solid with a melting point of 133-136 ° C. [Mass spectrum (ESI) MH ⁺ = 501].

7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [4- (phthalimidomethyl) phenyl] pyrimido [4,5-d] pyrimidine used as starting material 7-anilino-3- (2-bromophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl in a manner similar to that described in Example 54, for -2 (1H) -one ] Pyrimido- [4,5-d] pyrimidin-2 (1H) -one (prepared in Example 63).

Example 65

3- (2-bromophenyl) -3,4-dihydro-7-methanesulfonyl-1- (1-naphthyl) pyrimido [4,5-d] pyrimidin-2 (1H) -one 160 A mixture of mg (0.3 mmol) and 200 μl (2.2 mmol) of aniline was heated at 120 ° C. for 2 hours. The residue was partitioned between 10 ml of ethyl acetate and 10 ml of 2M hydrochloric acid, the ethyl acetate layer was separated and then washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2 Bromophenyl) -3,4-dihydro-1- (1-naphthyl) pyrimido [4,5-d] pyrimidin-2 (1H) -one 100 mg (67%) with melting point 120-125 Obtained as an orange solid at ° C. [Mass spectrum (ESI) MH ⁺ = 522].

3- (2-bromophenyl) -3,4-dihydro-7-methanesulfonyl-1- (1-naphthyl) pyrimido [4,5-d] pyrimidine-2 (used as starting material) 1H) -one was prepared from ethyl 4-chloro-2-methylthio-pyrimidin-5-carboxylate and 1-naphthylamine in a similar manner to that described in Example 7.

Example 66

Methyl 3-[[7-benzylsulfonyl-3- (2-bromophenyl) -1,2,3,4-tetrahydro-2-oxopyrimido [4,5-d] pyrimidin-1-yl A mixture of 0.655 g (1.1 mmol) of 0.5] methyl] benzoate and 0.55 ml (6 mmol) of aniline was heated at 100 ° C. for 2 hours. The reaction mixture was partitioned between 10 ml of dichloromethane and 10 ml of 2M hydrochloric acid, the dichloromethane layer was separated, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using ethyl acetate / hexane 1: 1 as eluent. Fractions containing product were combined and evaporated to methyl 3-[[7-anilino-3- (2-bromophenyl) -1,2,3,4-tetrahydro-2-oxopyrimido [4,5-d 120 mg (20%) of] pyrimidin-1-yl] methyl] benzoate were obtained as a white solid with a melting point of 79 to 82 ° C. [Mass spectrum (ESI) MH ⁺ = 546].

Methyl 3-[[7-benzylsulfonyl-3- (2-bromophenyl) -1,2,3,4-tetrahydro-2-oxopyrimido [4,5-d] pyri used as starting material Midin-1-yl] methyl] benzoate was prepared as follows:

a) 650 μl (8.8 mmol) of thionyl chloride was added dropwise to a stirred solution of 1 g (5.8 mmol) of 3- (chloromethyl) benzoic acid in 40 ml of methanol at 0 ° C. under nitrogen stream and then stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in 30 ml of dichloromethane, washed with 2 × 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of brine, dried over magnesium sulfate, filtered and evaporated to 0.94 g of methyl-3- (chloromethyl) benzoate ( 88%) was obtained as a colorless flowing liquid.

b) 1 g of 7-benzylsulfonyl-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one in 20 ml of dimethylformamide (2.2 mmol) was cooled under nitrogen stream at 0 ° C., treated with 112 mg (4.2 mmol) of 60% sodium hydride in mineral oil and then stirred for 30 minutes. 440 mg (2.4 mmol) of methyl-3- (chloromethyl) benzoate were added and the reaction was then heated at 90 ° C. for 3 hours. The solvent was evaporated and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of water, the ethyl acetate layer was separated and washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane in a 1: 1 ratio. Fractions containing product were combined and evaporated to methyl 3-[[7-benzylsulfonyl 3- (2-bromophenyl) -1,2,3,4-tetrahydro-2-oxopyrimido [4,5- d] pyrimidin-1-yl] methyl] benzoate 750 mg (56%) were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 607].

4-amino-5-carb commercially available 7-benzylsulfonyl-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one In a manner similar to that described in Examples 8 (a) to (f), starting from ethoxypyrimidine-2-thiol and using 2-bromoaniline instead of benzyl bromide and 2,6-dichloroaniline instead of iodomethane Prepared.

Example 67

Methyl 3-[[7-anilino-3- (2-bromophenyl) -1,2,3,4-tetrahydro-2 in tetrahydrofuran / methanol / water (6 ml: 6 ml: 1.5 ml) A solution of 90 mg (0.17 mmol) of oxopyrimido [4,5-d] pyrimidin-1-yl] methyl] benzoate was treated with 27 mg (1.125 mmol) of lithium hydroxide monohydrate followed by 3 hours at 60 ° C. Heated under nitrogen stream. The solvent was evaporated and the residue was partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml). The ethyl acetate layer was separated, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3-[[7-anilino-3- (2-bromophenyl) -1,2,3,4 30 mg (35%) of tetrahydro-2-oxopyrimido [4,5-d] pyrimidin-1-yl] methyl] benzoic acid were obtained as a pale yellow solid at a melting point of 180 to 183 ° C. [Mass spectrum (ESI) MH ⁺ = 530].

Example 68

3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro 1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one prepared in Example 7 A mixture of 158 mg (0.35 mmol) and 250 μl (1.9 mmol) of 4-ethoxyaniline was heated at 90 ° C. for 2 hours. The reaction mixture was partitioned between 10 ml of dichloromethane and 10 ml of 2M hydrochloric acid, the dichloromethane layer was separated, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel, eluting ethyl acetate / hexane in 1: 1 ratio. Fractions containing the product were combined and evaporated to 3- (2,6-dichlorophenyl) -7- (4-ethoxyanilino) -3,4-dihydro-1-phenylpyrimido [4,5-d] pyrid 126 mg (71%) of midin-2 (H) -one were obtained as a white solid with a melting point of 224 to 226 ° C. [Mass spectrum (ESI) MH ⁺ = 506].

Example 69

7-anilino-1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -3,4-dihydro in 8 ml of anhydrous tetrahydrofuran A solution of 960 mg (1.29 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one was treated with 1.6 ml of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran at 0 ° C. The reaction was allowed to warm overnight at room temperature. The solvent was evaporated and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid, the ethyl acetate layer was separated, washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 730 mg of a dark brown solid. It was. The crude material was triturated with diethyl ether and the solid collected by filtration and washed with additional diethyl ether to give 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- 240 mg (37%) of [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as an off-white solid above the melting point of 250 ° C. [Mass spectrum (ESI) MH ⁺ = 506].

7-anilino-1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -3,4-dihydro-pyri used as starting material Middo [4,5-d] pyrimidin-2 (1H) -one was prepared as follows:

a) 5- (2,6-dichloroanilino) methyl-4- [3- (2-hydroxyethyl) phenyl] amino-2-methylthiopyrimidine in 5 ml of dimethylformamide (Example 37 (f) Prepared from the solution of 0.8 g (1.84 mmol), 580 μl (2.2 mmol) tert-butylchlorodiphenylsilane, 0.38 mg (5.5 mmol) imidazole and 15 mg of N, N-dimethylaminopyridine under a nitrogen stream. Stir overnight at room temperature. The solvent was evaporated and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of 2M hydrochloric acid, the ethyl acetate layer was separated, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 4- [3- (2 1.36 g of -tert-butyldiphenylsilyloxyethyl) phenyl] amino-5- (2,6-dichloroanilino) methyl-2-methylthiopyrimidine was obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 673].

b) 1.35 g of 4- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] amino-5- (2,6-dichloroanilino) methyl-2-methylthiopyrimidine in 5 ml of anhydrous toluene (2 mmol) and a solution containing 0.85 ml (6 mmol) of triethylamine were added dropwise to 3.2 ml (6 mmol) of a 20% phosgene solution in toluene dissolved in 10 ml of toluene at 0 ° C. under a stream of nitrogen. The reaction was then heated to reflux for 6 hours and then evaporated. The residue was partitioned between 40 ml of ethyl acetate and 40 ml of 2M hydrochloric acid, the ethyl acetate layer was separated, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 1- [3- (grades 2-3). -Butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H)- 1.5 g of warm was obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 699].

c) 1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -7-methylthio-3,4-dihydropyrimido [4, 1.4 g (2 mmol) of 5-d] pyrimidin-2 (1H) -one are reacted with 3-chloroperbenzoic acid in a manner similar to that described in Example 7 (f) to give 1- [3- (2-tertiary) -Butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H) 0.98 g (67%) of -temperature was obtained as a milky solid. [Mass spectrum (ESI) MH ⁺ = 731].

d) 1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydropyrimido [4 A mixture of 980 mg (1.22 mmol) and 5 ml of aniline, 5-d] pyrimidin-2 (1H) -one, was heated at 100 ° C. for 30 minutes. The reaction was cooled and then poured into 50 ml of 2M hydrochloric acid. The product was collected by filtration, washed with 50 ml of water followed by 50 ml of hexane and dried to 7-anilino-1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2 960 mg (96%) of, 6-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a pale tan solid. [Mass spectrum (ESI) MH ⁺ = 744].

Example 70

7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyridine in 5 ml of 33% methylamine in ethanol A solution of 125 mg (0.214 mmol) of mid [4,5-d] pyrimidin-2 (1H) -one was heated at 60 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of 120: 14: 3: 2. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2,6-dichlorophenyl) -3,4-di 38 mg (34%) of hydro-1- [3- (2-methylamino) ethyl] phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one at a melting point of 122 to 125 ° C. as a white solid Obtained as [Mass spectrum (ESI) MH ⁺ = 519].

7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyrimido [4,5 used as starting material -d] pyrimidin-2 (1H) -one was prepared in Example 69 with 7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- (2- Hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one was prepared in a similar manner as described in Example 54 (a).

Example 71

7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyrimido in 5 ml of 33% dimethylamine in ethanol A solution of 125 mg (0.214 mmol) of [4,5-d] pyrimidin-2 (1H) -one (prepared as described in Example 70) was heated at 60 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of (120: 14: 3: 2). Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2,6-dichlorophenyl) -3,4-di 18 mg (16%) of hydro-1- [3- (2-dimethylamino) ethyl] phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one at a melting point of 101 to 105 ° C. Obtained as [Mass spectrum (ESI) MH ⁺ = 533].

Example 72

3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidine A mixture of 1.09 g (2.2 mmol) and -2 (1H) -one and aniline was heated at 120 ° C. for one hour. The reaction mixture was partitioned between 20 ml of dichloromethane and 20 ml of 2M hydrochloric acid, the dichloromethane layer was separated, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using 5: 1 ethyl acetate / hexanes as eluent. Fractions containing product were combined and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4, 630 mg (55%) of 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 213 to 217 ° C. [Mass spectrum (ESI) MH ⁺ = 506].

3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5 used as starting material -d] pyrimidin-2 (1H) -one was prepared as follows:

a) 1- [3- (2-tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,4-dichlorophenyl) -3,4-dihydro-7-methylthio-pyrimido [4 , 5-d] pyrimidin-2 (1H) -one (prepared in a manner similar to that described in Examples 53 (a) and (b) using 2,4-dichloroaniline instead of 2-chloro-6-methylaniline) 1.97 g (2.83 mmol) was reacted with a tetrabutylammonium fluoride 1M solution in a similar manner as described in Example 69. 3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methylthio-pyrimido [4,5-d] pyrimidine- 1.3 g (100%) of 2 (1H) -one were isolated as a yellow solid. [Mass spectrum (ESI) MH ⁺ = 461].

b) 3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methylthio-pyrimido [4,5-d] pyrid 1.3 g (2.8 mmol) of midin-2 (1H) -one was reacted with 3-chloroperbenzoic acid in a similar manner as described in Example 7 (f) to 3- (2,4-dichlorophenyl) -3,4- 1.1 g (78%) of dihydro-1- [3- (2-hydroxyethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidin-2 (1H) -one as milky white Obtained as a solid. [Mass spectrum (ESI) MH ⁺ = 493].

Example 73

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5 in 5 ml of dichloromethane / methanol A solution of 370 mg (0.6 mmol) of pyrimidin-2 (1H) -one and 0.3 ml (6 mmol) of hydrazine hydrate was stirred overnight at room temperature under a nitrogen stream. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of (120: 14: 3: 2). Fractions containing the product were combined and evaporated and the residue was evaporated again with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- 100 mg (33%) of (2,4-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one are obtained as a white solid having a melting point of 131 to 135 ° C. It was. [Mass spectrum (ESI) MH ⁺ = 505].

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d used as starting material ] Pyrimidin-2 (1H) -one in a similar manner as described in Example 54 to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2 -Hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one (prepared in Example 72).

Example 74

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyri in 4 ml of 40% methylamine in ethanol A solution of 120 mg (0.2 mmol) of mido [4,5-d] pyrimidin-2 (1H) -one was heated at 50 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of 120: 14: 3: 2. Fractions containing product were combined and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2- (methylamino) ethyl] phenyl] pyrimido [ 18 mg (16%) of 4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 120 to 122 ° C. [mass spectrum (ESI) MH ⁺ = 519].

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyrimido [4,5 used as starting material -d] pyrimidin-2 (1H) -one in a similar manner as described in Example 54 (a) to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- Prepared from [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one (prepared in Example 72).

Example 75

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] pyri in 4 ml of 33% dimethylamine in ethanol A solution of 204 mg (0.35 mmol) of mino [4,5-d] pyrimidin-2 (1H) -one (prepared in Example 74) was heated at 40 ° C. for 2 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of 120: 14: 3: 2. Fractions containing product were combined and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-dimethylamino) ethyl) phenyl] pyrimido [4 80 mg (43%) of, 5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 101-105 ° C. [Mass spectrum (ESI) MH ⁺ = 533].

Example 76

240 mg of 7-benzylsulfonyl-3- (2-bromophenyl) -1-cyclohexylmethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 0.4 mmol) and 0.39 ml (4.3 mmol) of aniline were heated at 150 ° C. for 2 hours. The reaction mixture was cooled to room temperature and then partitioned between 20 ml of 2M hydrochloric acid and 20 ml of dichloromethane. The organic layer was separated, washed with 20 ml of saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using ethyl acetate / hexane 1: 2 as eluent. The fractions containing the product were combined and evaporated to 7-anilino-3- (2-bromophenyl) -1-cyclohexylmethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 ( 80 mg (42%) of 1H) -one were obtained as an off-white solid with a melting point of 200 to 202 ° C. [Mass spectrum (ESI) MH ⁺ = 492].

7-benzylsulfonyl-3- (2-bromophenyl) -1-cyclohexylmethyl-3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) used as starting material -On was prepared in Example 66 in a similar manner as described in Example 66 (b) 7-benzylsulfonyl-3- (2-bromophenyl) -3,4-dihydropyrimido [4,5- d] prepared from pyrimidin-2 (1H) -one and bromomethylcyclohexane.

Example 77

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [4- (2-phthalimidoethyl) phenyl]-in methanol / dichloromethane (3 ml: 3 ml) A solution of 195 mg (0.3 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one and 150 μl (3 mmol) of hydrazine hydrate was stirred at room temperature overnight under a nitrogen stream. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / acetic acid / water in a ratio of (120: 14: 3: 2). Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 1- [4- (2-aminoethyl) phenyl] -7-anilino-3- 90 mg (67%) of (2,4-dichlorophenyl) -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one are obtained as a white solid at a melting point of 117-121 ° C. It was. [Mass spectrum (ESI) MH ⁺ = 505].

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [4- (2-phthalimidoethyl) phenyl] -pyrimido [4,5- used as starting material d] Pyrimidin-2 (1H) -one in ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate and 4- [2- (tert-butyldiphenyl) in a manner similar to that described in Example 63. Prepared from silyloxy) ethyl] aniline. 2,4-dichloroaniline was used in place of 2-bromoaniline in step 63 (f).

4- [2- (tert-butyldiphenylsilyloxy) ethyl] aniline was prepared as follows:

3 g (18 mmol) of 4-nitrophenylalcohol in 20 ml of dimethylformamide, 5.2 ml (20 mmol) of tert-butylchlorodiphenylsilane, 3.05 g (45 mmol) of imidazole and 438 N, N-dimethylaminopyridine A solution of mg (3.5 mmol) was stirred for 3 hours at room temperature under a stream of nitrogen. The solvent was evaporated and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of 2M hydrochloric acid. The ethyl acetate layer was separated, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to yield 6.56 g of 4- [2- (tert-butyldiphenylsilyloxy) ethyl] nitrobenzene as a yellow gum. It was.

A solution of 6.5 g (16 mmol) of 4- [2- (tert-butyldiphenylsilyloxy) ethyl] nitrobenzene in 30 ml of methanol containing 750 mg of palladium on 10% carbon was hydrogenated at room temperature and atmospheric pressure for 2 hours. It was. The catalyst was removed by filtration and the solvent was evaporated to yield 5.7 g of 4- [2- (tert-butyldiphenylsilyloxy) ethyl] phenylamine as a colorless liquid. [Mass spectrum (ESI) MH ⁺ = 376].

Example 78

3- (2,4-dichlorophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d] pyrimidine-2 A mixture of 350 mg (0.7 mmol) of (1H) -one and 2 ml of aniline was heated at 120 ° C. for 3 hours. The reaction mixture was cooled at room temperature and then partitioned between 20 ml of 2M hydrochloric acid and 20 ml of dichloromethane. The organic layer was separated, washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [4- 200 mg (57%) of (hydroxymethyl) phenyl] -pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a yellow solid at a melting point of 121 to 125 ° C. [Mass spectrum (ESI) MH ⁺ = 492].

3- (2,4-dichlorophenyl) -3,4-dihydro-1- [4- (hydroxymethyl) phenyl] -7-methanesulfonyl-pyrimido [4,5-d used as starting material ] Pyrimidin-2 (1H) -one was prepared in a similar manner to that described in Example 63. In step 63 (f) 2,4-dichloroaniline was used instead of 2-bromoaniline.

Example 79

3- (2,4,6-trichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 200 mg (0.48 mmol) and a mixture of 300 mg (1.4 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes. The mixture was cooled and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,4,6-trichlorophenyl) -7- [4- [2 -(Diethylamino) ethoxy] anilino] -3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one 45 mg (17%) melting point 142 Obtained as a white solid at ° C.

3- (2,4,6-trichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-methylpyrimido [4,5-d] pyrimidine-2 (1H used as starting material ) -One using 2,4,6-trichloroaniline instead of 2,6-dichloroaniline to 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro of Example 1 Prepared in a similar manner to that for -1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one.

Example 80

To 1- [3- (tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) in 5 ml of tetrahydrofuran A solution of 200 mg (0.23 mmol) of oxy] anilino] -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one was dissolved in tetrabutylammonium fluoride in tetrahydrofuran. Treated with 0.5 ml (0.5 mmol) of solution. After one hour the mixture was evaporated and the product was purified by chromatography on silica gel using dichloromethane / methanol in a ratio of 20: 1 as eluent. Fractions containing product were evaporated and the residue was triturated with hexane and filtered to give 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4 -60 mg (42%) of dihydro-1- [3- (2-hydroxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one as a white solid having a melting point of 110 ° C. Obtained.

1- [3- (tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy used as starting material ] Anilino] -3,4-dihydropyrimido [4,5-d] pyrimidin-2 (1H) -one was prepared as follows:

1- [3- (tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,4-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-pyrimido [4,5- d] A mixture of 500 mg (0.7 mmol) of pyrimidin-2 (1H) -one and 1 g (4.8 mmol) of 4- [2- (diethylamino) ethoxy] aniline was heated at 180 ° C. for 30 minutes. The mixture was cooled and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 1- [3- (tert-butyldiphenylsilyloxyethyl) phenyl] -3- ( 2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydropyrimido [4,5-d] pyrimidine-2 (1H) 200 mg (33%) of -on was obtained as a yellow gum. [Mass spectrum (ESI) MH ⁺ = 859].

1- [3- (tert-butyldiphenylsilyloxyethyl) phenyl] -3- (2,4-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-pyrimido [4,5- d] pyrimidin-2 (1H) -one using 2,4-dichloroaniline instead of 2-chloro-6-methylaniline to give the 1- [3- (2- (tert-butyl) of Example 53 (d) Diphenylsilyloxy) ethyl) phenyl] -3- (2-chloro-6-methylphenyl) -3,4-dihydro-7-methanesulfonyl-pyrimido [4,5-d] pyrimidine-2 (1H Prepared in a similar manner to that for) -on.

Example 81

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2- in 5 ml of ethanol A solution of 50 mg (0.07 mmol) of phthalimidoethyl) phenyl] pyrimido- [4,5-d] pyrimidin-2 (1H) -one was treated with 0.5 ml of hydrazine hydrate. After 18 h the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (60: 18: 2: 3) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with pentane and filtered to give 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3 10 mg (23%) of-(2-aminoethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid with a melting point of 108 ° C.

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2 used as starting material -Phthalimidoethyl) phenyl] pyrimido- [4,5-d] pyrimidin-2 (1H) -one was prepared as follows:

a) 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1 of Example 80 in 10 ml of dichloromethane -A solution of 100 mg (0.16 mmol) of [3- (2-hydroxyethyl)) phenyl] pyrimido [4,5-d] pyrimidine-2 (1H) in 0.05 ml (0.32 mmol) of triethylamine and methane Treated with 34 mg (0.2 mmol) of sulfonic anhydride. After 4 hours the mixture was washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] Anilino] -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl)) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one 100 mg (90 %) Was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 699].

b) 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3 in 5 ml of dimethylformamide 50 mg (0.07 mmol) of a solution of (2-methanesulfonyloxyethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one with 17 mg (0.09 mmol) of phthalimide potassium The treatment and the mixture was heated at 90 ° C. for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase is dried over magnesium sulfate and evaporated to 3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [ 50 mg (95%) of 3- (2-phthalimidoethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 750].

Example 82

3- (2,4-dichlorophenyl) -7- [4- [2- (diethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- of Example 81 (a) 50 mg (0.07 mmol) of (2-methanesulfonyloxyethyl)) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one were treated with 3 ml of a 33% solution of dimethylamine in ethanol and the mixture Was heated at 50 ° C. for 3 h. The mixture was cooled and evaporated. The product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,4-dichlorophenyl) -7- [4- [2- (di Ethylamino) ethoxy] anilino] -3,4-dihydro-1- [3- (2-dimethylamino) ethyl) phenyl] pyrimido [4,5-d] pyrimidin-2 (1H) -one 10 mg (22%) were obtained as a white solid at melting point 92 ° C.

Example 83

300 mg (0.65) 3- (2,4-dihydrophenyl) -3,4-dihydro-7-methanesulfonyl-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one mmol) and 400 mg (1.9 mmol) of 4- [2- (diethylamino) ethoxy] aniline were heated at 180 ° C. for 30 minutes. The mixture was cooled and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 3- (2,4-dichlorophenyl) -7- [4- [2- (di Ethylamino) ethoxy] anilino] -3,4-dihydro-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one 30 mg (8%) with a melting point of 106 to 108 캜 Obtained as a white solid.

3- (2,4-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-phenylpyrimido [4,5-d] pyrimidin-2 (1H) -one used as starting material 3- (2,6-dichlorophenyl) -7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido of Example 7 using 2,4-dichloroaniline instead of 2,6-dichloroaniline Prepared in a similar manner to that for [4,5-d] pyrimidin-2 (1H) -one.

Example 84

(2- [3- [3- (2,6-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d] pyrimidine-1 -Yl] -phenyl] -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester 370 mg (0.6 mmol) and aniline 300 mg (3.2 mmol) were heated and cooled at 140 ° C. for 40 minutes. . 10 ml of dichloromethane and 10 ml of trifluoroacetic acid were added. After 10 minutes the mixture was evaporated and the product was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent. Fractions containing the product were combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated and triturated in dichloromethane / pentane to give 1- [3- (2-amino-2- Methyl-propyl) -phenyl] -3- (2,6-dichlorophenyl) -7-phenylamino-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one 73 mg (23%) were obtained as a white solid with a melting point of 128 ° C.

(2- [3- [3- (2,6-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d used as starting material ] Pyrimidin-1-yl] phenyl] -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester was prepared as follows:

a) An ethoxylated ice cold suspension of 50 g (215 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 300 ml of ethanol was prepared from 5.1 g (222 mg. atoms) of sodium and 300 ml of ethanol. Treated dropwise with sodium solution. After one hour the mixture was evaporated and the residue was partitioned between 400 ml of dichloromethane and 400 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 48 g (92%) of ethyl 4-ethoxy-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 243].

b) A dry ice / acetone cooling solution of 15 g (62 mmol) of ethyl 4-ethoxy-2-methylthiopyrimidine-5-carboxylate in 500 ml of dichloromethane was added to a diisobutylaluminum hydride 1M solution in dichloromethane. Treated dropwise with ml (185 mmol). After one hour 12 ml of saturated ammonium chloride solution was added and the mixture was allowed to warm to room temperature. The mixture was filtered through a hyflo filter and evaporated to give 12.4 g (100%) of 4-ethoxy-2-methylthio-5- (hydroxymethyl) pyrimidine as a pale yellow oil. [Mass spectrum (ESI) MH ⁺ = 201].

c) A solution of 12.4 g (62 mmol) of 4-ethoxy-2-methylthio-5- (hydroxymethyl) pyrimidine in 500 ml of dichloromethane was treated with 54 g (620 mmol) of manganese dioxide. After 3 hours the mixture was filtered and evaporated to give 12.7 g (100%) of 4-ethoxy-2-methylthiopyrimidine-5-carboxaldehyde as a white solid. [Mass spectrum (ESI) MH ⁺ = 199].

d) 12.7 g (64 mmol) of 4-ethoxy-2-methylthiopyrimidine-5-carboxaldehyde in 400 ml of toluene, 10.4 g (64 mmol) of 2,6-dichloroaniline and 0.6 g of toluenesulfonic acid monohydrate (3 mmol) was heated for 18 hours with azeotropic removal of water under reflux. The mixture was cooled and added dropwise to an ice cold suspension of 2.4 g (65 mmol) of lithium aluminum hydride in 400 ml of tetrahydrofuran. After one hour 2.4 ml of water, 1.2 ml of 2M aqueous sodium hydroxide solution and 3.6 ml of water were carefully added to quench the mixture. The mixture was filtered through a hyflo filter and evaporated to afford 22 g (100%) of 5- (2,6-dichloroanilinomethyl) -4-ethoxy-2-methylthiopyrimidine which was used without further purification. [Mass spectrum (ESI) MH ⁺ = 344].

e) 22 g (64 mmol) of 5- (2,6-dichloroanilinomethyl) -4-ethoxy-2-methylthiopyrimidine were treated with 100 ml of concentrated sulfuric acid and the mixture was heated at 120 ° C. for 20 minutes, Cool and carefully add 1500 ml of ice / water. The mixture was extracted with dichloromethane (3 x 300 ml). The combined organic phases were dried over magnesium sulfate, filtered and evaporated to afford 14 g of a brown solid. Small elution was carried out by flash chromatography using ethyl acetate / isohexane in a ratio of 1: 2 as eluent to give 5- (2,6-dichloroanilinomethyl) -2-methylthio-3H-pyrimidin-4-one. Was obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 316].

f) 13.6 g (43 mmol) of crude 5- (2,6-dichloroanilinomethyl) -2-methylthio-3H-pyrimidin-4-one are treated with 120 ml of phosphorus oxychloride and the mixture is 100 ° C. Heated for 15 minutes and then cooled. The mixture was evaporated and partitioned between 200 ml of ethyl acetate and 200 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel eluting with diethyl ether / isohexane in a 1: 9 ratio to give 3.2 g of 4-chloro-5- (2,6-dichloroanilinomethyl) -2-methylthiopyrimidine. (22%) was obtained as a pale yellow oil. [Mass spectrum (ESI) MH ⁺ = 334].

g) 520 mg (1.6 mmol) of 4-chloro-5- (2,6-dichloroanilinomethyl) -2-methylthiopyrimidine in 5 ml of dichloromethane, (2- (3-aminophenyl) -1,1 A solution of 420 mg (1.6 mmol) of dimethyl-ethyl) -carbamic acid tert-butyl ester and 250 mg (1.7 mmol) of N, N-diethylaniline was heated at 80 ° C. until the solvent evaporated and then 120 ° C. Heated for 30 minutes and then cooled. The product was purified by flash chromatography on silica gel eluting with diethyl ether / isohexane in a 1: 1 ratio to give (2- (3- [5-[(2,6-dichlorophenylamino) -methyl] -2- 350 mg (39%) of methylthiopyrimidin-4-yl-amino] -phenyl) -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 562].

h) (2- (3- [5-[(2,6-dichlorophenylamino) -methyl] -2-methylthiopyrimidin-4-yl-amino] -phenyl) -1,1- in 40 ml of toluene A solution of 320 mg (0.6 mmol) of dimethyl-ethyl) -carbamic acid tert-butyl ester was treated with 0.25 ml (1.8 mmol) of triethylamine and the resulting solution was added a solution of phosgene (20% solution in toluene) in 40 ml of toluene. 0.6 ml). The mixture was heated at reflux for 1 h and then cooled. 80 ml of ethyl acetate and 80 ml of water were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford (2- [3- [3- (2,6-dichlorophenyl) -7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido [ 350 mg (100%) of 4,5-d] pyrimidin-1-yl] -phenyl] -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 588].

i) (2- [3- [3- (2,6-dichlorophenyl) -7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido [4,5- in 10 ml of dichloromethane d] pyrimidin-1-yl] -phenyl] -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester solution of 350 mg (0.6 mmol) in 3-chloroperbenzoic acid (50% w / w water ) 400 mg (1.2 mmol) and the mixture was stirred for 3 hours. 0.5 ml of dimethylsulfoxide was added. After 10 minutes, 10 ml of saturated aqueous sodium bicarbonate solution was added. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford (2- [3- [3- (2,6-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido 370 mg (100%) of [4,5-d] pyrimidin-1-yl] -phenyl] -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 620].

The (2- (3-aminophenyl) -1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester used as starting material in (g) was prepared as follows:

j) A solution of 4 g (16.5 mmol) of ethyl 4-bromophenylacetate in 60 ml of diethyl ether was treated with 26 ml (36.4 mmol) of a 1.4 M solution of methylmagnesium bromide in toluene / tetrahydrofuran (3: 1) The mixture was heated at 40 ° C. for 1 h and then cooled. 100 ml of saturated aqueous ammonium chloride solution were added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 3.5 g (93%) of 1- (4-bromophenyl) -2-methyl-propan-2-ol as a colorless oil. [Mass spectrum (ESI) MH ⁺ = 229].

k) A solution of 3.5 g (15.4 mmol) of 1- (4-bromophenyl) -2-methyl-propan-2-ol in 20 ml of ice acetic acid was treated with 630 mg (15.4 mmol) of acetonitrile and ice cooled. 10 ml of concentrated sulfuric acid were slowly added and the mixture was stirred for 72 h. The mixture was poured into 300 ml of ice / water and neutralized with potassium bicarbonate. The product was extracted with diethyl ether (2 x 250 ml). The combined organic phases were dried over magnesium sulfate, filtered and evaporated. The product was purified by recrystallization with diethyl ether / hexanes to give 3.3 g (80%) of N- [2- (4-bromophenyl) -1,1-dimethyl-ethyl] -acetamide as a white solid. [Mass spectrum (ESI) MH ⁺ = 270].

l) 3.3 g (12 mmol) of an ice-cold solution of N- [2- (4-bromophenyl) -1,1-dimethyl-ethyl] -acetamide in 3 ml of concentrated sulfuric acid were added to 3 ml of concentrated sulfuric acid and 90% nitric acid 6 Treatment was performed dropwise with a mixture of ml. After an hour the mixture was carefully added to 200 ml of ice / water and the precipitated product was extracted with 150 ml of dichloromethane. The organic phase was dried over magnesium sulfate, filtered and evaporated to yield 3.7 g (98%) of N- [2- (4-bromo-3-nitrophenyl) -1,1-dimethyl-ethyl] -acetamide as a white solid. It was. [Mass spectrum (ESI) MH ⁺ = 315].

m) A solution of 3.5 g (11 mmol) of N- [2- (4-bromo-3-nitrophenyl) -1,1-dimethyl-ethyl] -acetamide in 60 mg of ethanol was added to 3 ml of triethylamine. mmol) and 500 mg of palladium on 10% activated carbon. The mixture was hydrogenated at atmospheric pressure for 6 hours, filtered and evaporated. The residue was partitioned between 60 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 1.7 g (75%) of N- [2- (3-aminophenyl) -1,1-dimethyl-ethyl] -acetamide as an orange gum. [Mass spectrum (ESI) MH ⁺ = 207].

n) a solution of 1.7 g (8.3 mmol) of N- [2- (3-aminophenyl) -1,1-dimethyl-ethyl] -acetamide in 20 ml of ethylene glycol was treated with 3 g (75 mmol) of sodium hydroxide The mixture was heated at 195 ° C. for 20 hours. The mixture was cooled and added to 150 ml of saturated aqueous 1 M sodium hydroxide solution with sodium chloride. The product was extracted with diethyl ether (3 × 100). The combined organic phases were dried over magnesium sulfate, filtered and evaporated to give 1.2 g (88%) of 3- (2-amino-2-methyl-propyl) -aniline as a colorless oil. [Mass spectrum (ESI) M + CH ₃ CN ⁺ = 206].

o) 1 g (6.1 mmol) of dry ice / acetone cooling solution of 3- (2-amino-2-methyl-propyl) -aniline in 30 ml of tetrahydrofuran was added di-tert-butyl di in 20 ml of tetrahydrofuran. The solution was added dropwise with a solution of 1.13 g (6.1 mmol) of carbonate. After one hour cooling was removed and the mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. 40 ml of saturated aqueous ammonium chloride solution were added. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel using diethyl ether / isohexane in a ratio of 1: 1 as eluent to give (2- (3-aminophenyl) -1,1-dimethyl-ethyl) -carbamic acid tertiary 960 mg (60%) of -butyl ester were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 265].

Example 85

(2- [3- [3- (2,6-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d] pyrimidine-1 -Yl] -phenyl] -2-ethyl-butyl) -carbamic acid tert-butyl ester A mixture of 400 mg (0.62 mmol) and 600 mg (6.5 mmol) of aniline was heated and cooled at 140 ° C. for 45 minutes. The residue was dissolved in 20 ml of a 1: 1 mixture of dichloromethane and trifluoroacetic acid. After 10 minutes the mixture was evaporated and the product was purified by flash chromatography on silica gel using a gradient elution of dichloromethane / methanol 98: 2 to dichloromethane / methanol 95: 5. Fractions containing product were evaporated and the residue was dissolved in 4 ml of dichloromethane. The product was precipitated by addition of pentane and then filtered and dried to give 1- [3- (1-aminomethyl-1-ethyl-propyl) -phenyl] -3- (2,6-dichloro-phenyl) -7-phenylamino 65 mg (19%) of -3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one trifluoroacetate were obtained as a white solid at a melting point of 232 ° C.

(2- [3- [3- (2,6-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d used as starting material ] Pyrimidin-1-yl] -phenyl] -2-ethyl-butyl) -carbamic acid tert-butyl ester (2- (3-aminophenyl) -1,1-dimethyl-ethyl) -carbamic acid tertiary (2- [3- [3- (2,6-dichloro) of Example 84 using (2- (3-aminophenyl) -2-ethyl-butyl) -carbamic acid tert-butyl ester instead of -butyl ester Phenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d] pyrimidin-1-yl] -phenyl] -1,1-dimethyl-ethyl) Prepared using a method similar to that described for carbamic acid tert-butyl ester.

(2- (3-Aminophenyl) -2-ethyl-butyl) -carbamic acid tert-butyl ester was prepared as follows:

a) 2 g (12 mmol) of dry ice / acetone cooling solution of 3-nitrophenylacetonitrile in 100 ml of tetrahydrofuran was added 4.4 g (26.5 mmol) of iodoethane and 3 g (27 mmol) of tert-butoxylated potassium And 18-crown-6 800 mg (3 mmol). The mixture was stirred for 18 hours to allow the reaction temperature to slowly rise to room temperature. 100 ml of saturated ammonium chloride solution were added and the organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel using diethyl ether / hexane in a 3: 7 ratio as eluent. Fractions containing the product were evaporated to yield 2.1 g (80%) of 2-ethyl-2- (3-nitro-phenyl) -butyronitrile as light brown oil. [Mass spectrum (ESI) MH ⁺ = 219].

b) A solution of 3.2 g (14.7 mmol) of 2-ethyl-2- (3-nitro-phenyl) -butyronitrile in 50 ml of ethanol was treated with 350 mg of Raney Nickel wetted with water and the mixture was heated to 60 ° C. 10 ml of hydrazine hydrate was added dropwise over 20 minutes and the reaction was stirred at 60 ° C. for an additional hour. The cooled mixture was filtered through a Hyflo filter and evaporated to give 2.5 g (90%) of 2- (3-amino-phenyl) -2-ethyl-butyronitrile as an orange oil. [Mass spectrum (ESI) MH ⁺ = 189].

c) A solution of 2.5 g of 2- (3-amino-phenyl) -2-ethyl-butyronitrile in 30 ml of tetrahydrofuran was treated with 30 ml (30 mmol) of a lithium aluminum hydride 1M solution in tetrahydrofuran. The mixture was quenched carefully by the addition of 1 ml of water, 0.5 ml of 2M sodium hydroxide and 1.5 ml of water and filtered through a hyplo filter. The filtrate was evaporated to yield 0.88 g (35%) of 3- (1-aminomethyl-1-ethyl-propyl) -aniline as a pale yellow oil. [Mass spectrum (ESI) MH ⁺ = 193].

d) A solution of 880 mg (4.6 mmol) of dry ice / acetone in 3- (1-aminomethyl-1-ethyl-propyl) -aniline in 30 ml of tetrahydrofuran was added di-tert-butyl di in 30 ml of tetrahydrofuran. The solution was added dropwise with a solution of 850 mg (4.6 mmol) of carbonate. After one hour cooling was removed. After a further 2 hours, 40 ml of saturated aqueous ammonium chloride solution were added. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel using diethyl ether / isohexane in a 2: 3 ratio as eluent. Fractions containing the product were evaporated to yield 950 mg (71%) of (2- (3-aminophenyl) -2-ethyl-butyl) -carbamic acid tert-butyl ester as a pale orange oil. [Mass spectrum (ESI) MH ⁺ = 293].

Example 86

2- (3- [3- [3- (2,4-dichlorophenyl) -2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido [4,5-d in 10 ml of ethanol A solution of 200 mg (0.3 mmol) of] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione was treated with 1 ml of hydrazine hydrate 18 hours later the mixture was evaporated at room temperature and the product Was purified by column chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) as eluent, the fractions containing the product were combined and evaporated and the residue was evaporated with toluene. Dissolved in 40 ml of methane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated, triturated with dichloromethane / pentane and then 1- [3- (3-amino-propyl) -phenyl] -3 25 mg (16%) of-(2,4-dichlorophenyl) -7-phenylamino-3,4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one Obtained as a solid at a melting point of 120 ° C.

2- (3- [3- [3- (2,4-dichlorophenyl) -2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido [4,5- used as starting material d] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione was prepared as follows:

a) 2.1 g (53 mmol) of an ice-cooled suspension of sodium hydride (dispersion in 60% w / w mineral oil) in 120 ml of tetrahydrofuran was added 6.5 g (47 mmol) of 4-methoxybenzyl alcohol in 40 ml of tetrahydrofuran. The solution was added dropwise into the solution. After 30 minutes, a solution of 10 g (43 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate was added slowly. After an additional 40 minutes, the reaction was quenched by the careful addition of 60 ml of saturated aqueous ammonium chloride solution. The mixture was separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to yield 14.2 g (99%) of ethyl 4- (4-methoxy-benzyloxy) -2-methylthiopyrimidine-5-carboxylate as a pale yellow oil. It was. [Mass spectrum (ESI) MH ⁺ = 335].

b) An ice-cooled suspension of 1.6 g (42 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added to ethyl 4- (4-methoxy-benzyloxy) -2-methylthiopyrimidine-5-carboxyl in 150 ml of tetrahydrofuran. Treated slowly with a solution of 14 g (42 mmol) of rate. After 15 minutes the reaction was quenched by careful addition of 1.5 ml of water, 0.8 ml of 2M aqueous hydrochloric acid and 2.3 ml of water. The final suspension was filtered with a hyflo filter. The filtered solid was washed thoroughly with tetrahydrofuran and the combined filtrates and washes were evaporated. The residue was partitioned between 200 ml of dichloromethane and 100 ml of water. The organic phase was dried over magnesium sulfate and filtered. An additional 100 ml of dichloromethane was added to the filtrate and then treated with 36 g (414 mmol) of manganese dioxide. The mixture was stirred at room temperature for 2 hours and filtered through a Hyflo filter. The filtrate was evaporated to give 11.6 g (95%) of 4- (4-methoxy-benzyloxy) -2-methylthiopyrimidine-5-carboxaldehyde as pale yellow oil. [Mass spectrum (ESI) MH ⁺ = 291].

c) 11.6 g (40 mmol) of 4- (4-methoxy-benzyloxy) -2-methylthiopyrimidine-5-carboxaldehyde, 6.5 g (40 mmol) of 2,4-dichloroaniline and toluenesulfonic acid il A mixture of 400 mg (2.1 mmol) of hydrate was heated and cooled for one hour with azeotropic removal of water under reflux. The mixture was added dropwise to an ice cold suspension of 1.5 g (40 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran. After an hour 1.5 ml of water, 0.7 ml of 2M hydrochloric acid aqueous solution and 2.2 ml of water were carefully added to quench the reaction. An additional 100 ml of tetrahydrofuran was added and the filtered mixture was filtered through a hyflo filter and the filtrate was evaporated to 5- (2,4-dichloroanilinomethyl) -4- (4-methoxy-benzyloxy) -2 10.5 g (60%) of methylthiopyrimidine was obtained as an orange viscous oil and used without further purification. [Mass spectrum (ESI) MH ⁺ = 436].

d) refluxing a solution of 5 g (11.5 mmol) of 5- (2,4-dichloroanilinomethyl) -4- (4-methoxy-benzyloxy) -2-methylthiopyrimidine in 30 ml of trifluoroacetic acid Under 20 min, cooled and evaporated. The product was purified by flash chromatography using ethyl acetate / isohexane in a 1: 2 ratio as eluent. Fractions containing the product were combined and evaporated to yield 1.2 g (24%) of 5- [2,4-dichloroanilinomethyl] -2-methylthio-3H-pyrimidin-4-one as a pale yellow solid. [Mass spectrum (ESI) MH ⁺ = 316].

e) A solution of 1.2 g (3.8 mmol) of 5- [2,4-dichloroanilinomethyl] -2-methylthio-3H-pyrimidin-4-one in 40 ml of phosphorus oxychloride was subjected to N, N-diethylaniline Treated with 0.6 ml (3.7 mmol) and the mixture was heated at 110 ° C. for one hour, cooled and evaporated. The residue was carefully partitioned between 40 ml of ice / water and 30 ml of diethyl ether. The aqueous phase was extracted by addition of 30 ml of diethyl ether, and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give 1.1 g of 4-chloro-5- (2,4-dichloroanilinomethyl) -2-methylthiopyrimidine ( 87%) was obtained as an oil that slowly solidified as a white solid. [Mass spectrum (ESI) MH ⁺ = 334].

f) A solution of 180 mg (0.54 mmol) of 4-chloro-5- (2,4-dichloroanilinomethyl) -2-methylthiopyrimidine in 3 ml of dichloromethane was added to 2- [3- (3-aminophenyl) -Propyl] -isoindole-1,3-dione 150 mg (0.54 mmol) and 85 mg (0.57 mmol) N, N-diethylaniline and the mixture was heated to 120 ° C. to evaporate dichloromethane followed by 120 ° C. Heated for an additional 30 minutes. The cooled mixture was purified by flash chromatography on silica gel eluting with ethyl acetate / isohexane in a ratio of 1: 2. Fractions containing product were combined and evaporated to give 2- [3- [3- [5-[(2,4-dichloroanilinomethyl] -2-methylthiopyrimidin-4-yl-amino] -phenyl] -propyl] 200 mg (64%) of isoindole-1,3-dione were obtained as a white solid [mass spectrum (ESI) MH ⁺ = 578].

g) 2- [3- [3- [5-[(2,4-dichloroanilinomethyl] -2-methylthiopyrimidin-4-yl-amino] -phenyl] -propyl] -iso in 10 ml of toluene A solution of 200 mg (0.35 mmol) of indole-1,3-dione was treated with 0.15 ml (1.05 mmol) of triethylamine and the resulting mixture was added with 0.4 ml of phosgene (20% solution in toluene) with 20 ml of toluene. 0.7 mmol) was added drop wise, the mixture was heated at reflux for 1 h and then cooled The organic phase was dried over magnesium sulfate, filtered and evaporated to 2- [3- [3- [3- (2,4- Dichlorophenyl) -7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1, 180 mg (85%) of 3-dione were obtained as a white solid [mass spectrum (ESI) MH ⁺ = 604].

h) 2- [3- [3- [3- (2,4-dichlorophenyl) -7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido [4, in 10 ml of dichloromethane 5-d] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione solution of 180 mg (0.3 mmol) in 200 mg of 3-chloroperbenzoic acid (50% w / w water) (0.6 mmol) and the mixture was stirred at room temperature for 18 hours. 0.1 ml of dimethyl sulfoxide was added. After an additional 15 minutes 10 ml of dichloromethane and 20 ml of saturated aqueous sodium bicarbonate solution were added. The organic phase is dried over magnesium sulfate, filtered and evaporated to 2- [3- [3- [3- (2,4-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H- 190 mg (100%) of pyrimido [4,5-d] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione were obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 636].

i) 2- [3- [3- [3- (2,4-dichlorophenyl) -7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido [4,5-d] A mixture of 190 mg (0.03 mmol) of pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione and 1 ml of aniline was heated at 140 ° C. for 35 minutes and then cooled. The mixture was added to 40 ml of 2M aqueous hydrochloric acid and the precipitated product was filtered off, washed with 2M aqueous hydrochloric acid solution followed by water and then dried to give 2- [3- [3- [3- (2,4-dichlorophenyl) -2-oxo- 200 mg (100%) of 7-phenylamino-3,4-dihydro-2H-pyrimido [4,5-d] pyrimidin-1-yl] -phenyl] -propyl] -isoindole-1,3-dione ) Was obtained as a light brown solid. [Mass spectrum (ESI) MH ⁺ = 649].

2- [3- (3-aminophenyl) -propyl] -isoindole-1,3-dione used as starting material in (f) was prepared as follows:

j) To a solution of 15 g (100 mmol) of sodium iodide in 120 ml of acetone 3 g (11 mmol) of N- (3-bromopropyl) phthalimide were added and the mixture was heated at reflux for 30 minutes. The cooled mixture was filtered and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.6 g (75%) of N- (3-iodopropyl) phthalimide as a white solid. [Mass spectrum (ESI) MH ⁺ = 316].

k) Under a stream of nitrogen, 1.6 g (24 mg. atom) of a stirred suspension of zinc dust (less than 10 microns in diameter) in 20 ml of dimethylformamide was treated with 0.11 ml (1.2 mmol) of 1,2-dibromoethane. The mixture was heated to 60 ° C. and then cooled to room temperature. Heating and cooling were repeated two more times. 0.04 ml (0.24 mmol) of chlorotrimethylsilane were added and the mixture was stirred at room temperature for 30 minutes. The mixture was then treated with 1.26 g (4 mmol) of N- (3-iodopropyl) phthalimide and the resulting suspension was stirred at room temperature for 30 minutes and then heated and cooled at 35 ° C. for one hour. The mixture was then mixed with 750 mg (3 mmol) of 1-iodo-3-nitrobenzene, 60 mg (0.06 mmol) of tris (dibenzylideneacetone) dipalladium and 70 mg (0.23 mmol) of tri (o-tolyl) phosphine. It was added in turn. The suspension was filtered and the filtrate was diluted with 50 ml of ethyl acetate, washed twice with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel using ethyl acetate / isohexane in a ratio of 1: 2 as eluent. Fractions containing the product were combined and evaporated to yield 190 mg (20%) of 2- [3- (3-nitrophenyl) -propyl] -isoindole-1,3-dione as a pale pink solid. [Mass spectrum (ESI) MH ⁺ = 311].

l) A solution of 190 mg (0.6 mmol) of 2- [3- (3-nitrophenyl) -propyl] -isoindole-1,3-dione in 20 ml of ethanol was treated with 50 mg of palladium on 10% activated carbon and hydrogen stream Shake for 2 hours. The mixture was filtered and the filtrate was evaporated to yield 120 mg (71%) of 2- [3- (3-aminophenyl) -propyl] -isoindole-1,3-dione as a yellow oil. [Mass spectrum (ESI) MH ⁺ = 281].

Example 87

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] -pyrimido [4,5 in 2 ml of ethanol -d] Pyrimidin-2 (1H) -one (prepared in Example 74) A solution of 58 mg (0.1 mmol) and 0.5 ml of diethylamine was heated at 50 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel eluted with 5% methanol in dichloromethane. Fractions containing product were combined and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -1- [3- [2- (diethylamino) ethyl] phenyl] -3,4-dihydro-pyri 16 mg (28%) of mido [4,5-d] pyrimidin-2 (1H) -one were obtained as an off-white solid with a melting point of 187 ° C. [Mass spectrum (ESI) MH ⁺ = 561].

Example 88

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] -prepared in Example 74 in 2 ml of ethanol. A solution of 58 mg (0.1 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one and 0.5 ml of morpholine was heated at 50 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel eluted with 5% methanol in dichloromethane. Fractions containing product were combined and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-morpholinoethyl) phenyl] -pyrimido [ 26 mg (45%) of 4,5-d] pyrimidin-2 (1H) -one were obtained as a pale yellow solid at a melting point of 118 ° C. [Mass spectrum (ESI) MH ⁺ = 575].

Example 89

7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro-1- [3- (2-methanesulfonyloxyethyl) phenyl] -prepared in Example 74 in 2 ml of ethanol. A solution of 58 mg (0.1 mmol) of pyrimido [4,5-d] pyrimidin-2 (1H) -one and 100 mg of piperazine was heated at 50 ° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / acetic acid / water (90: 18: 3: 2). The residue was dissolved in 10 ml of dichloromethane, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to 7-anilino-3- (2,4-dichlorophenyl) -3,4-dihydro -1- [3- [2- (1-piperazinyl) -ethyl] phenyl] -pyrimido [4,5-d] pyrimidin-2 (1H) -one 3 mg (5%) has a melting point of 126 DEG C. Obtained as a white solid. [Mass spectrum (ESI) MH ⁺ = 574].

Example 90

3- (2,6-dichlorophenyl) -3,4-dihydro-7-methanesulfonyl-1-methylpyrimido [4,5-d] pyrimidine-2 (prepared in Example 1 (f)) A mixture of 100 mg (0.26 mmol) of 1H) -one and 2 ml of furfurylamine was stirred at room temperature overnight under a nitrogen stream. The reaction mixture was partitioned between 10 ml of dichloromethane and 10 ml of 2M hydrochloric acid, and the organic phase was washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The crude material was triturated with diethyl ether / hexanes, filtered and dried in vacuo to afford 3- (2,6-dichlorophenyl) -3,4-dihydro-7- (furan-2-yl-methylamino)- 80 mg (76%) of 1-methylpyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a light brown solid with a melting point of 150 ° C. (decomposition). [Mass spectrum (ESI) MH ⁺ = 404].

Example 91

1- [3- (2-tert-butyldiphenylsilyloxyethyl) -phenyl] -3- (1-oxy-pyridin-3-yl) -7-phenylamino-3 in 5 ml of anhydrous tetrahydrofuran, 0.425 ml (0.425) tetrabutylammonium fluoride (1M solution in tetrahydrofuran) of a solution of 320 mg (0.47 mmol) of 4-dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one mmol) and then stirred at room temperature for 2 hours. The solvent was evaporated and the crude material was purified by flash chromatography on silica gel eluted with 10% methanol in dichloromethane. Fractions containing product were combined and evaporated to 1- [3- (2-hydroxyethyl) -phenyl] -3- (1-oxy-pyridin-3-yl) -7-phenylamino-3,4-dihydro- 95 mg (61%) of pyrimido [4,5-d] pyrimidin-2 (1H) -one were obtained as a pale brown solid with a melting point of 220 ° C. (decomposition). [Mass spectrum (ESI) MH ⁺ = 455].

1- [3- (2-tert-Butyldiphenylsilyloxyethyl) -phenyl] -3- (1-oxy-pyridin-3-yl) -7-phenylamino-3,4- used as starting material Dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one is substituted with 3-aminopyridine and 2 molar equivalents (instead of 2-chloro-6-methyl-aniline (Example 53 (b)) Prepared in a manner similar to that described in Example 53, using 3 molar equivalents of 3-chloroperbenzoic acid instead of Example 53 (d)).

Example 92

1- [3- (2-tert-butyldiphenylsilyloxyethyl) -phenyl] -3- (furan-2-yl-methyl) -7-phenylamino-3,4- in 5 ml of anhydrous tetrahydrofuran A solution of 320 mg (0.47 mmol) of dihydro-pyrimido [4,5-d] pyrimidin-2 (1H) -one was dissolved in tetrabutylammonium fluoride (1M solution in tetrahydrofuran) 0.6 ml (0.6 mmol) Treated with and stirred at room temperature for 2 hours. The solvent was evaporated and the crude material was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes at a ratio of 4: 1. Fractions containing product were combined and evaporated to 3- (furan-2-yl-methyl) -1- [3- (2-hydroxyethyl) -phenyl] -7-phenylamino-3,4-dihydro-pyrimido 170 mg (82%) of [4,5-d] pyrimidin-2 (1H) -one were obtained as a pale pink solid with a melting point of 195 ° C. Mass Spectrum (ESI) MH ⁺ = 442.

1- [3- (2-tert-butyldiphenylsilyloxyethyl) -phenyl] -3- (furan-2-yl-methyl) -7-phenylamino-3,4-dihydro used as starting material -Pyrimido [4,5-d] pyrimidin-2 (1H) -one in Example 53 using furfurylamine instead of 2-chloro-6-methyl-aniline (Example 53 (b)) Prepared in a similar manner as described.

Claims (21)

A pharmaceutically acceptable salt of a compound of formula (I), or a basic compound of formula (I) with an acid, or a pharmaceutically acceptable salt of an acidic compound of formula (I) with a base: Formula I Where R ¹ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl; R ² is lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl; R ³ is hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl, lower cycloalkenyl or lower cycloalkyl-lower alkyl. The method of claim 1, Compounds having Formula Ia Formula Ia Where R ¹⁰ is lower alkyl, aryl or aryl-lower alkyl; R ²⁰ is aryl; R ³⁰ is hydrogen, lower alkyl, aryl or aryl-lower alkyl. The method of claim 2, Compounds having the general formula (Iai) Chemical Formula Iai Where R ¹⁰¹ is aryl; R ²⁰ and R ³⁰ are each as defined in claim 2. The method of claim 3, wherein R ¹⁰¹ is phenyl. The method of claim 4, wherein R ²⁰ is halophenyl. The method of claim 4, wherein R ²⁰ is 2,6-dichlorophenyl. The method according to any one of claims 2 to 6, R ³⁰ is a general formula —Z—NR ⁴ R ⁵ wherein Z is a spacer; R ⁴ and R ⁵ are each hydrogen or lower alkyl or one or more hetero selected from nitrogen, sulfur and oxygen together with the nitrogen atom to which they are attached; 4-, 5- or 6-membered saturated or partially unsaturated, unsubstituted or unsubstituted, benz-condensed or condensed with one or more substituents including atoms and selected from the group consisting of lower alkyl, lower alkoxy and oxo Or phenyl substituted by a group of 5- or 6-membered aromatic heterocycle group. The method of claim 1, Compounds having Formula Ib Formula Ib Where R ¹¹ is lower alkyl; R ²¹ is aryl; R ³¹ is heteroaryl-lower alkyl. The method of claim 8, R ¹¹ is isopropyl. The method according to claim 8 or 9, R ²¹ is halophenyl. 1- [3- (2-aminoethyl) phenyl] -7-anilino-3- (2,6-dichlorophenyl) -3,4-dihydro-pyrimido [4,5-d] pyrimidine-2 (1H) -on. delete (a) reacting a compound of formula (II) with an amine of formula (III) and optionally, protecting hydroxy groups or protected amino groups or protected carboxylic acid groups present in the reaction product with free hydroxy groups or free amino groups or Converting to a carboxylic acid group; or (b) cleaving an aryl-methyl group from a compound of formula (I) wherein R ¹ is aryl-methyl for preparing a compound of formula (I) wherein R ¹ is hydrogen; and (c) if necessary, converting the obtained basic compound of formula (I) to a pharmaceutically acceptable salt using an acid or converting the acidic compound of formula (I) to a pharmaceutically acceptable salt using a base Letting step A process for preparing a compound according to claim 1 comprising: Formula II [Wherein, R ² and R ³ are each as defined in claim 1 except that hydroxy, amino or carboxylic acid groups may be present in protected form; L is benzylsulfonyl or lower alkanesulfonyl.] Formula III [Wherein, R ¹ is as defined in claim 1 except that hydroxy, amino or carboxylic acid groups may be present in protected form.] A compound of formula II: Formula II Where R ² and R ³ are each as defined in claim 1, provided that hydroxy, amino or carboxylic acid groups may be present in protected form; L is benzylsulfonyl or lower alkanesulfonyl. Treatment or prevention of inflammation, immunological diseases, oncological diseases, bronchial lung diseases, skin and cardiovascular diseases, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a compatible pharmaceutical carrier material, asthma, central Agents for the treatment of neurological diseases or diabetic complications or for the prevention of transplant rejection following transplant surgery. Inflammatory, immunological diseases comprising one or more compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances in a herbal dosage form with a compatible pharmaceutical carrier. A method for the preparation of a medicament for the treatment or prevention of oncological diseases, bronchial lung diseases, skin and cardiovascular diseases, treatment of asthma, central nervous system diseases or diabetes complications, or prevention of transplant rejection after transplantation surgery. delete delete delete delete delete