TW201302200A - Optical pure quinazoline compounds - Google Patents

Abstract

The present invention provides optical pure quinazoline compounds, especially the compounds of general formula (I), and a pharmaceutical composition containing therapeutical effective amount of the compounds. The present invention also provides the preparation of a medicament for the treatment of diseases related to the modulation of c-erbB-2 and/or EGF-R protein tyrosine kinase.

Description

Optically pure quinazoline compound

The present invention relates to an optically pure quinazoline compound, and a pharmaceutical composition comprising the therapeutically effective amount of the compound, and a medicament for the treatment of a disease associated with the regulation of c-erbB-2 and/or EGF-R protein tyrosine kinase activity Use in medicine.

Protein tyrosine kinase catalyzes the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth and differentiation. Protein tyrosine kinases can be broadly classified into receptors (such as EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (eg, c-src, lck, zap70) kinases. Inappropriate or unregulated initiation of many such kinases has been demonstrated, i.e., abnormal protein tyrosine kinase activity, e.g., caused by overexpression or mutation, can cause uncontrolled cell production.

Abnormal activities of protein tyrosine kinases such as c-erbB-2, c-src, c-met, EGFr, PDGFr are associated with human malignancies. For example, elevated EGFr activity is associated with non-small cell lung cancer, bladder cancer, and head and neck cancer, and elevated c-erbB-2 activity is associated with cancers of the breast, ovary, stomach, and pancreas. Therefore, inhibition of protein tyrosine kinase should provide treatment for the above tumors.

Abnormal protein tyrosine kinase activity is also associated with a variety of other diseases: such as psoriasis, fibrosis, atherosclerosis, restenosis, autoimmune diseases, allergies, asthma, etc., which have been shown to be acyl kinase by some receptors. The role is to regulate these diseases.

Chinese Patent 99803887.3 discloses a series of compounds which have protein tyrosine kinase inhibitory activity; Chinese Patent 20081000815 also discloses a series of new quinazoline compounds, but all developed in the form of racemates, and there is no Its optically pure isomers were studied.

An object of the present invention is to provide an optically pure quinazoline compound represented by the formula (I) and use thereof.

It is also an object of the present invention to provide a pharmaceutical composition comprising an effective amount of an optically pure quinazoline compound represented by the general formula (I), and their use in the treatment of diseases such as cancer, malignancy and psoriasis;

The invention discloses a compound of the formula (I):

Wherein R ¹ represents Wherein Ar is a furan or thiazole optionally substituted with 1 or 2 substituents selected from a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group; and R ² and R ³ are independent of each other Is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, or cycloalkylalkyl; Y is phenyl optionally substituted by R ⁴ , R ⁵ Or 1H-carbazolyl; wherein R ^{4 is} selected from benzyl, halo-, dihalo- or trihalobenzyl, benzyloxy, halo-, dihalo- or trihalobenzyloxy R ^{5 is} selected from the group consisting of hydrogen, a hydroxyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, an amine group, a cyano group or a trifluoromethyl group; the * carbon atom is a chiral carbon atom to R) or (S) single enantiomer form or enriched in one enantiomeric form; B is selected from the group consisting of tartaric acid, lactic acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, malic acid, nitric acid, hydrochloric acid, sulfuric acid, oxalic acid, Succinic acid, methanesulfonic acid, maleic acid or p-toluenesulfonic acid.

In a preferred embodiment of the invention, Ar is selected from unsubstituted furan or thiazole, more preferably unsubstituted furan.

In a preferred embodiment of the invention, R ² and R ³ are independently selected from hydrogen, C _1-4 alkyl, C _2-5 alkenyl, C _1-4 alkoxy, C _1-4 alkoxy. C _1-4 alkyl, C _3-8 cycloalkyl, or C _3-8 cycloalkyl-C _1-4 alkyl.

In a preferred embodiment of the invention, R ^{4 is} selected from the group consisting of benzyl, halo-benzyl, halo-benzyloxy, preferably halo-benzyl, halo-benzyloxy; R ^{5 is} selected from hydrogen A halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group.

In a preferred embodiment of the invention, the *carbon atom is present as a single enantiomer (R) or in an enriched (R) form, preferably in a (R) configuration. 90%.

In the embodiment of the present invention, preferred compounds include p-toluenesulfonate of the following compounds:

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)furan -2-yl)quinazolin-4-amine; (Compound 105)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(methylamino)-2-(methylsulfonyl)ethyl Furan-2-yl)quinazolin-4-amine; (Compound 106)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(ethylamino)-2-(methylsulfonyl)ethyl Furan-2-yl)quinazolin-4-amine; (Compound 107)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(propylamino)-2-(methylsulfonyl)ethyl Furan-2-yl)quinazolin-4-amine; (Compound 108)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(cyclopropylmethylamino)-2-(methylsulfonyl) Ethyl)furan-2-yl)quinazolin-4-amine; (Compound 109)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N,N-dimethylamino)-2-(methylsulfonate) Mercapto)ethyl)furan-2-yl)quinazolin-4-amine; (Compound 110)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N,N-diethylamino)-2-(methylsulfonate) Mercapto)ethyl)furan-2-yl)quinazolin-4-amine; (Compound 111)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N,N-dipropylamino)-2-(methylsulfonate) Mercapto)ethyl)furan-2-yl)quinazolin-4-amine; (Compound 112)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N-methyl, N-ethylamino)-2-() Methanesulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (Compound 113)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(allylamino)-2-(methylsulfonyl)B (furan-2-yl)quinazolin-4-amine; (Compound 114)

(R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(propargylamino)-2-(methylsulfonyl)B Furyl-2-yl)quinazolin-4-amine. (Compound 115)

In the embodiment of the present invention, a more preferred compound is as shown in the formula (IX):

In the present invention: "enriched in one enantiomer" means the content of one of the enantiomers such as the (R) configuration 60%; "alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group; preferably a branched or straight-chain saturated aliphatic alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, isobutyl, etc.; "alkenyl" means a branched, straight-chain or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond, such as a vinyl group. , allyl, allyl, butenyl, cyclohexene, etc.; "alkynyl" means a branched, straight-chain or cyclic hydrocarbon radical containing at least one carbon-carbon triple bond, such as ethynyl, propynyl , butynyl, 3-methylbutynyl, alkynyl, propargyl and the like.

"Cycloalkyl" means a monocyclic saturated aliphatic hydrocarbon group, preferably a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl - cyclobutyl, ethyl-cyclopentyl, cyclohexyl, etc.; "alkoxy" means a radical of a straight or branched alkyl group attached to an oxygen atom, such as methoxy, ethoxy, n-propoxy , isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group and the like; "halogen atom" means a fluorine, chlorine, bromine or iodine atom.

The method of preparing a compound of formula (I) comprises the steps of:

1) reacting a compound of the formula (II) with a third butyl sulfinamide to give a compound of the formula (III);

2) reacting a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (V);

3) a compound of the formula (V) is reacted under acidic conditions to give a compound of the formula (VI);

4) reacting a compound of the formula (VI) with a reagent R ² -L or R ³ -L to give a compound of the formula (VII);

5) reacting a compound of the formula (VII) with an oxidizing agent to give a compound of the formula (VIII);

6) reacting a compound of the formula (VIII) with an acid to give a compound of the formula (I);

Wherein R ¹ , Y, Ar, R ² , R ³ , a carbon atom bearing a * and an acid are as defined in the formula (I); T is a sulfur atom or a sulfinyl group; and the third butyl sulfinamide is Optically pure, in the form of (R) or (S) single enantiomer or enriched in one enantiomeric form; L is a leaving group selected from a halogen atom or a sulfonyloxy group.

In the preparation of the compound of the formula (III), the reaction is carried out in the presence of a metal reagent. The metal reagent includes titanium tetraethoxide, titanium tetraisopropoxide or the like, preferably titanium tetraisopropoxide; and the reaction temperature is controlled at 0 to 100 ° C, preferably 0 to 50 ° C.

In the preparation of the compound of the formula (VI), the reaction is carried out under acidic conditions, and the acid used is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid or a mixed acid of the above acids, preferably hydrochloric acid.

In the preparation of the compound of the formula (I), the reaction of oxidizing a sulfur atom or a sulfinyl group to a sulfonyl group is well known to those skilled in the art, and the oxidizing agent used is selected from the group consisting of: m-chloroperoxybenzoic acid, peroxygen Acetic acid, hydrogen peroxide, potassium hydrogen persulfate, etc., but potassium hydrogen persulfate is preferred.

Another method of preparing a compound of formula (I) comprises the steps of:

1) reacting a compound of the formula (II) with a third butyl sulfinamide to give a compound of the formula (III);

2) reacting a compound of the formula (III) with a compound of the formula (A) to give a compound of the formula (B);

3) a compound of the formula (B) is reacted under acidic conditions to give a compound of the formula (C);

4) reacting a compound of the formula (C) with a reagent R ² -L or R ³ -L to give a compound of the formula (VIII);

5) reacting a compound of the formula (VIII) with an acid to give a compound of the formula (I);

Wherein R ¹ , Y, Ar, a carbon atom bearing a * is as defined in the formula (I); a third butyl sulfinamide, L is as defined above; and M is an alkali metal ion or a halogen-alkaline earth metal ion , selected from Li ⁺ , Na ⁺ , K ⁺ , [MgCl) ⁺ or [MgBr) ⁺ .

In the preparation of the compound of the formula (I), L represents a leaving group well known to those skilled in the art, such as a halogen atom (e.g., fluorine, chlorine, bromine, iodine atom), preferably a bromine, iodine atom; a base (such as methanesulfonyloxy, p-toluenesulfonyloxy), etc.; in the preparation of the compound of the formula (C), the reaction is carried out under acidic conditions, the acid used is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like. A mixed acid of fluoroacetic acid or the above acid, preferably hydrochloric acid.

Step 4) of the reaction is carried out under alkaline conditions, and the base used is selected from inorganic bases (such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.) or organic bases (such as ethylamine, triethylamine). Amine, diisopropylethylamine, etc.).

A further object of the present invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

A further object of the present invention is to provide a use of a compound of formula (I) or a pharmaceutical composition comprising the same for the manufacture of a medicament for the treatment of a disease associated with the regulation of c-erbB-2 and/or EGF-R protein tyrosine kinase activity.

A further object of the present invention is to provide a use of a compound of formula (I) or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment of cancer and malignancy.

A further object of the present invention is to provide a use of a compound of the formula (I) or a pharmaceutical composition containing the compound for the preparation of a medicament for the treatment of psoriasis.

The compounds provided by the present invention have excellent antitumor activity, efficacy and stability in vitro.

The pharmaceutical preparations of the present invention may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, depending on the disease to be treated, the route of administration, and the age, weight, condition, and the like of the patient.

The pharmaceutical preparations can be administered by any suitable route, such as oral, rectal, nasal, topical or parenteral (including subcutaneous, intramuscular, intravenous or transdermal) routes. The above various preparations can be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier or excipient.

The compounds of the invention may be administered alone or in combination with other therapeutic agents for the treatment of the above disorders. In particular, in the treatment of anti-tumor, it should be considered in combination with other chemotherapeutic agents, hormones or antibody drugs.

In order to explain the present invention in more detail, the following examples are given. However, the scope of the invention is not limited thereto.

The enantiomeric excesses (e.e.) of the enantiomers in the following examples refer to the relative amounts of each enantiomer. This value is defined as the difference between the relative percentages of the two enantiomers. Thus, for example, when the percentage of the (R) enantiomer is 90%, the content of the (S) enantiomer is 10%, and the (R) enantiomeric excess is 80%, that is, the e.e value is: 80%. .

The composition of each compound enantiomer was determined by chiral HPLC under the following conditions:

Pipe column: AD column of DAICEL company;

Mobile phase: n-hexane-ethanol-diethylamine (50:50:0.1).

Preparation Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine

Add 6-iodo-3H-quinazolin-4-one (100 g) to a 2000 mL flask and dissolve in a mixture of dichlorohydrazine (1000 ml) and N,N-dimethylformamide (20 ml). In the solvent, it was heated to reflux until the reaction liquid was clear and transparent. The dichlorohydrazine was distilled off and dried twice with toluene, and was used.

The spare intermediate was dissolved in isopropanol (2000 ml), 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine hydrochloride (70 g) was added, and anhydrous K ₂ CO ₃ was added with mechanical stirring ( 150 g), heated to reflux overnight. The next day the reaction was cooled to room temperature, vacuum filtration, wash the filter cake was slurried with water to neutral K ₂ CO _3, vacuum filtration, and dried in vacuo to give the title product: 95g, white solid.

m/z (M+1) ⁺ : 506.

Preparation 2 Preparation of N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)-6-iodoquinazolin-4amine

The procedure was the same as in Preparation Example 1, except that 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine hydrochloride was changed to 1-(3-fluorobenzyl)-1H-indazole-5amine. Hydrochloride.

m/z (M+1) ⁺ : 496.

Preparation of 35-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-aldehyde

Preparation of the compound of Example 1 (50 g), 5-boronic acid-2-furaldehyde (21 g), Pd(PPh ₃ ) ₂ Cl ₂ (6.2 g), triethylamine (62 ml), methanol (1000 ml) was placed in the reaction flask The reflux reaction was carried out for 2 hours. After cooling to room temperature, the mixture was filtered, and then filtered, washed with EtOAc EtOAc

m/z (M+1) ⁺ : 473.

Preparation of 45-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-aldehyde

The procedure was the same as in Preparation Example 3 except that the starting material was changed from the compound of Preparation Example 1 to the compound of Preparation Example 2.

m/z (M+1) ⁺ : 464.

Preparation 52-(4-(4-(3-Fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)thiazole-5-aldehyde

Preparation Example 1 compound (50 g), 2-boronic acid-5-thiazolyl (21 g), Pd(PPh ₃ ) ₂ Cl ₂ (6.2 g), triethylamine (62 ml), methanol (1000 ml) In the bottle, reflux reaction was carried out for 2 hours. After cooling to room temperature and filtration, the cake was washed with a small amount of methanol and then dried at 50 ° C to give the title compound: 30 g.

m/z (M+1) ⁺ : 490.

Preparation 62- Preparation of 4-(1-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)thiazole-5-aldehyde

The procedure was the same as in Preparation Example 5 except that the starting material was changed from the compound of Preparation Example 1 to the compound of Preparation Example 2.

m/z (M+1) ⁺ : 480.

Embodiment 1 (S)-N-((5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-yl)methylene Preparation of 2-methylpropane-2-sulfinamide

Preparation Example 3 compound (47.3 g, 0.1 mol), S-t-butylsulfinamide (14.5 g, 0.12 mol), titanium tetraisopropoxide (85 g, 0.3 mol) and anhydrous THF (1000 ml) It was poured into a reaction flask and allowed to react at room temperature overnight. The next day, work-up: water (50 ml), ethyl acetate (500 ml), stirred for 10 min, filtered, and the filter cake was washed three times with THF. The filtrate was dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound: 50 g. m/z (M+1) ⁺ : 577.

Embodiment 2 (R)-N-((5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-yl)methylene Preparation of 2-methylpropane-2-sulfinamide

The preparation method was the same as that in Example 1, except that the reaction raw material was changed from S-t-butyl sulfinamide to R-t-butyl sulfinamide. m/z (M+1) ⁺ : 577.

Embodiment 3 (S)-N-((2-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)thiazol-5-yl)methylene Preparation of 2-methylpropane-2-sulfinamide

The preparation method was the same as that in Example 1, except that the reaction raw material was changed from the compound of Preparation Example 3 to the compound of Preparation Example 5. m/z (M+1) ⁺ : 594.

Embodiment 4 (R)-N-((2-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)thiazol-5-yl)methylene Preparation of 2-methylpropane-2-sulfinamide

The preparation method was the same as that of the third embodiment except that the reaction raw material was changed from S-t-butyl sulfinamide to R-t-butyl sulfinamide. m/z (M+1) ⁺ : 594.

Embodiment 5 (S)-N-((5-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-yl) Preparation of methyl)-2-methylpropane-2-sulfinamide

The preparation method was the same as that in Example 1, except that the reaction raw material was changed from the compound of Preparation Example 3 to the compound of Preparation Example 4. m/z (M+1) ⁺ : 567.

Embodiment 6 (R)-N-((5-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-yl) Preparation of methyl)-2-methylpropane-2-sulfinamide

The preparation method was the same as that of the second embodiment except that the reaction raw material was changed from the compound of Preparation Example 3 to the compound of Preparation Example 4. m/z (M+1) ⁺ : 567.

Example 7 (S)-N-((2-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)thiazol-5-yl) Preparation of methyl)-2-methylpropane-2-sulfinamide

The preparation method was the same as that in Example 1, except that the reaction raw material was changed from the compound of Preparation Example 3 to the compound of Preparation Example 6. m/z (M+1) ⁺ : 584.

Example eight (R)-N-((2-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)thiazol-5-yl) Preparation of methyl)-2-methylpropane-2-sulfinamide

The preparation method was the same as that in Example 1, except that the reaction raw material was changed from the compound of Preparation Example 3 to the compound of Preparation Example 6. m/z (M+1) ⁺ : 584.

Example nine (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylthio)ethyl)furan- Preparation of 2-yl)quinazolin-4-amine

The methylthiomethylmagnesium chloride/THF solution (0.3 mol) was placed in the reaction flask, and the reaction solution was cooled to below -80 ° C for 5 min, and the compound of Example 1 (57.6 g, 0.1 mol) and anhydrous THF (200) were quickly added. Ml) solution, keep the internal temperature below -80 °C. Stir for 10 min with heat and treat. The reaction solution was poured into a saturated aqueous solution of EtOAc (3 mL). Filtration and concentration of the filtrate under reduced pressure afforded 50 g.

The yellow solid obtained in the previous step was dissolved in THF (1000 ml), pH was adjusted with HCl-ethanol, and stirred at room temperature for 2 hours. The concentrated aqueous solution was adjusted to pH=9, and brine (2000 ml) and ethyl acetate (1500 ml) were evaporated. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc EtOAcjjjjjjj 1. m/z (M+1) ⁺ : 535.

Example ten (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(methylamino)-2-(methylthio)ethyl) Preparation of furan-2-yl)quinazolin-4-amine

Method A: The compound obtained in Example 9 (2.0 g), methylene chloride (0.5 g) and triethylamine (0.7 g) was dissolved in THF (150 ml) and heated to reflux for 2 h. The heating was stopped, and saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Filtration, and the filtrate was concentrated under reduced pressure.

Method B: The compound of Example 9 (5.4 g) was dissolved in DMSO (50 ml), EtOAc (EtOAc) The reaction solution was poured into ice water (500 ml), filtered, and dried. The filtered cake was dissolved in THF. m/z (M+1) ⁺ : 549.

According to the preparation method of the tenth embodiment, the compound obtained in the ninth compound is used as a starting material, and reacted with a reaction reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Embodiment 11 (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylthio)ethyl)thiazole- Preparation of 2-yl)quinazolin-4-amine

The preparation method was the same as that of Example 9, except that the reaction raw material was changed from the compound of Example 1 to the compound of Example 3, and the compound was designated as Compound 14. m/z (M+1) ⁺ :552.

According to the method of the tenth embodiment, the compound of the eleventh compound is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Example twelve (S)-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)-6-(5-(1-(amino)-2-(methylthio)ethyl) Preparation of furan-2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 9, except that the reaction raw material was changed from the compound of Example 1 to the compound of Example 5, and the compound was designated as Compound 27. m/z (M+1) ⁺ : 525.

According to the method of the tenth embodiment, the compound of the twelfth embodiment is used as a starting material, and reacted with a reaction reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Example thirteen (R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylthio)ethyl)furan- Preparation of 2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 9, except that the reaction starting material was changed from the compound of Example 1 to the compound of Example 2, and the compound was designated as Compound 40. m/z (M+1) ⁺ : 535.

According to the preparation method of the tenth embodiment, the compound obtained in the thirteenth embodiment is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: belt * carbon atom is (R) type

Embodiment 14 (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylthio)ethyl)thiazole- Preparation of 2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 9, except that the reaction starting material was changed from the compound of Example 1 to the compound of Example 4, and the compound was designated as Compound 53. m/z (M+1) ⁺ :552.

According to the method of the tenth embodiment, the compound of the fourteenth embodiment is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: belt * carbon atom is (R) type

Example fifteen (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfinyl)ethyl) Preparation of furan-2-yl)quinazolin-4-amine

Dimethyl hydrazine (0.4 mol) was dissolved in anhydrous THF (2000 ml), cooled to -20 ° C under nitrogen atmosphere, and n-BuLi (0.3 mol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 30 minutes. The reaction solution was cooled to below -80 ° C, and kept for 5 min, and a solution of the compound of Example 1 (57.6 g, 0.1 mol) and anhydrous THF (200 ml) was quickly added to maintain an internal temperature of -80 ° C or less. Stir for 10 min with heat and treat. The reaction solution was poured into 3,000 ml of a saturated aqueous solution of sodium chloride, and ethyl acetate (200 ml) was added. Filtration and concentration of the filtrate under reduced pressure gave a white solid.

The yellow solid obtained in the previous step was dissolved in THF (1000 ml), pH was adjusted with HCl-ethanol, and stirred at room temperature for 2 hours. The concentrated aqueous solution was adjusted to pH=9, and brine (2000 ml) and ethyl acetate (1500 ml) were evaporated. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted 66. m/z (M+1) ⁺ : 551.

Example sixteen (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(methylamino)-2-(methylsulfinyl)B Preparation of furyl-2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 10 except that the reaction starting material was changed from the compound of the seventh embodiment to the compound of the fifteenth embodiment, and the compound was designated as the compound 67. m/z (M+1) ⁺ : 566.

According to the preparation method of the tenth embodiment, the compound obtained in the fifteenth embodiment is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Example seventeen (R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfinyl)ethyl) Preparation of furan-2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 15, except that the reaction raw material was changed from the compound of Example 1 to the compound of Example 2, and the compound No. 79 was used. m/z (M+1) ⁺ : 551.

According to the preparation method of the tenth embodiment, the compound obtained in the seventeenth embodiment is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: belt * carbon atom is (R) type

Example 18 (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)furan Preparation of 2-yl)quinazolin-4-amine

Method A: Dimethyl hydrazine (37.6 g, 0.4 mol) was dissolved in anhydrous THF (2000 ml), cooled to -20 ° C under nitrogen atmosphere, and n-BuLi (0.3 mol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 30 minutes. The reaction solution was cooled to below -80 ° C, and kept for 5 min, and a solution of the compound of Example 1 (57.6 g, 0.1 mol) and anhydrous THF (200 ml) was quickly added to maintain an internal temperature of -80 ° C or less. Stir for 10 min with heat and treat. The reaction solution was poured into 3,000 ml of a saturated aqueous solution of sodium chloride, and ethyl acetate (200 ml) was added. Filtration and concentration of the filtrate under reduced pressure gave a white solid.

The yellow solid obtained in the previous step was dissolved in THF (1000 ml), pH was adjusted with HCl-ethanol, and stirred at room temperature for 2 hours. The concentrated aqueous solution was adjusted to pH=9, and brine (2000 ml) and ethyl acetate (1500 ml) were evaporated. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted 92.

Method B: 50 g of each of the compounds obtained in Example 9 or Example 15 and a mixed solvent of methanol/water (7:3, 1000 ml) were placed in a reaction flask, and after dissolution, a potassium persulfate preparation (100 g) was added in portions. After the addition was completed, the reaction was further stirred at room temperature for 2 hours. Filtration, the filter cake was washed with a mixed solution of methanol/water, and the filtrate was adjusted to pH=8 with saturated sodium hydrogen carbonate solution, and concentrated under reduced pressure, ethyl acetate (500 ml×2) was added to extract, and the organic layer was combined. dry. Filtration, and the filtrate was evaporated to dryness crystals crystals crystals m/z (M+1) ⁺ : 567; ee value: 95.2% [(S): 97.6%, (R): 2.4%].

According to the preparation method of the tenth embodiment, the compound obtained in the eighteenth embodiment is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Example 19 (R)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)furan Preparation of 2-yl)quinazolin-4-amine

Method A: Same as Example 18, Method A, except that the starting material was changed from the compound of Example 1 to the compound of Example 2, and the number was compound 105; m/z (M+1) ⁺ : 567; ee value : 95.8% [(R): 97.9%, (S): 2.1%].

Method B: Same as Example 18, Method B, except that the starting material was changed from Example IX, Example 15 compound to Example 13 or Example 17 compound.

According to the preparation method of the tenth embodiment, the compound obtained in the nineteenth embodiment is used as a starting material, and reacted with a reaction reagent to complete the preparation of the following compounds:

Remarks: belt * carbon atom is (R) type

Example twenty (S)-N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)thiazole Preparation of 2-yl)quinazolin-4-amine

The preparation method was the same as that of Example 18, Method A except that the reaction starting material was changed from the compound of Example 1 to the compound of Example 3, and the compound was designated as Compound 118.

m/z (M+1) ⁺ : 584; ee value: 91.4% [(S): 95.7%, (R): 4.3%].

The preparation of the following compounds was carried out by the method of Example 10, using the compound of Example 20 as a starting material and reacting with a reagent:

Remarks: with * carbon atoms for (S) type

Embodiment 21 (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)thiazole Preparation of 2-yl)quinazolin-4-amine

The preparation method was the same as that in Example 18, Method A, except that the reaction starting material was changed from the compound of Example 1 to the compound of Example 4 and designated as Compound 131.

m/z (M+1) ⁺ : 584; ee value: 92.2% [(R): 96.1%, (S): 3.9%].

According to the method of the tenth embodiment, the compound of the twenty-first example is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: belt * carbon atom is (R) type

Example twenty two (S)-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl Preparation of furan-2-yl)quinazolin-4-amine

Method A: The preparation method was the same as that in Example 18, except that the reaction starting material was changed from the compound of Example 1 to the compound of Example 5, and was designated as Compound 144.

m/z (M+1) ⁺ : 557; ee value: 93.0% [(S): 96.5%, (R): 3.5%].

Method B: The preparation method was the same as Example Method A except that the reaction starting material was changed from the compound of Example IX and Example 15 to the compound of Example 12.

According to the method of the tenth embodiment, the compound of the twenty-two compound is used as a starting material, and reacted with a reagent to complete the preparation of the following compounds:

Remarks: with * carbon atoms for (S) type

Example twenty-three Preparation of compounds of formula (IX)

Remarks: The carbon atom with * is a chiral carbon atom and exists in the form of enriched (R) enantiomers.

Compound 110 (931.3 g, 1.56 mol), THF (14 L) was added to the reaction mixture, and p-toluenesulfonic acid monohydrate (754.0 g, 3.96 mol) was added under stirring, and stirred at room temperature overnight. Filtration, blast drying (60 ° C, 6h) gave compound ( IX) (yellow solid, 1370.2 g), yield 147.2%, e.e.

¹ H NMR (DMSO-D ₆ , 400 M) δ: 2.274 (s, 6H, 38), 2.836 (s, 6H, 30), 2.994 (s, 3H, 29), 4.065 (d, 1H, 28a), 7.480- 7.500 (m, 5H, 10), 7.944 (d, 1H, 25)

Test Example 1 Evaluation of antitumor activity in vitro

Test method: SRB

Cell line: A431; MCF-7

Experimental Design: cells with different concentrations of compounds were incubated for 72 hours, using the degree of inhibition of the compound evaluated by SRB assay of cell proliferation inhibition rate, _50, Comparative antitumor activity of the compounds according to the inhibition rate calculated using the Logit method IC.

Inhibition rate calculation method: inhibition rate (%) = (control group OD value - medication group OD value) / control group OD value × 100%

The test results are shown in Table 1.

Test example 2 Stability test of the compound of formula (IX)

(1) Basic situation

1, sample situation

2. Basis for investigation

In accordance with the "Guidelines for the Stability Test of APIs and Pharmaceutical Preparations" (Chinese Pharmacopoeia 2005 Edition Part II Appendix XIX C).

3. Survey indicators

Appearance, melting point, specific rotation, loss on drying, related substances, dextro isomers, content, etc.

(II) Influencing factors test

1. Test process

(1) High temperature test: The sample of batch number 20000210 was placed in a flat dish and placed in a dish at 40 ° C, 60 ° C for 10 days, and sampled on the 5th and 10th days.

(2) High-humidity test: The sample of batch number 20000210 was placed in a flat dish and placed in a constant humidity container at 25 ° C, RH 75% and 25 ° C, RH 92.5%, and sampled on the 5th and 10th days. analysis.

2, test results and conclusions

(1) The influencing factors are shown in Table 2.

(2) Influencing factors Conclusion: The influencing factors of the test for 10 days showed that under the conditions of high temperature (60 ° C) and high humidity (RH 92.5%), the quality indexes of the samples did not change significantly, indicating that the samples were high humidity. High temperature stability.

(3) Accelerated and long-term tests

1. Accelerated test and test results

The sample 3 batches (batch numbers: 20090219, 20090302, 20090314) were placed at a temperature of 40 ° C ± 2 ° C and a relative humidity of 75% ± 5% for 6 months, respectively, at 0 months, 1 month, 2 months. Samples were taken at the end of 3 months and 6 months. The results are shown in Table 3.

2. Long-term test and test results

(1) Sample 3 batches (batch numbers: 20090219, 20090302, 20080314) were placed at a temperature of 25 °C ± 2 °C and a relative humidity of 60% ± 10% for a long time, sampling at 0 months, 3 months, and 6 months respectively. Detection.

(2) The measurement results are shown in Table 4.

3. Test results and conclusions

(1) Accelerated test results

The sample was examined at a temperature of 40 ° C ± 2 ° C and RH 75% ± 5% for 6 months. The results showed that there was no significant change in the indicators except for a slight increase in the relevant substances, which met the quality standards.

(2) Long-term test results

The sample was examined at a temperature of 25 ° C ± 2 ° C and a relative humidity of 60% ± 10% for 6 months. The results showed that the quality indexes of the samples did not change significantly. The results showed that the samples were at 25 ° C ± 2 ° C, RH 60%. Placement is stable under ±10% conditions.

(3) Conclusion

According to the stability study results, the quality of the sample is stable.

Test Example 3 Efficacy of compound of formula (IX) on human ovarian cancer SK-OV-3 nude mice xenografts

1. Experimental purpose

The efficacy of the compound of formula (IX) and Lapatinib on human ovarian cancer SK-OV-3 nude mice xenografts was evaluated and compared under different dosing regimens.

2. Test drugs

Drug name and batch number: compound of formula (IX) (abbreviated as HER-036), tender yellow powder, content 99.5%, batch number: 20090201; Lapatinib ditosylate (lapatinib bis-p-toluenesulfonate, referred to as Lapatinib), khaki powder , batch number: 20090105, content 99.1%.

Provided by: Jiangsu Haosen Pharmaceutical Co., Ltd.

Preparation method: HER-036 and Lapatinib were all formulated to the required concentration with 0.5% CMC containing 0.1% Tween-80.

3. Experimental animals

BALB/cA-nude nude mice, 6 to 7 weeks old, purchased from Shanghai Slack Laboratory Animals LLC. Certificate No.: SCXK (Shanghai) 2007-0005. Feeding environment: SPF level.

4, the experimental steps

Nude mice were subcutaneously inoculated with human ovarian cancer SK-OV-3 cells, and after the tumors were grown to 150 to 250 mm ³ , the animals were randomly divided into groups (d0). The dosage and administration schedule are shown in Table 5. The tumor volume was measured 2 to 3 times a week, and the rats were weighed and recorded. The tumor volume (V) is calculated as: V = 1/2 × a × b ² , where a and b represent length and width, respectively.

5 Conclusion

Both HER-036 and lapatinib significantly inhibited the growth of human ovarian cancer SK-OV-3; the effect of once-daily administration was better than that of twice daily; HER-036 was superior to lapatinib in the treatment of SK-OV-3.

Claims (13)

A compound of the formula (I): Wherein R ¹ represents Wherein Ar is a furan or thiazole optionally substituted with 1 or 2 substituents selected from a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group; and R ² and R ³ are independent of each other Is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, or cycloalkylalkyl; Y is phenyl optionally substituted by R ⁴ , R ⁵ Or 1H-carbazolyl, wherein R ^{4 is} selected from benzyl, halo-, dihalo- or trihalobenzyl, benzyloxy, halo-, dihalo- or trihalobenzyloxy R ^{5 is} selected from the group consisting of hydrogen, a hydroxyl group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, an amine group, a cyano group or a trifluoromethyl group; a carbon atom with a carbon atom is a chiral carbon atom, and R Configuration or R-rich enantiomer form; B is selected from tartaric acid, lactic acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, malic acid, nitric acid, hydrochloric acid, sulfuric acid, oxalic acid, succinic acid, methanesulfonic acid , maleic acid or p-toluenesulfonic acid. The compound of claim 1, wherein the Ar is selected from the group consisting of unsubstituted furan or thiazole. The compound according to claim 1 or 2, wherein R ² and R ³ are each independently selected from the group consisting of hydrogen, C _1-4 alkyl, C _2-5 alkenyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _3-8 cycloalkyl or C _3-8 cycloalkyl-C _1-4 alkyl. The compound of claim 3, wherein R ^{4 is} selected from the group consisting of benzyl, halo-benzyl, halo-benzyloxy, and R ^{5 is} selected from hydrogen, halogen atom, C _1-4 alkyl or C _1-4 alkoxy. The compound of claim 4, wherein R ^{4 is} selected from the group consisting of halo-benzyl or halo-benzyloxy. The compound of claim 1, wherein the carbon atom bearing the * is present in the R configuration. The compound according to claim 1, wherein the carbon atom with * is present in an R-rich form, and the R configuration is 90%. The compound according to any one of claims 1 to 7, wherein the compound comprises p-toluenesulfonate of the following compound: (R)-N-(4-(3-fluorobenzyloxy)- 3-chlorophenyl)-6-(5-(1-(amino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (R)-N -(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(methylamino)-2-(methylsulfonyl)ethyl)furan-2- (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(ethylamino)-) 2-(Methanesulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)- 6-(5-(1-(propylamino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (R)-N-(4-( 3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(cyclopropylmethylamino)-2-(methylsulfonyl)ethyl)furan-2-yl) Quinazoline-4-amine; (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N,N-dimethylamine) (2-)-(4-(3-fluorobenzyloxy)-3-chlorobenzene, 2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine 6-(5-(1-(N,N-diethylamino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (R )-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl - 6-(5-(1-(N,N-dipropylamino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; (R) -N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-(1-(N-methyl,N-ethylamino)-2-(methylsulfonate) (ethyl)furan-2-yl)quinazolin-4-amine; (R)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-( 1-(allylamino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazolin-4-amine; and (R)-N-(4-(3-fluorobenzyl) Oxy)-3-chlorophenyl)-6-(5-(1-(propargylamino)-2-(methylsulfonyl)ethyl)furan-2-yl)quinazoline-4- amine. The compound according to claim 8, wherein the structure is as shown in the formula (IX): Among them, the carbon atom of the band * is a chiral carbon atom and exists as an enantiomer of the R configuration. The compound according to claim 8, wherein the structure is as shown in the formula (IX): Among them, the carbon atom with a * is a chiral carbon atom and exists in an enantiomer enriched in the R configuration. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier. The use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the preparation of a therapeutically regulated c-erbB-2 and/or EGF- A drug for a disease associated with R protein tyrosine kinase activity. The use of claim 12, wherein the disease is malignancy or psoriasis.