TW201002704A - Heteroaromatic compounds, and preparation method and use thereof - Google Patents

Abstract

The present invention is related to a heteroaromatic compound of general formula (I), and the preparation method and the use thereof, wherein, A, D and Y is defined as in the specification.

Description

201002704 IX. Description of the invention: [Technical field to which the invention pertains] 八有ί Invented the f-series heteroaromatic compounds, their preparation methods, and the use of m-medicine compositions and their use in medicine; The intermediate used in the compound. [Prior Art] Various:::: 驮 kinase catalyzes the regulation of cell growth and differentiation. The enzyme can squamize the residue of the octazone. Protein glutamate. Knife is a receptor-type kinase (such as EGFr, c-erbB-2, c-met, .2, 2, café, postal) or non-receptor-type kinase (such as coffee, food, township 7〇) ). Improper or uncontrolled initiation of such kinases, such as abnormal protein (tetra) acid kinase activity resulting from over or under mutation, can result in uncontrolled cell production. The isokinetic activity of proteolipid kinases such as c-erbB-2, c_src, c_met, EGFr, GFr' is associated with human malignancies. For example, elevated "synthesis is associated with non-small cell lung cancer, bladder cancer, and head and neck cancer with Zt ° 6 _2 activity and cancer of the breast, ovary, stomach and pancreas, 卩 蛋白 tyramine Acid kinases should provide treatment for the above tumors. Abnormal protein 酉 酉 胺 kinase activity is also associated with a variety of other diseases, cutaneous atherosclerotic H atherosclerosis, restenosis, autoimmune disease allergy, asthma, etc., have been shown to be through some tyrosine kinase Controlled by the role. Patent WO 99/35146 discloses a series of compounds having 94332 5 201002704, protein tyrosine kinase inhibitory activity, but it is still necessary to develop such novel compounds with higher activity and application value. - SUMMARY OF THE INVENTION Novel heteroaromatization shown is an object of the present invention to provide a compound of the formula (I) and a process for the preparation thereof. It is also an object of the present invention to provide a pharmaceutical composition comprising an effective amount of the novel heteroaromatic compound shown, for use in diseases such as cancer, malignancy and psoriasis; ', another object of the present invention is to provide a general formula (II), (V), which are useful intermediates for the preparation of the compound of the formula (1). The object of the present invention is to achieve the compound of the formula (I) by the following technical solution:

(1) wherein A is CR1 and D is N, or A is CR1 and D is CR2; = is not CH3S02[CH2]nCH(NH2)[CH2k_Ar•, the following groups which are substituted or unsubstituted: phenyl, House = 2 2 fluorenyl and (tetra)yl, the substituent is selected from a halogen atom, and the number of substituents of the "complex = base" is 1 or 2; m, ~ or R is hydrogen, C!_4 Alkoxy or halogen atom; 94332 6 201002704 : y selected from R3 or R4, if necessary, can be taken from R3 or R4, 3H-imidazolyl, 吲_, the following groups: phenyl, pyridyl; fluorenyl, 1H is a pendant dihydro-m-supplement R is selected from the group consisting of benzyl, dentate _, dihalo _ or third generation- or tridentate benzyloxy, D to one-zero thiol, #代-, and two-tooth ^ oxy, oxy group; ^ group, 定 定 methoxy, 2-methyl R 4 is selected from hydrogen, silk, arginyl, phyl, cyano or trifluoromethyl. Alkoxy, amine in a preferred embodiment of the invention, hydrogen & wind or methoxy, more preferably in the preferred embodiment of the invention, & selected from: fusphon, porphinyl Or (d), taken from the base of the oxy group, the number of substituents is 4: == 4 thiol, thienyl or thiazole In the preferred embodiment of the invention, mK), !, (4), 2 In a preferred embodiment of the invention, γ is selected from the group consisting of the following substituents: ♦ phenyl, _ group I = A preferred embodiment is that the following groups are available for Yii self-contained; phenyl, erythro-indenyl; or R-substituted: selected from the group consisting of a base group, a southern generation, a base group, a tooth generation, and an oxygen-saving Biting base oxy, "radyl-yl, oxy-:::, alkoxy: halo-oxyl, pyridylmethoxy; "for the tooth - -4 is selected from hydrogen, a sulphide atom, C"Alkyl or C" alkoxy. In the present invention, c]-4 is a radical, ethyl, propyl, isopropyl, succinimide, sulphur, sulphate, butyl, etc.; (I) Compounds, when a chiral carbon atom is present, the compound is present in a racemic form or in a single (R) or (s) configuration. The compound of the formula (I) disclosed herein is preferably the following compound: 6-(2-(1-Amino-2-((methylsulfonyl)ethyl)thiazolyl)-^^(3_chloro_4_(.~~~~~yloxy)phenyl)quina Oxazoline_4_amine; 6-(2-(2-amino-3_(methylsulfonyl)propyl)thiazole _4_基)_Ning3_Chlorine_4_(Bite-2-ylmethoxy)phenyl)quinazoline_4_amine; Amino-2_(methylsulfonyl)ethyl)carbazole_2 _ base)_ team (3_chloro_4 疋-2-ylmethoxy)phenyl) oxime. sitting _4_amine; pyridine methoxy) phenyl) quinazoline bee; amine ·2•(曱 基)ethyl)pyran-2-yl) ' 'gas 疋-2-ylmethoxy)phenyl)quinazoline _4_amine; 6 (5-(2-amino) _3-(甲石黄醯基)丙美啶田产# 土)内基) furan_2_yl)-1^(3'chloro-4-(pyridinium-2-ylmethyl)phenyl) quinazoline Porphyrin_4_amine; (1 (3-murinyl)_ 1H-.引ηη_5-其,< /yl η 乙臭V銮岫〇甘土)-6-(4-(1^•amino-2-(methylsulfonyl))) 吐吐_2- Base) 啥Wahlin>4-amine; fluorobenzyl)_1H_carbazolylpropyl)thiazole 9 I, #土)·6-(4-(2-Amino-Hong (Metsulfonyl)) Carbazole-2·yl)quinazoline_4_amine; nOG-fluorobenzyl)_1Η_carbazole ethyl)furazan 1, large earth) 4-(5-(1-amino-2-() Methanesulfonyl) soil) 夭南-2-yl)quinazoline_4_amine; id-G-fluorobenzyl)_1H_carbazole propyl) 嗔-2-yl)啥η坐琳_4 _ Amine diamine! (Continuously brewed) 94332 8 201002704 N-(4-(3-Fluorobenzyloxy)_3_chlorophenyl)_6_(5_(1 _Amino-2_(sulfonyl)ethyl) oxafuran -2-yl) 喧junlin-4-amine; 6-(5-(1-amino-2_(sulfonyl)ethyl)furan·2_yl)_ice (3_chloro_4_(6_) Methyl 0 is more than 3-oxo)phenyl)indole.坐琳_4_amine; N-(4-(3·fluoroethoxy)_3_ gas phenyl χία amine 1 (methylsulfonyl) propyl) furan-2-yl) quinazoline _4- Amine; 6 (5 (2 & _3-(methyl)-yl) propyl) 咬 _2 _ _ 善 善 善 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3啥 啥 琳 琳 , , , , ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ; j4, !! gas oxy) _3_ chlorophenyl) _6-(2-(2·aminomethyl hydrazide) soil) ° soil salivation _4-yl) 啥 啥 胺 ,, · Ν-( 4-(3-Fluorobenzyloxy)_3_ 产,政u. Benji>6_(4-〇-amino-2-(methionine, ethyl) sold sal-2-())(四)# _4_amine; (Tj-based) n_(4-(3-fluorohexyloxy)_3_chlorophenyl)_ I propyl) 嗔嗓·2_yl) 啥 琳 · 4 4 4 4 4 4 4 Or a salt or solvate thereof. Method Another method of the present invention is to provide a method for producing a compound of the formula (1).

201002704

(iv) (i) where A, D, Y are as defined above; A' is CR1', R1' is CH3S02[CH2]nCH(NH-R5)[CH2]m-Ar-, and R5 is selected from hydrogen or amine Base protecting groups; "amino protecting groups" are various groups well known to those skilled in the art including, but not limited to, the following groups: a third butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, a decyl group, Ethyl, trifluoroethyl, 4-decyloxybenzyl, triphenylsulfonyl; preferred embodiment is that R5 is selected from hydrogen or a third butoxycarbonyl group. When R5 is a different group, the method of deprotecting the group used is also different. For example, when R5 is a group such as a third butoxycarbonyl group or a triphenylsulfonyl group, the deprotection group is reacted under acidic conditions such as trifluoroacetic acid. Or in the presence of hydrochloric acid or the like, when 10 94332 201002704 & is a group such as benzyloxycarbonyl, benzyl, 4-methoxybenzyl, etc., it is demethylated, and J is completed by hydrogenation; When a group such as an acidic or an experimental group is used, the deprotecting group reacting agent; = :(:=)::), the shrinkage is used, and the catalyst used for the ruthenium is selected from the group consisting of bis(triphenylphosphine)-indole phenylphosphine. a palladium catalyst of 'or bis(cyanobenzene)di-n-phenylphosphine)palladium chloride. (Another & day and month of the other - the purpose is to provide formulas which are useful intermediates for the preparation of compounds of formula (1):)

-X ΗΝ R5 Άγ—β 0~R6 (II) (V) where

Ar, m, n are as defined above; R5, R6, X are as defined above. , -S: Y'cT'Br pass gn), (V) compounds can be prepared by various methods to combine NH. Route as an example 'There are mainly two synthetic methods: 94332 11 201002704 ο Ο

Ο Br^'O^Y^S^ NHBOC vOMe

ΝΗ 巳 OC Route 2

Another object of the present invention is to provide a pharmaceutical preparation comprising an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant. A further object of the present invention is to provide a use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof 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 (1) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment of psoriasis. 12 94332 201002704 - The pharmaceutical preparations referred to in the present invention may be in the form of a unit dosage form, and the amount of the mother's early sword contains a predetermined amount of the active ingredient. Such a unit may contain, = 5. 5mg-ig', the specific amount depends on the disease to be treated, the age, weight, and condition of the patient. The pharmaceutical preparations can be administered by any suitable route, such as oral, rectal, f-cavity, topical or parenteral (including subcutaneous, intramuscular, intravenous or transdermal). The above various formulations may be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier or excipient. The compound of the present invention or a pharmaceutically acceptable salt or solvate thereof may be used alone or in combination with other therapeutic agents for treating the above diseases. In particular, in the treatment of anti-tumor, it should be considered in combination with other chemotherapeutic agents, hormones or steroids. [Embodiment] In order to explain the present invention in more detail, the following examples are provided. However, the scope of this invention is not limited to this. a 实例例例6-Broken-Ν-(3'Chloro_4 ratio bit_2-methoxy)phenyl)(四)琳_4_amine Preparation In the 2000 mL flask, add 6_iodine_3 Zhaquinazolinone g) 'dissolved in 1 L of a mixture solvent of chlorosulfoxide (thi〇nyi chl〇ride) and N,N-dimethylformamide (20 m 1 ), heated and refluxed The reaction solution is clear and transparent. The dichlorohydrazine was distilled off and dried with phthalic acid twice for use. The spare intermediate was dissolved in isopropanol (2 L), and 3_gas_4_(pyridin-2-yloxy)-phenylamine hydrochloride (66 g) was added, and anhydrous, 94332 13 201002704 K was added under mechanical stirring: 2C〇3 (150 g), heated to reflux overnight, the reaction solution was cooled to room 1 under reduced pressure, and the filter cake was washed with a little cold isopropanol, then the cake was filtered and washed to remove ΚΑ〇3 to neutral. The mixture was filtered under reduced pressure and dried in vacuo to give EtOAc (EtOAc, EtOAc) m/z (M+l)+: 489 can be obtained in the same manner as in Example 1. Ν·(4_(3-Fluoroethoxy)_3_chlorophenyl)-6-Moth quinazoline _4-amine; m/z(M+l)+ : 506 N-(l-(3-fluoroanthryl ymjtj-s--5-yl)-6.-disc. saliline; m/z (M+ l)+ : 496 6-Broken-N-(3-chloro-4-(6-methyl. -3--3-yloxy)phenyl) 啥君琳-4_amine· m/z (M+l ) + : 489 Example 2 - 6 - rotten acid - Ν - (3 · chloro-4-bu than "deacetyl-2 methoxy" phenyl) 啥 η sit _4 amine jy prepared, will 6_ Iodine-> 1-(3-chloro-4-(pyridin-2-yloxy)phenyl)oxazoline-4-amine (2.0 g) and dry-treated thF (20 ml) were placed in a reaction flask. After dissolution, a yellow solution was obtained. After cooling to 〇t:, ethylmagnesium bromide/THF solution (1.0 M, 4.75 ml) was added to the reaction mixture to give a bright yellow solution. After cooling to -78 °C, boron triisopropylborate (3.73 ml) was quickly added to the reaction mixture, and then a n-butyllithium/n-hexane solution (2·5 Torr, 3 95 ml) was added, and the temperature was maintained until the reaction was completed. Add acetic acid (〇·84 ml) to the reaction mixture with complete reaction, stir a small amount of Βτ′, add saturated aqueous sodium hydrogencarbonate solution to adjust to pH=8, extract with ethyl acetate to 14 94332 201002704, and combine the organic layers. Wash with saturated brine and dry. Filtration, concentration to dryness and column chromatography gave the title compound. M/z(M+l)+ : 407 In the same manner as in Example 2, N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6--acid π奎奎琳胺. • m/z(M+l)+ : 424 N-(l-(3-fluorobenzyl)-m-oxazol-5yl)-6--acid quinazolinamine ; m/z(M+l)+ : 414 6·acid-N-(3-chloro-4·(6-fluorenylpyridine-3-yloxy)phenyl)quinazoline_heart amine; m/ z(M+l)+ : 403 Embodiment 3

Process for the preparation of 1-(5 odorant-2-yl)-2-(methylglycosyl)ethylamine A. N-Methoxy-N-mercapto-2-(methylthio)acetamide (5 6 g), 2,5-dibromofuran or 2-iodo-5-bromofuran (10.6 g or 12.8 g) was dissolved in treated THF (40 ml) and degassed under vacuum. . Cool to -10 to -2 CTC under nitrogen, add a solution of tert-butylmagnesium chloride/THF (2M, 40 ml) to the solution, control the drop rate to allow the internal temperature to rise to room temperature and react. overnight. 5N Hydrochloric acid (23 ml) was placed in another reaction flask and cooled to hydrazine. 〇, the above reaction droplets were added to hydrochloric acid to control the drop acceleration to an internal temperature of $5. After adding a third butyl methyl ether (20 ml), the layers were separated, and the organic layer was washed with water and brine and dried. Filtration, concentration to dryness, purification by column chromatography to give 1-(5-bromofuran-2-yl)-2-(methylthio)ethanone. 94332 15 201002704 The upper intermediate (23.5 g), pyridine (20 ml), hydrochloric acid (m.sub.g) and ethanol (100 ml) were placed in a reaction flask and refluxed until the reaction was completed. The mixture was concentrated to dryness under reduced pressure, and water and a mixture of water and gas were added, and the layers were separated, and the aqueous layer was extracted, and the organic layer was combined and washed with brine and dried. After filtration, the filtrate was concentrated to dryness and used directly in the next step. The upper intermediate was dissolved in methanol (1 〇〇 ml), cooled to 〇 5 ° C, and sodium borohydride was added in portions to complete reduction. Water was slowly added to the reaction mixture to decompose unreacted sodium borohydride, concentrated under reduced pressure, and extracted with dichloromethane. Filtration, the filtrate was concentrated to dryness under reduced pressure to give Intermediate 1-(5-bromofuran-2-yl)-2-(methylthio)ethylamine which was directly used as the next step. The upper intermediate (33.6 g) was dissolved in methanol/water (7/3, 250 ml), and the mixture was cooled to below 20 C. The potassium persulfate preparation (5 〇g) was added in portions to the reaction flask. After the completion of the reaction at this temperature for 45 minutes, and then rose to room reaction for 2 hours. Filtration, the filtrate was adjusted to P^-chloromethane with saturated sodium bicarbonate solution and the organic layers were combined and dried. The sputum is diluted to dryness and purified by column chromatography to give the target compound.

Method B 5 糠 糠 ( (17.5 g) and dried THF (200 ml) were put into the reaction flask, and then the r gan solution was added to the & & & 乐 乐 丁基 亚 亚 亚 醯 醯 醯 醯(13.3 g), wait/close at room temperature, and after clarification at night, quickly add tetraisopropylurethane (70 ml) and continue to stir. The next day, the reaction solution was flushed into _S ιν Λ. ^ T was burned with a rolling mannequin, and the organic layer was dried with anhydrous sodium sulfate, indifferent & limbs. 24 g, yield 80 〇 / 〇. 94332 16 201002704 Dimethyl hydrazine (28 g) was dissolved in dry THF (700 ml), cooled to -40 ° C. Add n-butyllithium (150 mmol) dropwise at this temperature and add to natural Room temperature is 1.5 hours. Cool down again to -40. Hey, quickly add the upper step intermediate (18 g)' Canadian dollar naturally to room temperature. The reaction solution was flushed into water, washed with water, extracted with ethyl acetate, and the organic layer was concentrated. The residue was added to a solution of hydrochloric acid in methanol, and the mixture was stirred at room temperature overnight to give ammonia in methanol for 5 weeks to neutral. After concentration of the liquid, column chromatography gave the title compound: 15 g, yield: 93%. In the same manner as in Example 3, 1-(2-bromothiazol-4-yl)-2-(methylsulfonyl)ethylamine; m/z(M+l)+: 286 1- (4-bromothiazol-2-yl)·2-(methylsulfonyl)ethylamine; m/z(M+l)+ : 286 1_(5-bromofuran-2-yl)·3-(methylsulfonate Mercapto) propyl-2-amine; m/z (M+l) + : 281 % 1-(2-bromothiazol-4-yl)-3-(methylsulfonyl)propyl-2-amine; m/z(M+l)+ : 300 1-(4-bromothiazole-2-ylhong(methylsulfonyl)propyl-2-amine; m/z(M+l): 3〇〇Example 4 Ν-(Preparation of the second butoxy succinylamine-furan-2-yl)-2-(methylsulfonyl)ethyl group was added to N-(t-butyl)ethylamine (2.8 g), magnesium (0.27 g) in anhydrous THF (25, methoxycarbonyl)-1-(5-boronic acid-furan-2-yl)_2_(f-sulfonyl) 94332 17 201002704 Dislocation 3 _ human, protected with helium. To reflux, add appropriate amount of 1,2-dibromoethane to initiate the reaction, maintain the re-cooling ^ R ± ^,, 々IL 0 '5 hours, stop heating, about 1.5 hours after the reaction ',, ° beam, get the format Reagents. The prepared format is continued to be cooled by Nanxun, Ren, and Yiba to -2 (TC to 15. (:, slow drop plus three) Propoxy boron (2.: 53 ml) 〇, Jing* — Tian... 士) After the addition of the element, the reaction was carried out for 0.5 牯 while maintaining the temperature. Add water (5 mi) and adjust to pH=3 with dilute hydrochloric acid. To 4, stir os " inch S stone anti-酉 钾 potassium solution to adjust to pH = 8 'filter, filter cake washed with ethyl acetate 3 times, add 50 ml of water to the filtrate, extract with ethyl acetate (25mlx2), and dry. Column chromatography (petroleum ether: ethyl acetate = 1 〇: 1-3: hydrazine) gave the title compound: 〇.87 g. The same procedure as in Example 4 was carried out to obtain: N-(Third Oxycarbonyl)-bp-boric acid·thiazol-4-yl; (methylsulfonyl)ethylamine; ', m/z(M+l)+ : 351 N-(third butoxycarbonylboronic acid-thiazole_2_ Base)_2_(sulfonyl)ethylamine; m/z(M+l)+ : 351 N-(t-butoxycarbonyl Η _(5·boric acid-furan-2-yl)-3_(methylsulfonate) Methyl)propyl-2-amine; m/z(M+l)+: 346 N·(t-butoxycarbonylboronic acid-thiazole-4-yl)_3_(sulfonyl)propyl-2-amine; m/z(M+l)+ : 365 N-(t-butoxycarbonyl)_H4_boronic acid-thiazole-2_yl)_3_(methylsulfonyl)propane 9432 18 201002704 base-2-amine; m/z (M+l)+ : 365 Example 5

Preparation of 6-(2-(1-amino-2-(indolyl)ethyl)thiazole-4-yl)pyridin-2-ylindolyl)phenyl)indolyl-4-amine Method A 6-boronic acid-N-(3-gas-4-(pyridine-2-ylmethoxy)phenyl)quinazoline-4 amine (4.2 g) and 1-(4-bromothiazole-2-yl) _2_(Methanesulfonyl)ethylamine (27 phantom added to 200 ml of decyl alcohol, then added triethylamine (3 ml), bis(triphenylphosphine) dipalladium (0.2 g). The reaction was carried out for 4 hours. Concentration, the residue was added to water, ethyl acetate was evaporated, and the organic layer was concentrated and then subjected to column chromatography to give the title compound, ie, the compound of the present invention 1: 3.% m/z (M +l)+ : 581

Method B 6-Iodine·N_(3_chloro.4_(pyridin-2-yloxy)phenyl)quinazolinamine 4 (4.5 g) and N-(dioxaoxyl)_1_(4_酸酸_嗔. Sitting _2_ ki)_2_(methionite) ethylamine (3.0 g) was added to 2 〇〇ml of sterol, then added triethylamine 3 =1 again (monophenylphosphine) Two gasified palladium 0.2 g. The reaction was carried out under reflux with heating for 4 hours. The mixture was concentrated, and the residue was evaporated to ethylamine. The intermediate (3.5 g) was added to dichloromethane (50 ml). Water was added to the reaction mixture, and the layers were separated, and the organic layer was washed with saturated brine (50 ml) and saturated sodium bicarbonate (50 ml) and dried. The mixture was filtered, concentrated to dryness, and then applied to the column layer 94332 19 201002704 to give the title compound: 2.6 g. EXAMPLE 6 Preparation of 6-(2-(2-Amino-r-but-2-yloxy)phenyl)-indenyl 4-amine The same procedure as in the Example The title compound was Compound 5 of the present invention. m/z(M+l)+ : 595 Example 7 6-(4-(1-Amino-2·(曱石黄)基)嗟 _2_2_2)) Preparation of the decyl-2-ylmethoxy)phenyl)oxazole _4-amine The title compound is the compound 3 of the invention, which is prepared in the same manner as in the fifth embodiment. ' m/z(M+l)+ ·* 581 Example VIII 6-(4-(2-Amino-3-(methylsulfonyl)propyl)thiazol-2-yl)_N_(夂氯_4 Preparation of bis-Butyl-2-ylmethoxy)phenyl)oxazoline The title compound is the compound 4 of the present invention, which is prepared in the same manner as in Example 5. m/z(M+l)+ : 595 Example IX 6-(5-(1-Amino-2-(methylsulfonyl)ethyl)furan-2-yl)_Ν·(3·Chlorine_ Preparation of palpitidine than c疋-2-ylmethoxy)phenyl)indoline The title compound is the compound 5 of the present invention, which is prepared in the same manner as in the fifth embodiment. 94332 20 201002704 m/z(M+l)+ : 564 Example Decylamino-3_(methyl gamma)propyl) cough | base) _ chloro clock ratio ° 疋-2-yl methoxy) benzene Preparation of phenyl phenyl porphyrin _4_amine. The compound is the compound 6 of the present invention, and the preparation method is the same as the example m/z(M+l)+ : 578. Example 11 N^l-(3-fluoro-based HH-indazole ιyl)i (4_(i -Preparation of Amino-2-((methylsulfonylethyl)thiazol-2-yl)quinazoline-4-amine The title compound is the compound 7 of the present invention, which is prepared in the same manner as the implementation of 50 m/z (M+ l) + : 574 Example 12 ν·(ι-(3-fluoro-based HH, azole i-based) winter (4·(2-aminomethylpropyl) 嗟嗤-2-yl) 啥. The title compound is the compound 8 of the present invention, and the preparation method is the same as the solid m/z (M+l)+: 588. Example 13 Ν_(1-(3·(tetra)yl)_ The title compound of the present invention is the compound 9 of the present invention, which is prepared according to the compound 9 of the present invention, and its preparation is 94932 21 201002704 m/z (M+l)+ : 557 Example Fourteen N-(l-(3-fluorobenzyl)-1Η-indazol-5-yl)-6-(5-(2-amino-3-(methylsulfonyl)propyl) The preparation of the title compound is the compound of the present invention, which is prepared in the same manner as in the fifth embodiment. m/z(M+l)+ : 571 Example 15 N-(4-(3-Fluoroethoxy)_3_chlorophenyl)_6_(5-(1 Amino-2-((methylsulfonyl)) Preparation of the furyl-2-yl)quinazoline-4 amine The title compound is the compound n of the invention, which is prepared in the same manner as in the fifth embodiment. μ m/z(M+l)+ : 567 Example XVI 6-(5-(1-Amino-2-(methylsulfonyl)ethyl)pyran-2-yl> Ν_(3ϋ( Preparation of 6-mercaptopyridine-3-oxo)phenyl)quinazolinamine The title compound is the compound 12 of the present invention, and the preparation method thereof is as follows. Example 5: m/z (M+l)+: 550 Example 17 N Preparation of (:(3fluorodecyloxy)_3_chlorophenyl)_6_(5 ing 2_amino-propyl)furan-2-yl)quinazoline-4-amine (Part A) Inventive compound 13,1, the method of preparation and preparation of the same as the implementation of 94332 22 201002704 m / z (M + l) + : 581 Example 18: 6-(5-(2-amino-based W-propyl) propyl) bite Preparation of the oxime _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ' m/z(M+l)+ : 564 Example 19 N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)_6_(2_(1_ ^ , . , , λ 1 Amino Preparation of 2-(f-sulfonyl)ethyl)thiazol-4-yl)quinazoline-4-amine The title compound is the compound 15 of the invention, which is prepared in the same manner as the example m/z (M+l) + : 584 Example Twenty-N-(4-(3-fluorohexyloxy)_3_chlorophenyl)_6_(2-(2-propyl)indol-4-yl)indolyl-4-amine Preparation... (Metformin) The title compound is the compound of the present invention 16', which is prepared in the same manner as in the example m/z (M+l) + : 6 施 施 二十 = = = = = = = =曱 (4) Preparation of quinazoline-4-amine. The title compound is the compound 17 of the present invention, which is prepared in the same manner as in the practice of 94332 23 201002704 m/z (M+l) + : 584 Example Twenty-two -3-(methylsulfonyl N-(4-(3-fluoro) Preparation of benzyloxy)_3_chlorophenylpropyl hydrazin-2-yl) 啥α坐琳·4_amine The title compound is the compound 18 of the invention, and the preparation method thereof is the same as the implementation of the warehouse m/z (M+l)+ : 600 Test Example 1 In vitro anti-tumor activity test Experimental method: SRB; Cell line: SK-BR-3; Experimental design: Evaluation of compound inhibition of cell proliferation by cell and different concentrations of chemical methods Degree 22 =: tumor activity. . Calculation method for in vitro anti-inhibition rate of ten, 1~' comparative compounds: value - drug group 0D value) / control group 〇d value χΙΟΟ%

Inhibition rate (%) = (control group 〇 D 94332 24 201002704 Evaluation of control group in nude mice Inventive compound 1 Inventive compound 3 Inventive compound 5 Inventive compound 7 Inventive compound 11 Inventive compound Π Inventive compound 18 Lapatinib group do not

78.0 49.5* 61.1 56.3* 37.0* 57.8* 72.0 50.2* Dosage (mg/kg Solvent 50 100 50 100 100 100 100 100 po, qd, do-19 Number of animals. dO/dpΤοϊϊο 5/5 5/5 5/5 5 /5 5/5 5/5 5/5 5/5 RTV X+SD 4.22+2.34 3.29±1·82 2.09+1.81 2.58±1.52 2.38±0·68 1.56±1·26 2.44+0.47 3.04+0.68 2.12± 0.82 for the first time, dn: 丨 9 days after the first dose; TV: swollen experiment results compound name ~~~~~~- IC5 〇lapatinib (Lapatinib) (Germans company 0.044 Inventive compound 1 ~ ~~~ - 0.040 Inventive compound 3 - 0.036 Inventive compound 4 '----- 0.055 Inventive compound 5 ~~~~- 0.030 Inventive compound 7 - 0.033 Inventive compound 9 - 0.042 - Inventive compound 11 ' ~~~~- 0.025 "Inventive compound 12 ~~*- 0.100 "¥明化合物17 " 0.001 Experimental example 2 tumor volume; RTV: relative tumor volume, based on the tumor volume at the start of administration; X± SD ··mean±standard deviation; T/c (%): the ratio of the tumor volume of the drug group to the tumor volume of the control group (5)(10)^: Oral, once daily; *?<0.01 vs. control group 94332 25 201002704 Brief Description of the formula [Yi] Main reference numerals DESCRIPTION

Claims (1)

201002704 X. Patent application scope: 1. A compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof: ΥHN A' II D, CD wherein A is CR1 and D is N; or A is CR1 and D is CR2; R1 represents CH3S02[CH2]nCH(NH2)[CH2k_Ar, wherein μ is selected from substituted or unsubstituted groups: phenyl " fluoromethyl, aryl, pyrrolyl or oxime The substituent is selected from a halogen atom, a base or a Cw alkoxy group, and the number of substituents is! Or 2; m, n are each independently 〇, 1 or 2; R is 虱, C · 4 alkoxy or a halogen atom; s I is selected from the following groups which may be substituted by mR4: phenyl, Base 3 (tetra) sial, yl, y, or 2,3 dioxin-m: bis(e), dentate, dentate, genus, or genus, or dentate , pyridyl, yl, pyridyl r 4 yl 2 -methyl σ than methoxy or ethoxy; and from oxime, donor, halogen atom, C, ρ, ^ η amine, cyano or trigas . Cl-4 Tiger Base, C" Alkoxy, 2· as claimed in the scope of patents! A compound of the formula or a pharmaceutically acceptable salt thereof 94332 27 201002704 or a solvate wherein R2 represents hydrogen or methoxy. 3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof wherein R2 represents hydrogen. 4. The compound of claim ", or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of substituted or unsubstituted groups of furanyl, thienyl or thiazolyl, substituents. It is selected from the group consisting of a dentate atom, a Ci-4, an alkyl group or a Cl_4 alkoxy group, and the number of substituents is 〖, preferably an unsubstituted furyl group, a thienyl group or a thiazolyl group. a compound or a pharmaceutically acceptable substance or solvate thereof, wherein m = 〇 or 1, η = ι or 2. s. 6. A compound of the scope of the application of claim PCT or a pharmaceutically acceptable hydrazine or solvent thereof a compound wherein the oxime is selected from the group which can be substituted as needed; = group: phenyl "than the bite group, (1) a pendant group, a 2,3-dihydro group, preferably a phenyl group, a 1H-carbazolyl group; R is selected from the group consisting of a benzylidene group, a ii-tertiary group, a halogeno-oxyloxy group, a π-pyridylmethylpyrazine=pyridylmethoxy group, a 2-decylpyridyloxy group or a hydroxy group; Hydrogen, _ atom, Ci_4 alkyl or c" alkoxy. A compound of claim 6 or a pharmaceutically acceptable oxime thereof, wherein R3 is selected from halo, phenyl, halooxy or ketone; ^, a compound of the first patent of claim 1 or a pharmaceutically acceptable thereof An interesting or glutamic compound in which, when chirality is present in the hand, the compound is either cold or suspected—the (R)4(S) configuration exists. 9. The compound of claim 5, or a pharmaceutically acceptable 贱94332 28 201002704 or solvate thereof, wherein the compound comprises: 6-(2-(1-amino-2-(indolyl) Ethyl)thiazole_4_yl)_N-(3j _4-(π-Bist-2-ylmethoxy)phenyl)indole. Sitting _^_amine; 6-(2-(2-amino-3-(indolyl)propyl)thiazole _4_yl)_1^_(3_chloro-4-(° ratio bite- 2-ylmethoxy)phenyl)indolyl-4-amine; 6-(4-(1-amino-2-(indolyl)ethyl). ^_(3_Chloro-4-(0-But-2-ylmethoxy)phenyl)喧喧琳_4_amine; 6-(4-(2-Amino-3-(曱石黄醯基)) Propyl)pyrene_2_yl)_;^-(3-chloro-4-(pyridin-2-yloximeoxy)phenyl)quinazoline_4_amine; '6-(5-(1) -amino-2-(indolyl)ethyl)furan-2-yl)-4-(inden-2-ylmethoxy)phenyl)indolyl; 6-(5-(2) -amino-3-(indolyl)propyl)furan-2-yl)-4-(πΛη疋_2_ylmethoxy)phenyl)indole; Ν·(1-(3 -fluorobenzyl)-1 Η-oxazol-5-yl)-6-(4-(1-amino-2-(indolyl fluorenyl)ethyl) ° sputum-2-yl) 啥 嘛 _4 _amine; N-(l-(3-fluorobenzyl)_1H•carbazole_5_yl)_6_(4_(2_amino-3)(indolyl)propyl)thiazol-2-yl)quina Oxazoline _4_amine; Ν-(1-(3·fluorobenzyl)·1Η•carbazole _5_yl)_6<5_(1_amino-2_(sulfonyl)ethyl) π -2--2-yl)喧喧琳_4 ·N-(l-(3-fluorobenzyl)_1Η_Πbendazole _ _)_6_(5_(2_Amino_3 gassulfonyl) propyl) π pentan-2-yl)氟 嘛 嘛 amine; fluorobenzyloxy) _3 · chlorophenyl) _6_ (5_(1_amino-2_(methylsulfonyl) ethyl) ° flu-2-yl) 喧 琳 _ _ _ amine 6-(5-(1-Amino-2_(methylsulfonyl)ethyl)furan-2-yl)_n_(夂chloro 29 94332 201002704 (methyl ratio.疋_3-oxy)phenyl)喧Salicylamine; ((fluorobenzyloxy)-3-chlorophenyl)-6-(5-(2-amino-3_(sulfonyl)propyl)propan-2-yl)quinoxaline _4_amine; ((2amino(sulfonyl)propyl)furan-2-yl)_N-(3-chloro-4-(6-methyl.pyridin-3-oxy)phenyl)quinazoline -4-amine; N (4 (3fluorobenzyloxy)_3_chlorophenylamino 2 - (methylsulfonyl) ethyl) β 塞 ° sit-4-yl) 喧 琳 _ _ 4-amine; ((fluorobenzyloxy)-3-phenylphenyl)-6-(2-(2-amino-3_(indolyl)propyl)pyrazole-4-yl)quinazoline_4_ Amine; Ν (4 (3_fluorobenzyloxy)-3_ phenyl)-6-(4-(1-amino-2-((sulfonyl)ethyl)thiazol-2-yl) quinazoline Porphyrin_4_amine; N (4 (3-fluorobenzyloxy)_3_gasphenyl)_6_(4_(2_ _3_ group (acyl methanesulfonamide) propyl) ° saliva plug 2-yl) amine noise saliva leaching _4-. 1. A method of producing a compound of the formula (I) as defined in the first paragraph of the patent scope, the method comprising: 1) a compound of the formula (π) and a compound of the formula (ΠΙ) in the presence of a catalyst Carrying out a condensation reaction to prepare a compound of the formula (IV) 2) The compound of the formula (IV) is deprotected to give an amine group protecting compound to give a compound of the formula (1) 94332 30 201002704 wherein ηνΛ (I) Α ' is CR1', Ri' represents CH3S〇2[CH2]nCH(NH_R5)[CH2]m good, r5 is selected from a or an amine protecting group; R is selected from hydrogen, or Ci_4 straight or divided A branched alkyl group; X is a halogen atom. ^ The method of claim 10, wherein the method is again desert or moth. • A process for preparing a compound of the formula (1) as defined in the scope of claim 4, which comprises: 1) a condensation reaction of a compound of the formula (v) with a compound of the formula (VI) in the presence of a catalyst to prepare a pass Compound of formula (IV) (V) (VI) 2) Deprotection of the amine group of the compound of the formula (IV) (IV) to give the compound of the formula (1) 94332 31 201002704 (i) (IV) wherein A' is CR1', Ri' represents CH3S〇2[CH2]nCH(NH_R5)[CH2]m_Ar_, from a chlorine or amine protecting group; R is selected from hydrogen, or C!· 4 linear or branched alkyl; X is a pheromone atom. 13 14 15 16. The method of claim 12, wherein the X is indifferent or broken. The method of any one of claims 10 to 13, wherein the pyrolysis catalyst is selected from the group consisting of di(triphenylphosphine)dichloride, tetrakis(triphenylphosphine) ibar or bis(cyano) Benzene) is a miscible catalyst for the gasification of the gas. The method of claim 2, wherein the miscible catalyst is mono(diphenylphosphine) dichloride. A compound represented by the formula (Π) or (V) as an intermediate for synthesizing a compound of the formula (I) as in the first aspect of the patent application: °^〇 R5 -Αγ-X Ar—B 0—R6 0—R6 (II) wherein R 5 is selected from hydrogen or an amine protecting group 94332 32 (V) 201002704 R 6 is selected from hydrogen or a linear or branched alkyl group, and X is a halogen atom. 17. The compound of claim 16, wherein the cockroach is a cockroach or a touch; the medicinal preparation containing at least one compound of the formula (1) or a pharmaceutically acceptable salt thereof Use of one or more pharmaceutically acceptable carriers, diluents or compounds of formula (1) according to any one of claims 1 to 8 of the patent field, acceptable salts or solvates, the use A medicament for the treatment of a disease modulated by 2 and/or EGF_R protein alanine kinase. Use of claim 19 of the scope of patents' This use is for the preparation of a medicament for the treatment of cancer and malignant tumors. The use of item 19 of the monthly patent range, which is used to prepare the #物物. ~1U noon 94332 33 201002704 VII. Designated representative map: There is no schema in this case (1) The representative representative map of this case is: (). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case is not represented by the chemical formula 94332 201002704 Sticking barcode when inventing Lffi·Book of the invention Please do not change it arbitrarily, please do not fill in the ※ mark. (This manual format 'order and bold font ColD^l/ιμ. (2006.011 Festival 1卩 (: Category: °°7P♦ Tao<2006·01^ 6〇 7〇屮7/^ (2006.01# {2006.01# ※Application number: ※Application period: 1. Invention name: (Chinese/English) Heteroaromatic compound, its preparation method and its use 丨heteroaromatic compounds, preparing method and Use thereof Applicant: (1 in total) Name: (Chinese/English) Sun Feiyang / $UN, PIAO YANG Representative: (Chinese / English) (signature) Address of residence or business office: (Chinese / English) 145 Renmin East Road, Xinpu District, Lianyungang City, Jiangsu Province, China Post Code: 222〇〇2 No. 145 East Renmin Road, Lianyungang, Jiangsu Province, China Nationality: (Chinese/English) China/CHINA, Inventor: (Total 7 people) Name: (Chinese / English) 1. Chen Gangsheng / CHEN, GANGSHENG 2. Liu Sheng / LIU, SHENG 3. Xiong Long / XIONG, LONG 4. Yang Baohai / YANG, BA0HAI 5. Feng Ruimao / FENG, RUIMA0 6. He Lei/HE, LEI?·吕爱锋/LU, AIF ENG Nationality: (Chinese / English) 1. to 7. Mainland China / CHINA 1 94332