TW201134816A - Dual inhibitors of EGFR and VEGFR-2 and uses and production processes thereof - Google Patents

Abstract

The present invention relates to dual inhibitors of Epithelial Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2, and the uses and preparation processes thereof.

Description

201134816 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to a novel 4-anilino 01: ° sitin derivative, and its use and preparation method. DETAILED DESCRIPTION OF THE INVENTION The 4-anilinoquinazoline derivative of the present invention is an epidermal growth factor receptor (EGFR) and a vascular endothelial growth factor receptor _Vascular

Endothelial Growth Factor Receptor-2; VEGFR-2) is a dual inhibitor that can be used to inhibit abnormal cell growth and to treat neoplastic diseases, tumors or cancer. [Prior Art] Cancer is one of the major health problems in most developed countries. According to the statistics of the Department of Health, the top ten causes of death among the cancer couples have been more than a year. In the 1990s alone, there were 36,357 Chinese people who died of cancer. On average, about 100 people died every day. Cancer cells or tumor lines are formed over a long period of time due to mutations in multiple genes. Normal cells may be genetically mutated due to congenital genetic factors, or stimulated by environmental factors (for example, violent roads, asbestos, ultraviolet rays or radioactive substances, or infected with viruses), causing gene mutations that cause overexpression of oncogenes. Or the expression of the tumor suppressor gene is reduced, resulting in cancerous cells and rapid division, transformation, hyperplasia, enlargement, and then formation of malignant tumors. The traditional treatment of cancer removes the cancer lesion along with a portion of the surrounding normal tissue and lymph nodes. This type of therapy works best in the early stages of cancer. If the cancer is not early, it is usually necessary to combine radiation or chemotherapy depending on the characteristics of the cancer. Μ 117649.doc 201134816 Radiation therapy uses high-energy radiation to illuminate cancerous tissues, preventing cancer cells from continuing to grow and divide, and achieving cancer treatment. However, radiation does not have cell and tissue specificity, so it will also destroy the side effects of normal cells and tissues, such as "seeing regional organization, sclerotherapy, systemic burnout, and loss of food." Chemotherapy uses cytotoxicity. Chemical drugs that destroy or inhibit the chromosomal division of cells to kill cancer cells. However, cytotoxic chemicals are also toxic to normal cells, so they can cause damage to normal cells and bone marrow while killing cancer cells. Common side effects of this therapy include: nausea, vomiting, loss of appetite, diarrhea, endophthalmitis, dry skin, sweating, rash, palpitations, hair loss, myelosuppression (leukopenia, thrombocytopenia, anemia), neurotoxicity, renal toxicity And hepatotoxicity, etc. Studies have shown that 'the growth of cancer cells requires specific growth factor stimulation, so 'cell growth inhibitors have become a new class of cancer therapeutics. Epidermal growth factor receptor (EGFR) has a molecular weight of 17kDa. Membrane glycoprotein with ligand-dependent tyrosine kinase activity. Excessive manifestations in cancer and tumors, such as colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, and non-small cell lung cancer. EGFR is derived from cancer and tumor cells through autologous secretion, > death, dedifferentiation, angiogenesis (angiogenesis), invasion and transfer play an important role, and its over-expression is often associated with cancer and tumor progression and rapid metastasis. Therefore, inhibition of signal transmission via EGFR can inhibit the growth of abnormal cells or tumors. 117649.doc 201134816 Angiogenesis is a phenomenon in which microvessels are branched and extended. Studies have shown that angiogenesis plays an important role in the occurrence and deterioration of cancer. Cancer cells can absorb nutrients from the host through new blood vessels, and Transfer to other sites. Vascular endothelial growth factor is the most important regulator of angiogenesis in cancer cells. Vascular endothelial growth factor receptor 2 (¥11 (31711_2) will initiate angiogenesis, resulting in vascular endothelial cell proliferation and vascular access Permeability. Therefore, 'VEGFR-2 is also an important target for the treatment of cancer cells. US Patents 5, 747, 498 and 5, 7 No. 7,599, and U.S. Patent Nos. 5,457,1,5, and 6,414,148, each of which discloses quinazoline derivatives, wherein the first two derivatives are EGFR inhibitors, and the latter derivatives are EGFR and Dual Inhibitor of VEGFR-2 [Invention] The present invention provides a novel 4-anilinoquinazoline derivative. The present invention also provides the use of the novel 4-anilinoquinazoline derivative of the present invention for the preparation of a medicament, The agent is a dual inhibitor of £(}1?11 and VEGFR_2' which can be used for inhibiting abnormal cell growth, and treating f-borne diseases, tumors or cancer. The present invention also provides a dual inhibitor of sclerotherapy and VEGFR_2. A medicinal composition comprising a therapeutically effective amount of a novel lysine-based quinoxaline derivative of the invention. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a novel 4-anilinoquinazoline derivative of the invention, which inhibits abnormal cell growth. The present invention provides a pharmaceutical composition for treating a neoplastic disease, tumor or cancer comprising a therapeutically effective amount of the novel anionic anilinoquinoxaline 117649.doc 201134816 derivative of the present invention. The invention further provides a process for the preparation of the 4-anilinoquinazoline derivatives of the invention. The detailed description of the invention is set forth below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Embodiment] The present invention provides a compound of the formula (1) shown below

among them:

The direct key ' η is 〇, 1, 2 or 3; R1 and R2 are independently selected from: 1) Η ; 2) C -6 -6 烧 base ' can be replaced by _NR5R6, where rule 5 and rule 6 are independent C ???6·alkyl' or R5 and R6 together with the subsequent n form a 3- to 10-membered saturated heterocyclic ring containing n, at least one methylene group on the ring _(cH2)_ may be -〇- Substituted by -(NR7)_ or _(CHR8)_, wherein R7 is H or C1_6-alkyl' r8 is a 3- to 1-membered saturated heterocyclic ring containing n, or 3- to 10-containing N a member-saturated heterocyclic substituted Ci6-alkyl; and 3) a 3- to 1-membered saturated heterocyclic ring containing N, at least one methylene group on the ring. 117649.doc 201134816 (CH2) - _ 〇_, _(NR7) or _(CHr8)_ is substituted; or, R1 and R2 and its subsequent N form a 3_ to 1〇_membered saturated heterocyclic ring containing at least one methylene group on the ring _ (CH2)_ may be replaced by _〇_, _(nr7)_ or -(CHR8)-; R is H or Cl·6-alkyl, wherein the alkyl group may be selected from 1 to 3 Substituted from the following groups of substituents: dentate, Cl.4_alkoxy, -n(r9)(r9) and -SORi〇' where r9 is independently H*R10 and the ruler (7) is ^4 Base; R4 Is selected from the group of the following groups: 1) Hydroxyl group, amine group, carboxyl group, amine sulfhydryl group, urea group, ^ "alkoxyamine fluorenyl group" NC 〗 4 alkyl amide amine, n , N-di(Cw alkyl)amine oxime, trans-amino group, Cm alkoxyamino group, Cw alkoxyamino group, trifluoromethoxy group, Cw alkyl group, C _4 alkoxy group Or (: 丨_3 alkylenedioxy; 2) bis[(C丨.4.alkyl)]amino C2·4·alkoxy, α-pyridylpyridyl _(32.4_alkylφ oxy, Hexahydropyridinyl C2-4-homoyloxy, phosphatyl C2-4-alkoxy, pyridin-1-yl-Cw alkoxy, 4-CN4-alkylpiperazin-1-yl- C2.4-alkoxy, imin-1-yl-C2.4•alkoxy, bis[(Cy alkoxy)-C2.4·alkyl]-amino-C2·4-alkoxy a thiomorpholinyl C2.4-alkoxy group, a 1-oxothiomorpholinyl C2.4-alkoxy group, or a 1,1-dioxothiomorpholinyl c24-alkoxy group, wherein the aforementioned The fluorenyl-(CH2)- group contained in a group may be substituted by a hydroxyl group if it is not bonded to N or 0 atoms; 3) hydrazine, halogen, hydroxyl group, hydroxylamine group, carboxyl group, nitro group, thiol group, Urea, cyano, trifluoromethyl or Cm alkyl-W-phenyl, where W is 11764 9.doc 201134816 direct bond, hydrazine, S or NH; 4) cyano substituted Cl.4 alkyl or Rn or wherein R11 is selected from R1Q, -OR9, -NR9R9, -C(0)R12,- NHOR1. , -OC(0)R9, cyano, U and _VR10, wherein R12 is R10, -OR9 or _NR9R9,1; is selected from the group consisting of hexahydropyridyl, morpholinyl, pyrrolidinyl, 4-R9-peri Pyrazine-1 _ base, π m. Sit -1 _ base, 4_. Ratio D to -1 -yl, C 1 -4 alkylene (CO2H), phenoxy, phenyl, phenylsulfonylamino, C2-4 alkenyl and (^_4 alkylene C(0)NR9R9 , V is S, SO, S〇2, wherein the alkyl group of the alkyl group, -OR9 and -NR9R9 may be substituted by 1 to 3 halogens, and may be substituted by 1 to 2 R11, and the R&quot The alkyl group in the complex case is replaced by halogen or R11, the former title: there can be no two heteroatoms on the same carbon, 5) selected from -NHS02R10, quinone imine (^.4 alkyl sulfonate) Mercaptoamine, benzoguanamine, benzoquinone, 3-phenylureido, 2-oxaindole, each of the ketone-1-yl' 2,5-dioxapyridinium-1 a base and RnC2.4, which are selected from the group consisting of halogen, -OR9, C2_4, aryl, _C(〇)R12 and -NR9R9' and the R4 group as defined above may be 1 to 2 Independently selected from the group shown below: halogen, R10, cyano, methanesulfonyl and Ci-4 alkoxy; and 6) two R4 and its attached carbon form a 5 to 8 member ring, which contains a hetero atom selected from the group consisting of hydrazine, S and N; and m is 1, 2 or 3; or a stereoisomer, prodrug or pharmaceutically acceptable Or solvate thereof. M7649.doc 201134816 The terminology used herein, when it refers to a substituent or group, if it occurs more than once, its definition in each occurrence is independent of its definition at each other. Moreover, the combination of each substituent or group can only be allowed to exist before the combination forms a stable compound. Unless otherwise indicated, the terms shown below apply to the full text of this patent specification (the scope of the patent application). The following definitions of terms apply to the term alone and in relation to other terms (IV). For example, the definition of "burning base," also applies to "burning oxy""hospital" The alkyl group is a straight chain or a branched saturated hydrocarbon chain having a hydrocarbon chain of from 1 to 12 carbon atoms, more preferably from 6 to 6 carbon atoms or from 1 to 4 carbon atoms. "alkoxy" means an alkyloxy group (-alkyl group-bonded alkyl group. Among them, 1 group, as defined above. Silk group is non-limiting (4) - methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy-, "soil" means a straight or divergent aliphatic hydrocarbon group having at least one carbon-analytic bond And 2 to 15 carbon atoms +, preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbon atoms. Non-limiting examples of the block group include an ethyl group, a propyl group, a 2-butyl block Base, 3-methylbutanyl, n-pentyl and fluorenyl. Halogen-based fluorene, bromine or iodine. Preferably, fluorine, chlorine or bromine is fluorine and gas. "Ring" means a non-aromatic saturated monocyclic system containing N containing from 3 to 10 ring atoms; Λ 'm'', for example 3 to 7 ring atoms, preferably 5 to 1 ring atoms , wherein - the gamma ίκ π 畏 原子 atom is Ν, and the remaining ring atoms are carbon. Or 117649.doc 201134816, the N-containing ring system, the mountain's extra N atom, or the rabbit's ring atom' Contains atoms. / atoms. Better and mixed There are 5 or 6 rings, 3 and heterocyclic rings. The non-limiting examples include: pyridine, pyrrolidine, pyrazole, imidazole - each, piperazine 'carbazole , benzimidazole, cumin, imidazolidinone, lin. sub, /, W sit ° than ° sitting, D bow sputum, sputum sitting, sing. sit and yolin. This article uses "Μβ" Further, referring to a chemical structure or a chemical formula, a methyl group. A preferred embodiment of the present invention is a compound of the formula (1)_1 shown below.

Wherein Y and R1 to R4, 11 and 111 are as defined above. Among the compounds of the formula (I)-1, preferred are the compounds shown below:

R—C—NRR where R and NWR2 are as defined below: R NW 3-BrC6H4- -n(ch2ch2)2n-ch3 4-BrC6H4- -n(ch2ch2)2n-ch3 3-BrC6H4CH2--N(CH2CH2) 2N-CH3 4-ΒΓ〇βΗ4〇Η2* -n(ch2ch2)2n-ch3 4-BrC6H4OCH2- -n(ch2ch2)2n-ch3 117649.doc •10· 201134816 Alternatively, the preferred compound of formula (I)-1 is Compounds as shown below:

Wherein R and NWR2 are defined as follows: R NR!R2 3-BrC6H4- -N(CH2CH2)2N-CH3 4-BrC6H4- -N(CH2CH2)2N-CH3 3-BrC6H4CH2- -n(ch2ch2)2n-ch3 4 -BrC6H4CH2- -n(ch2ch2)2n-ch3 4-BrC6H4OCH2- -n(ch2ch2)2n-ch3

Another preferred embodiment of the present invention is a compound of the formula (1)-2 shown below:

Wherein Y and R1 to R4, η and m are as defined above. Among the compounds of the formula (1)-2, preferred are the compounds shown below:

117649.doc • 11 - 201134816 where nWr2 is defined as follows: _NR]R2 -N(CH2CH2)2N-CH3 -N(CH2CH2)2C-N(CH2)4 -n(ch2)3chch2-n(ch2)4 - NH(CH2)3N(CH2CH3)2 -nh(ch2)2n(ch2ch3)2 -NH(CH2)3N(CH3)2_ -nh(ch2)2n(ch3)2_ -nh(ch3)(ch2)2n(ch2ch3 2 -NH-N(CH2CH2)2N-CH3 -nh(ch2)2n(ch2)5_-nh(ch2)2n(ch2)4_-nhn(ch2ch2)2o_ or, preferably, the compound of the formula (1)-2 is Compounds as shown below:

The definition of nWr2 is as follows: _NR»R2 -n(ch2ch2)2n-ch3 -N(CH2CH2)2C-N(CH2)4 -n(ch2)3chch2-n(ch2)4 -nh(ch2)3n(ch2ch3 ) 2 -nh(ch2)2n(ch2ch3)2 -nh(ch2)3n(ch3)2_ -NH(CH2)2N(CH3)2 -nh(ch3)(ch2)2n(ch2ch3)2 -NH-N( CH2CH2)2N-CH3-nh(ch2)2n(ch2)5_-NH(CH2)2N(CH2)4_-NHN(CH2CH2)2〇_ A further preferred embodiment of the present invention is the following formula (1)- Of the 3 compounds, 117649.doc -12- 201134816

Wherein Y and R1 to R4, η and m are as defined above. Among the compounds of the formula (1)-3, preferred are the compounds shown below:

The definition of NWR2 is as follows: _NR'R2 - N(CH2CH2)2N-CH3 - -NH-N(CH2CH2)2N-CH3 -NH(CH2)2N(CH2)5 - -nh(ch2)2n(ch2)4 — Alternatively, preferred compounds of formula (1)-3 are the compounds shown below:

The definition of NWR2 is as follows: _NR] R2 - N(CH2CH2)2N-CH3 - -NH-N(CH2CH2)2N-CH3 -nh(ch2)2n(ch2)5 - -NH(CH2)2N(CH2)4 ~ 117649.doc -13- 201134816 The compound of the formula (i) of the present invention can be produced by the method shown in the scheme shown below.

R3, R4 and m are as described above

Bis(Pentamic acid) diborate PdCl2 (dppf), KOAc, DMF, 80 °C RCONRjR2 decylamine (VI) wherein R, R1 and R2 are as described above PdCl2 (dppf), 2M aq. Na2 C03

In particular, the compound of formula (II) shown below can be used. 117649.doc • 14· 201134816

Wherein R3, R4, R5 and R6 are as defined above, and hydrazine is halogen or sulfonyl sulfonyl, in the presence of a suitable catalyst, in a suitable solvent, with a suitable Suzuki coupling agent, such as bis (Pingan a diborate or dipentane boron diboration to produce a boronated intermediate, such as the compound of formula (III) as shown in the scheme; and subsequently, the boronated compound of formula (II) and formula (VI) of rconWr2 Indoleamines, wherein R, R1 and R2 are as defined above, are reacted in the presence of a suitable catalyst to obtain a compound of formula (I). Compounds of formula (II) can be prepared according to conventional techniques. For example, a compound of formula (II) wherein R3 is hydrazine can be prepared according to the teachings of U.S. Patent Nos. 5,457,105, 5,747,498 and 5,770,599; R3 is a compound of formula (II) which may be substituted with a Cw alkyl group, and may be in accordance with U.S. Patent No. 5,747,498. The teaching of the number is prepared. The entire text of these patents is incorporated herein by reference. The Suzuki coupling reaction can be carried out by a conventional method to boricize the compound of the formula (II); that is, at an elevated temperature, in the presence of a suitable catalyst and a base, in a suitable solvent, using a suitable Suzuki coupling agent. The compound of formula (II) is reacted to form a boronated compound of formula (II). Suitable Suzuki coupling agents include, but are not limited to, boric acid, boric acid esters or substituted side burns. For example, bis(pinacolato diboron; PIN2B2), Pinacol borate (PINB) 117649.doc 15 201134816 and isopropyl dipentane diborate ( Isopropyl Pinacol Borate; PINBOP), both suitable for the boronation of a compound of formula (II) wherein t is a dentate in the presence of a palladium catalyst. The compound of the formula (Π) which is a sulfonium sulfonate can be borated in the presence of a rhodium or ruthenium catalyst. For example, boronation of a compound of formula (II) using ΡΙΝ2Β2 can form a boronated compound of formula (III) as shown in the scheme. Catalysts suitable for carrying out the Suzuki coupling reaction include, but are not limited to, Pd(OAc)2, PdCl2(dppf), Pd(Ph3P)4, Pd(dba)2PCy3,

PdCl2(Ph3P)2 and palladium black (Pd black); suitable rhodium or ruthenium catalysts include, but are not limited to, RuCl2(Ph3P)2, RuC13, rhodium carbon catalyst, rhodium alumina catalyst and Rhodium black. Bases suitable for carrying out the Suzuki coupling reaction include, but are not limited to: KOAc, K2C03, triethylamine, KOH, NaOEt, NaOH, CS2CO3, and CsF. Suitable solvents for performing Suzuki coupling reactions include, but are not limited to, dimethyl methacrylate. Indoleamine (DMF), dimethyl hydrazine (DMSO), toluene, Benzene, tetrahydrofuran (THF), isopropanol, ethanol, dioxane, CH2C12 and CHC13 0

The Suzuki coupling reaction can be carried out at room temperature or elevated temperature to an elevated temperature of 190 ° C, for example at 80 ° C. The indoleamine of formula (VI) of RCONWR2 can be obtained by a known method using a corresponding hydrazine halide (RCOZ, wherein Z is a halogen) or decanoic acid (RCOOH), in combination with the corresponding disubstituted amine oxime. The boronated compound of the formula (II) and the decylamine of the formula (VI) of RCONWR2 can be reacted in the presence of a base and a catalyst in the form of a base 171649.doc -16 - 201134816 to obtain a compound of the formula (i). Suitable bases and catalysts include, but are not limited to, alkali KOAc, K2C03, triethylamine, KOH, NaOEt, NaOH, Cs2C03 and CsF with catalysts Pd(OAc)2, PdCl2(dPPf), Pd(Ph3P)4, Pd(dba) 2PCy3, PdCl2(Ph3P)2, and palladium black (Pd black). Certain compounds of the invention may exist in different stereoisomeric forms (e.g., for the present isomers, diastereomers, and atropisomers). The present invention is intended to cover all such stereoisomers, both in pure form and in mixtures, including racemic mixtures. Isomers can be prepared using conventional methods. Certain compounds are acidic in nature, such as compounds having a carboxy or phenolic hydroxyl group. These compounds form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold, and silver salts. Also intended to be encompassed are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-mercaptoglucosamine, and the like. Certain basic compounds also form pharmaceutically acceptable salts, such as acid addition salts. For example, a pyrido-nitrogen atom can form a salt with a strong acid, and a compound having a basic substituent such as an amine group also forms a salt with a weaker acid. Examples of suitable acids for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sulphuric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, amber, ascorbic acid, butene Diacids, decane sulfonic acids, and other mineral acids and carboxylic acids known to those skilled in the art. This salt is prepared in a conventional manner by contacting a free base form with a sufficient amount of the desired acid to produce a salt. The free form of the base form can be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. Free-form base 117649.doc -17- 201134816 Form and its individual salt form 4, in some physical and qualitative qualities, such as solubility in polar solvents, but for the purposes of the present invention, acid and alkali salts It is otherwise equivalent to its individual free-form base form. All such acid and base salts are intended to be pharmaceutically acceptable in the context of the present invention and for the purposes of the present invention, all acid and salt tests are considered to be equivalent to the free form of the corresponding compound. The compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated forms of pharmaceutically acceptable solvents such as water, ethanol, and the like, for the purposes of the present invention, are equivalent to unsolvated forms. The invention also includes prodrugs of the compounds of the invention. The term "prodrug" as used herein refers to a compound that is rapidly converted to the parent compound of the above formula, for example, via hydrolysis in the blood. Please refer to the literature published by T. Higuchi and V. Stella. Prodrug

For the new Lai transmission system " A.C.S. series of the 14th volume, and heart to B

Roche's "Bioreversible Drugs for Drug Design", American Medical Association and Pergamon Press (1987), both of which are incorporated herein by reference. 2 Tested 'The compounds of the invention inhibit EGFR It can also inhibit VE (JFR_, a dual inhibitor of EGFR and VEGFR_2, which can be used to inhibit the growth of unsinkable cells in patients, and to treat neoplastic diseases in patients. Tumor or cancer. Therefore, the present invention provides the novel of the present invention. - Anilinoquinone. The use of a guanidine derivative for the preparation of a pharmaceutical agent is a preparation of egfr^vegfr_2 117649.doc 201134816. The present invention also provides a novel 4-anilinoquinazoline derivative of the present invention. The use of a medicament for inhibiting abnormal cell growth. The invention provides and provides the use of the novel 4-anilinoquinazoline derivative of the invention for the preparation of a medicament for treating a neoplastic disease, In addition, the present invention provides a pharmaceutical composition comprising EGFR and VEGFR- octa- 4 Tetris, which comprises a therapeutically effective amount of the novel * present amino quinquin of the present invention The morpholin organism, and a pharmaceutically acceptable diluent, adjuvant or carrier. The invention further provides a pharmaceutical composition for inhibiting abnormal cell growth, which is a therapeutically effective amount of the novel lysine of the invention. Separation of the derivative, and the acceptable diluent, adjuvant or carrier for the medicinal herb. I. The replenishment of the medicinal disease, the sputum喧 = a prescription, and a pharmaceutically acceptable diluent, adjuvant or carrier. The term "patient," as used herein, refers to an animal, including humans and other mammals. In the preferred embodiment, the patient refers to a human Swollen = The term "treatment" is used to include the relief of the disease associated with the disease, swelling, long-term inhibition, actual reduction of the tumor, or inhibition of metastasis. The term "therapeable effective amount" is used herein alone or in this article. Invented 彳l· \ 1 , his drug's monthly δ substance, can provide therapeutic benefits for the symptoms, such as can be as described in the symptoms can alleviate the symptoms, inhibit tumor metastasis, etc.. Swollen _ small, or suppression Swollen 117649.doc -19· 2 01134816 The term "医筚璺卜可 ^ ^ ^ AS ^ , followed by diluents, adjuvants and carriers, k #Japanese general practitioners, and the D can be used to prepare the dilution of pharmaceutical compositions. Agents, adjuvants and excipients, or analogues thereof. The novel compounds of the present invention, sputum can be prepared by potting ># 〇 D times /, preparation of musical agents or pharmaceutical compositions can be used alone to inhibit non-positive cells Tumor or cancer. Cell growth, or plum disease, ii ^ month novel compound, or a pharmaceutical or pharmaceutical group prepared therefrom, or the following active silk or agent or therapy may be used simultaneously or sequentially to suppress malaria Long cell growth, or treatment of a living disease, tumor or cancer: (4) microtubule affecting agent; (8) anti-tumor or anti-angiogenesis; (4) anti-blood agent; (4) EGF receptor kinase inhibitor; (4) receptor kinase inhibitor, (4) f) VEGF receptor kinase inhibitor; (g) interferon, and/or (8) radiation therapy. The pharmaceutical preparations and pharmaceutical compositions prepared by the novel compounds of the present invention, whether or not the compounds of the present invention are used alone or in combination with other active ingredients (simultaneously or sequentially), can be prepared by conventional methods. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories "Powders and tablets may contain from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, sachets and capsules can be used as solid dosage forms suitable for oral administration. Pharmacology 1 can be used as an example of a carrier, and various methods of preparation can be found in A. Gennaro (eds.), i? (4) (10) on behalf of the table, the first edition, (1990), Mack Publishing Company (Easton, pennSyivania) . 117649.doc • 20- 201134816 — Liquid form preparations include solution 1 floats and emulsions. The following examples can be used to administer water or water-propylene glycol solutions for parenteral injection, or to add sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Suitable aerosol formulations for humans may include solutions and solids in powder form which may be combined with a pharmaceutically acceptable carrier such as an inert I condensing gas such as nitrogen. #包包(四)H Form Formulation' is intended to be converted into a liquid form preparation, shortly before use, whether for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The hairy S material can also be transported transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of a matrix or reservoir type, as is the art used in the art. the way. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the system is subdivided into appropriately sized unit doses containing the appropriate amount of active ingredient, such as an effective amount to achieve the desired purpose. The amount of active compound in a unit dosage formulation may be varied or adjusted, from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 75 mg, more preferably from about 0.01 mg to about 500. It is preferably from about 0.01 mg to about 250 mg, depending on the particular application. The actual dosage employed will vary depending upon the condition of the patient and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular condition is within the skill of the art. For convenience, the 117649.doc -21- 201134816 total agent can be divided and divided into females during the day; Wangdao - human skills, as needed. The compound of the present invention and/or its rate of Chinese medicine, the dosage of the sputum a master gossip to the acceptable salt and the frequency of the main pumping division are adjusted, taking into account some factors 's such as the age of the patient, 荇Strong Λ.^ Symptoms and size, as well as the severity of the symptoms being treated. For the oral administration of blood, /, the birth of 4 mother daily dose, the standard 〇. 〇 4 mg / day to about 4000 milligrams for the brother / day, in two to four separate doses. A microtubule-influencing agent which can be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared therefrom, is a compound which affects the formation and/or action of microtubules and interferes with mitosis of the cells, i.e., has an anti-mitotic effect. Such agents may be, for example, microtubule stabilizers or agents that disrupt microtubule formation. Microtubule-influencing agents useful in the present invention are well known to those skilled in the art, including but not limited to colchicine (all 〇c〇lchicine, NSC4〇6〇42), and Harry Chondroitin B (HaliCh〇). Ndrin B, NSC 609395), Colchicine (NSC757), colchicine derivatives (eg NSC33410), doxorubicin 10 (d〇lastatin_ 10, NSC376128), maytan ( Maytansine, NSC153858), Rhizoxin (NSC332598), pepirixol (paciitaxel, Taxol8, NSC125973), Taxol® derivative (NSC608832), thiocolchicine (NSC361792), triphenylsulfonyl 3-tritylthio-L-alanine (NSC83265), Vinblastine sulfate 'NSC49842', Vincentrine sulfate (NSC67574), Epsilon A (epsilon A), Ai Epothilone and discodermolide (see 117649.doc -22- 201134816)

Service' (1996) Science, 274: 2009) estramustine, unreachable. Sit (n〇c〇daz〇ie), MAp4, etc. Examples of such agents are also described in the scientific and patent literature, see, for example, Bulinski (1997) J. CellSci. no: 3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA94: 10560-10564; Muhlradt ( 1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) Nature 387: 268-272; Vasquez (1997) Mol. Biol. Cell. 8: 973-985;

Panda (1996) J. Bi〇i. chem. 271: 29807-29812. Antitumor agents which may be used in combination with a compound of the present invention, a pharmaceutical preparation or a pharmaceutical composition thereof, include, but are not limited to, gemcitabine, peclitaxel, 5-fluorouracil (5_FU), cyclophosphamide (Cyt〇xan®), temozol〇mide, tax〇tere and Changchun. An anticancer agent which can be used in combination with a compound of the present invention, a pharmaceutical preparation or a pharmaceutical composition thereof, including but not limited to: an alkylating agent, an anti-metabolizing agent, a natural product and a derivative thereof, a hormone, an anti-hormone, an anti-angiogenesis Agents and steroids as well as synthetic substances. The alkylating agents include N-Mustard, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes, non-limiting examples of which are: uracil mustard ), chloromethine, cyclophosphamide (Cytoxan®), ifosfamide, phenylalanine mustard 1-pam, chlorambucil, double-dipropyl propyl azine , triethylene-melamine, triethylene thiophosphoramide, white blood Fuen (Busulfan), nitrosourea mustard, cyclohexyl nitrosourea, streptavidin 117649.doc -23· 201134816 素, nitromethene Amine and tamoxime (tem〇z〇lQmide). Antimetabolites include folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, non-limiting examples of which are: methotrexate, 5-fluorouracil, 5-fluorodeoxyuridine, cytarabine , 6_巯基嘌呤, 巯 巯 嗓吟, fludarabine phosphate, pentostatin and gemcitabine 〇 natural products and derivatives thereof including vinca alkaloids, Anti-tumor antibiotics, enzymes, lymphokines and epipodophyllotoxin, non-limiting examples of which are vinblastine, vincristine, vinca, bleomycin, dycotin, and daun red Bacteriocin, erythromycin, erythromycin, idadamycin, paclitaxel, mithramycin, deoxy-inter-mycin, mitomycin-C, L-aspartate indolease, interferon (especially IFN_a), etoposide. Non-limiting examples of hormones and steroids are: 17α-alkynyl alcohol, diethylstilbestrol, anthrone, prednisone, hydroxymethyl ketone, Dromostanolone propionate, sputum lactone, hydroxytol Progesterone acetate, tamoxifen, methylprednisolone, thioglycolide, prednisolone, fluorohydrodehydrocortisol, tri-p-methoxybenzene, hydroxypregnant _, Amine-based sleep energy, estramustine, gestational g with acetate, leuprolide, flutaniide, toremifene, Zoladex ). Synthetic materials include inorganic complexes such as platinum coordination complexes, non-limiting examples of which are: Cisplatin, Platinum oxalate (platinum xaliplatin), Carboplatin, Amsacrine, Rice Totan (mit〇tan), 117649.doc • 24· 201134816

An anti-angiogenic agent, an EGF receptor kinase inhibitor, an EGF receptor inhibitor, a VEGF receptor kinase inhibitor, or a VEGF receptor kinase inhibitor which can be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared thereby Illustrative examples include, but are not limited to, those disclosed or described in the aforementioned U.S. Patent Nos. 5,457, 1, 5, 5, 745, 498, 5, 770, 599, and 6, 414, 148. The foregoing can be used in conjunction with the compounds, pharmaceutical agents or pharmaceutical compositions of the present invention in combination with therapeutic agents which are known to be safe and effective. In addition, its administration is described in the standard literature. For example, many chemotherapeutic agents are described in the "Physician's Desk Reference, (pDR), eg, version 2〇〇2 (Medical Economics, M〇ntvale, NJ〇7645_1742, USA), The full text of the disclosure is incorporated herein by reference. Therapeutic agents and/or radiation therapy for use in combination with the compounds of the present invention can be administered or administered in a manner well known in the art. Those who are familiar with this artist will be obvious

When judging whether the dose administered is effective, the clinician of negative shell will consider the general efficacy of H7649.doc •25- 201134816 patients, as well as more specific signs, such as whether or not the disease-related symptoms are alleviated, inhibition of tumor growth The actual shrinkage of the tumor: inhibition of metastasis. The size of the tumor can be measured by standard methods, such as radio-logic studies, such as CAT or MRI scans, and continuous metrics; use ° to determine if tumor growth has been slowed or even reversed. Disease-related symptoms such as pain relief and improvement in overall symptoms can also be used to help determine the effectiveness of treatment. The invention is further illustrated by the following non-limiting examples. Modifications and variations that may be readily made by those skilled in the art in light of the teachings of the present invention are included in the scope of the invention. The following four (4) examples ^ The limitations of the present invention, and the scope of the right in the case is defined in the request for the scope of the patent application. EXAMPLES A proton NMR (kneading) spectrum was obtained by a nuclear magnetic resonance spectrometer (Bruker AC 5 〇〇 MHz NMR), and a conventional literature was revealed with respect to tetradecyl (4) (10) s. Using liquid chromatography with tandem f spectrometer (perkin Ei

Sciex API 300 LC/MS/MS svstem, tracing / 曰 / A yStem) obtains a low resolution mass spectrum. Under flash conditions, 佶田目士 λ λ was chromatographed in a column chromatography (Merck) using a gelatin 60 having a particle size of 0.040 to 0.063 mm. Reagents and solvents are obtained from commercial sources and used after receipt. The compounds of the present invention can be prepared by the methods shown in the following schemes (Flowchart 1, Flowchart 2, Flow Diagram 3, and Flowchart 4). Π 7649.doc • 26 - 201134816 Flowchart 1: Synthesis of bromoaromatic quinazolines

Reagents and conditions: (8) formamide, 19 (TC; (b) P0C13, toluene reflux; (C) 3-bromo or 4-bromoaniline, NaH DMSO, 100 ° C ' Flow diagram 2: bromine aromatic or bromide Synthesis of aromatic guanamine

RCOCI or R'COOH 5 6 5a R=3-BrC6H4- 6a R1R2= -N(CH2CH2)2N-CH3 5b = 4-BrC6H4- 5c R'=3-BrC6H4CH2-5d R'=4-BrC6H4CH2-

5e R'=4-BrC6H4OCH2- 5f R,= ΒΓ^ζ^ ll 6c 6d 6e 6f 6g 6h 6i 6j 6k ΓΛ 61 5g R'= BrX〇X 6) 6k rconr1r2 or R.CONRA 7 7a 7b 7c 7d 7e

RiR2= -N(CH2CH2)2N-CH3=-n(ch2ch2>2c-n(ch2)4=-N(CH2)3CHCHrN(CH2)4 = -nh(ch2>3n(ch2ch3)2 = -mh(ch2 2n(ch2ch3)2 = -nh(ch2)3n(ch3)2 =-nh(ch2>2n(ch3>2 =-n(ch3)(ch2>2n(ch2ch3)2 = -NH-N(CH2CH2) 2N-CH3 =-NH(CH2)2N(CH2)5 = -NH(CH2)2N(CH2)4 =-NHN(CH2CH2)20 RiR2=-N(CH2CH2)2N-CH3 = -NH-N(CH2CH2) 2N-CH3 = -NH(CH2)2N(CH2)5 = 'nh(ch2>2n(ch2)4 7f-a 7f-b 7f-c 7f-d 7f-e 7f-f 7f-g 7f-h 7f -i 7f-j 7f-k 7f-l 7g-a 7g-i 7g-j 7g-k Reagents and conditions: (a) EDC1 · HC1, HOBt, CH2C12, room temperature] I7649.doc 27- 201134816 Flowchart 3 : Synthesis of aromatic quinazolinamine derivatives

Nr,r2 9a-7c 9a-7d 9a-7e 9b-7c 9l>7d 9b-7e Reagents and conditions: (a) bis(Pentamic acid) diborate, PdCl2 (dppf), KOAc, DMF, 80 ° C (b) 7a-7e,

PdCl2(dppf), 2M aq. Na2C03 Scheme :4: Synthesis of heteroaromatic guanidine amide derivatives

4a 3-Br 4b 4-Br 8a 3-Br 8b 4>Br

NRfRs x = s 9a-7f X = S 9b-7f x = o 9a-7g X = 0 9b-7g RiR2= -N(CH2CH2)2N-CH3 9a-7f-a 9b-7f-a =-N(CH2CH2 2C-N(CH2)4 9a-7f-b 9b-7f-b =-n(ch2)3chch2-n(ch2>4 9a-7f-c 9b-7f-c = -nh(ch2>3n(ch2ch3) ) 2 9a-7f-d 9b-7f-d = -nh(ch2)2n(ch2ch3)2 9a-7f-e 9b-7f-e =-NH(CH2)3N(CH3)2 9a-7f-f 9b -7f-f =-NH(CH2)2N(CH3)2 9a-7f-g 9b-7f-g =-n(ch3)(ch2)2n(ch2ch3>2 9a-7f-h 9b-7f.li = -nh-n(ch2ch2>2n-ch3 9a-7f-i 9b-7f-i =-NH(CH2)2N(CH2)5 9a-7f-j 9b-7f-j =-NH(CH2)2N(CH2 4 9a-7f-k 9b-7f-K = -NHN(CH2CH2)2〇9a-7f-l 9b-7f-l R!R2= -N(CH2CH2)2N-CH3 9a-7g-a 9b_7g-a = -NH-N(CH2CH2)2N-CH3 9a-7g-i 9b-7g-i =-nh(ch2)2n(ch2)5 9a-7g-j 9b-7g^j =-NH(CH2)2N( CH2)4 9a-7g-k 9b-7g-k Reagents and conditions: (a) bis(Pentamic acid) diborate, PdCl2 (dppf), KOAc, DMF, 80QC; (b) 7a_7e, PdCl2 (dppf) 5 2M aq. Na2C03 -28- 117649.doc 201134816 Example 1-4-((3-Bromophenyl)amino]-6,7-dimethoxyquinazoline (4a) and 4-[(4-bromo) Preparation of Phenyl)amino]-6,7-dimethoxyquinazoline (4b) (Scheme 1) (1) . 6,7-Dimethoxyquinazole _4(3H)-ketone (2) 2-Amino-4,5-dimethoxyoxybenzoic acid gram, 5 〇 millimolar (I) with formamide (8 ml, 200 mM) Mol) was thoroughly mixed in an oil bath and rapidly heated to 190 ° C. After 2 hours at 190 ° C, the reaction mixture was cooled to room temperature, and then diluted with 50 ml of distilled water. The resulting dark gray solid was collected. Rinse with water and acetone' and vacuum dry at 60eC to obtain 6,7-dimethoxyquinazolin-4(3H)-one (2) (2.51 g, 24%) which can be used directly. !H NMR [(CD3)2SO] 512.00 (br s, 1H, NH), 7.92 (s, 1H, H-2), 7.39 (s, 1H, H-5), 7.09 (s, 1H, H8), 3.88, 3.85(2s, 6H, 2-OCH3) (2) _ 4-gas-6,7-dimethoxyindole. Selin (3) dimethylformamide (DMF) (0.5 g, όmole) was added to sulfinium chloride (7.85 ml '66 mmol) and 6,7- under nitrogen at 25 °C. In a stirred solution of dimethoxyquinoxaline-4(3Η)-one (2) (206.1 mg, 1.0 mmol), an exothermic reaction and gas generation were caused. When the gas evolution ceased, the mixture was heated to reflux for 24 hours and cooled to 25 ° C, then the reaction was quenched with diluted aqueous NaHCI. The resulting mixture was stirred on an ice bath for 1 min, and the solid was collected, washed with water, and dried in vacuo at 45 ° C to give 4-chloro-6,7-dimethoxyquinazoline (3) (198.4 mg , 88%), which can be used directly. 117649.doc •29· 201134816 !H NMR (CD3OD) 69.13(s, 1H, H-2), 7.64(s, 1H, H-5), 7.37(s, 1H, H-8), 4.11, 4.05 ( 2s, 6H, 2-OCH3) (3) . 4-[(3-Bromophenyl)amino]-6,7-dimethoxyquinazoline (4a) will be subjected to nitrogen at 110 ° C for 24 hours. , 4-gas-6,7-dimethoxyquinazoline (677 mg, 3 mmol) and 3-bromoaniline (516 mg, 3 mmol) in stirring in DMF (6 mL). Quenching with water gave 4-[(3-bromophenyl)amino]-6,7-dimethoxyquinazoline (962 mg, 78%). 'H NMR [(CD3)2SO] 58.88 (1H, s), 8.43 (1H, s), 8.05 (1H, t, J = 1.85), 7.80 (1H, d, J = 8.46), 7.45 (1H, t , J=8.02), 7.40(1H, s) (4) · 4-[(4-Bromophenyl)amino]-6,7-dimethoxyquinazoline (4b) at ll ° ° C nitrogen Next, for 4 hours, 4-chloro-6,7-dimethoxyfluorene. The reaction of the porphyrin (3) (677 mg, 3 mmol) with 4-bromoaniline (516 mg, 3 mmol) in stirring with DMF (6 mL) and quenched with water to give 4_[(4_bromo) Phenyl)amino]-6,7-dimethoxyquinazoline (765 mg, 62%). ]H NMR [(CD3)2SO] δ11.20(1Η, s), 8.84(1Η, s), 8.24(1Η, s), 7.68(4Η, t, J=9.55), 7.32(1H, s), 4.01 (6H, d, J=6.7) Example Preparation of dibromoaromatic decylamine or bromide aromatic decylamine (7) (Scheme 2) 5-bromothiophene-2-carboxylic acid (207 mg, 1 mM) Mole), 1-hydroxy-peptidic (162 mg, 1.2 mmol) and 1-(3-didecylamino)propyl-3-ethylcarbodiimide hydrochloride (230 mg) , 1.2 mmol) placed in a dry, 10 mL round bottom flask equipped with a Teflon coated magnetic stir bar and rubber septum. The mixture was stirred at 25 ° C for 10 minutes and then cooled in ice cold water 117649.doc -30- 201134816 to o °c. The bottom noise (12 〇 mg, i 2 mmol) and triethylamine (542 μb 3.91 mmol) were added to the cooled solution. The mixture was dropped under 〇C for 1 minute' and then warmed to 25. 〇^ Under 25, stir the μ + compound to convert to -3G ml of the dichloromethane (4) separation funnel with iQ ml, followed by 1 G of 1 N aqueous hydrochloric acid solution, 1 mL of saturated aqueous sodium hydrogencarbonate solution. And 丨〇ml of water extraction product solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. Chromatography is carried out by recrystallization from cerium or from a solvent to give a bromine aromatic amide or a bromide aromatic amide. The following compound was obtained according to the method described below: (3-bromo-phenyl)-(4-methyl-bran-1-yl)-fluorenone (7a) H-NMR (CDC13) 57.55 (2H, t, J=5.8), 7.27(2H, m), 3.87(2H, s), 3.5(2H, s), 2.56(2H, s), 2.44(2H, s), 2.38(3H, s). (4- Bromo-phenyl)-(4-fluorenyl-pyrylene-l-yl)-methylnet (7b) ^-NMRCCDCb) δ 7.58 (2Η, d, J=8.33), 7.34(2H, d, J= 8.285), 2.88(3H, d , J=4.595). 2-(3-Mo-Phenyl)-1-(4-methyl-Brigade"Qin-1-yl)_乙明(7C) lH NMR (CD3OD) 67.41(2H, m), 7.22(2Η, q, 1=9.015), 3.78(2Η, s), 3.61(2Η, t, J=4.91), 3.55(2H, t, J = 5.11), 2.39(2H, t, J=5.125), 2.2758(3H, s). 2-(4-Mo-Phenyl)-1-(4-methyl-Benyl)-Binging (7d) • H- NMRiCDCh) δ7.44(2Η, d, 1=8.31), 7.11(2H, d, 1=8.265), 3.65(4H, d, J=9.16), 3.44(2H, t, J=4.99), 2.35( 2H, 117649.doc •31 · 201134816 t, J=5.01), 2.25 (5H, t, J=4.84). 2-(4-Bromo-phenoxy)-1-(4-methyl-piperazine- 1-yl)-ethanone (7e) 'Η NMR (CD3OD) δ 7.39 (2Η, d, J=8.95), 6.89 (2H, d, J=8.965), 4.79 (2H, d, J=4.175) , 3.58 (4H, d, J = 20.275), 2.43 (4H, d, J = 23.835), 2.31 (3H, s (5-Bromo-thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone (7f-a) NMR (CD3OD) δ 7.20 (1 Η, d, J = 3.91 ), 7.12(1H,d, J=3.96), 3.74(4H, t, J=5.04), 2.48 (4H, t, J=5.095), 2.32(3H, s). (5 - desert-sales- 2-yl)-(4-e-Butyl-1-yl-hexa-e-e-but-1-yl)-methanone (7f-b) *H NMR (CD3OD) δ7.22 (1Η, d, J =3.855), 7.15(1H, d, J=3.845), 4.41(2H, s), 3.14(2H, d, J=7.12), 2.68(4H, d, J=5.555), 2.40(1H, m) , 2.07(2H, d, J=12.985), 1.84(4H, q, J=3.2), 1.46(2H, m). (5-bromo-thiophen-2-yl)-(2-pyrrolidine-1- Methyl-pyrrolidin-1-yl)-methanone (7f-c) * NMR (CD3OD) δ 7.40 (1 Η, d, J = 3.335), 7.16 (1H, d, J = 4.065), 4.43 (1H, s), 3.80(2H, s), 2.78(1H, s), 2.59(5H, q, J=9.09), 2.06(2H, t, J=6.89), 1.99(2H, d, J= 10.095), 1.81 (4H, s). 5-Bromo-thiophene-2-carboxylic acid (3-diethylamino-propyl)-decylamine (7f-d) !H NMR (CD3OD) δ 7.44 ( 1Η, d, J=3.98), 7.14(1H, d, J = 3.96), 3.34(2H, t, J=8.355), 2.58(6H, m), 1.78(2H, s), 117649.doc -32 - 201134816 1.06(6H, t, J=7.205). 5-Moist 嗟--2-Resin (2-diethylamino-ethyl)-nitramine 7f-e) NMR (CD3OD) δ 7.42 (1 Η, d, J = 3.71), 7.12 (1H, d, J = 3.71), 3.42 (2H, t, J = 7.11), 2.67 (2H, t, J =7.11), 2.62 (4H, t, J = 7.11), 1.06 (6H, t, J = 7.11). 5-bromo-thiophene-2-carboxylic acid (3·didecylamino-propyl)-hydrazine Amine (7f-f) !H NMR (CD3OD) 67.69 (1H, d, J = 4.00), 7.3951 (1H, d, J = 4.00), 3.61 (2H, t, J = 6.97), 2.71 (2H, t , J=7.62), 2.05 (2H, quin, J=7.62, 6.97). 5-Bromo-thiophene-2-carboxylic acid (2-dimethylamino-ethyl)-decylamine (7f-g)! H NMR (CD3OD) δ 7.48 (1 Η, d, J = 4.03), 7.16 (1H, d, J = 3.96), 3.48 (2H, t, J = 6.78), 2.56 (2H, t, J = 6.715) , 2.32(6H, s). 5-Bromo-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-methyl-decylamine (7f-h) *H NMR (CD3OD) δ7.31 (1Η, d, J=3.65), 7.15(1H, d, J= 3.65), 3.64(2H, m), 3.32(3H, m), 2.6778 (6H, m), 1.07(6H, s). 5 -Bromo-thiophene-2-carboxylic acid (4-methyl-piperazin-1-yl)-decylamine (7f-i) !H NMR (CD3OD) 67.76 (1H, d, J = 4.13), 7.18 (1H , d, J=4.13), 2.86(4H, t, J=1 1.055), 2.52(4H, s), 2.39(3H, s). 5-bromo-thiophene-2-carboxylic acid (2-hexahydropyridine) -1-yl-ethyl)-decylamine (7f-j) lU NMR (CD3OD) 67.47 (1H, d, J= 3.95), 7.16(1H, d, J=4.01), 3.50(2H, t, J = 6.915), 2.57(2H, t, J=6.945), 117649.doc •33- 201134816 2.53(4H, s), 1.63(4H, q, J=5.665), 1.51(2H, s). 5-Bromo-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-decylamine (7f_k) 'Η NMR (CD3OD) δ7.48(1Η, d, J=4.03), 7·14(1Η,d, J=3.99), 3·53(2Η, t,J=6.625), 2.85(2H, t, J= 6.575), 2.82(4H, s), 1.88(4H, q, J=3.46). 5-Bromo-thiophene-2-carboxylic acid morpholin-4-yl decylamine (7f-1) 'H NMR (CD3OD) δ 7.39 (1Η, d, J=3.92), 7.09(1H, d, J=3.92), 3.75(4H, s (br.)), 3.30(4H, s (br.)). (5-bromo -furan-2-yl)-(4-methyl-piperazin-1-yl)-methanone (7g-a) *H NMR (CD3OD) δ7.02 (1 Η, d, J = 3.54), 6.59 ( 1H, d, J = 3.54), 3.79 (4H, s (br.)), 2.52 (4H, m), 2.34 (3H, s). 5-bromo-furan-2-carboxylic acid (4-methyl- Hexahydropyridin-1-yl)-nonylamine (7g-i) *H NMR (CD3OD) δ7.16(1Η, d, J=3.41), 6.63(1H, d, J = 3.41), 3.37(4H, s (br.)), 2.95 (4H, s (br.)) 5 2.34( 3H, s). 5->Smelly-° Fu Wei-2 - Rebel (2 - Six gas n ratio bite -1- -ethyl)-bristamine 4 NMR (CD3OD) δ 6.95 (1 Η, d, J = 3.44), 6.32 (1H, d, J = 3.44), 3.42(2H, m), 2.48(2H, m), 2.39(4H, m), 1.53(4H, m), 1.37(2H, m). 5-bromo-furan-2-carboxylic acid ( 2-pyrrolidin-1_yl-ethyl)-decylamine (7g-k) ]H NMR (CD3OD) δ7.10 (1Η, d, J = 3.49), 6.60 (lH, d, J = 3.49), 3.53(2H, t, J = 6.783), 2.75(2H, t, J=6.783), 2.68(4H, m), 1.84(4H, m). Example 3 [3,-(6,7-Dimethoxy) - quinazolin-4-ylamino)-biphenyl-3-yl]-(4-曱H7649.doc -34·201134816 ke-[upperazine-1-yl)-methanone (compound 9a- 7a) (Scheme 3) 4[(3-/Smellyl)amino]_6,7-dimethoxy oxime 0 sitting lin (18 〇 mg, 〇. 5 mmol), double (Pingnan Diboron (139.5 mg, 0.55 mmol), KOAc (147 mg, 1_5 mmol) and diferrocene phosphate palladium (PdCl2(dPPf)) (i2 mg, 0.015 mmol) In a dry, 1 mL round bottom flask, it was equipped with a Teflon coated magnetic stir bar and a rubber septum and flushed with nitrogen. Add DMF (3 ml) and at 80. (The reaction was stirred for 2 minutes. After cooling the solution to room temperature, it was then cooled to 0 C in an ice water bath. (3-Bromo-phenyl)-(4-methyl-indanazine-1-yl)- Ketone (7a) (283 mg '1 mmol), PdCl2 (dppf) (12 mg, 0.015 mmol) and 2 Μ Na2C03 (1.3 mL, 2.5 eq) were added and the mixture was mixed under 8 TC nitrogen. After overnight, the solution was cooled to room temperature, and the product was extracted with ethyl acetate (ethyl acetate), washed with water, brine, and dried over magnesium sulfate, and finally purified on silica gel using ethyl acetate and hexane as solvent. To give [3'-(6,7-dimethoxy-quinazolin-4-ylamino)-biphenyl-3-yl]methyl-piperazin-1-yl)-fluorenone (9a -7a). !H NMR (CD3OD) δ 8.43 (1 Η, s), 8.04 (1H, s), 7.79 (3H, m), 7.72 (1H, s), 7.57 (1H, t, 1 = 7.63), 7.51 (1H , t, J=7.78), 7.46(1H, d, J=7.78), 7.42(1H, d, J = 7.63), 7.17(1H, s), 4.04(3H, s), 3.99(3H, s) 2.56(2H, s), 2.44(2H, s), 2.34(3H, s). The following compounds were prepared using the appropriate starting materials as shown in the previous method and in Scheme 3: [3,-(6, 7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-(4-methyl 117649.doc -35· 201134816 ke-tour-1-yl)-hyperthyroid (9 a - 7 b ) !H NMR (CD3OD) δ 8.43 (1 Η, s), 8.07 (1H, s), 7.78 (4H, m), 7.51 (4H, m), 7.18 (1H, s), 4.04(3H, s), 4.01(3H, s), 3.81(2H, s (br.))5 3.55(2H, s (br.)), 2.56(2H, s (br.)), 2.46(2H , s (br.)) 5 2.35(3H, s). 2-[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-3-yl] -1_ (4-Methyl-t-Chloro-1 -yl)-acetamidine (9a-7c) 'Η NMR (CD3OD) 68.39 (1H, s), 7.97 (1H, s), 7.71 (1H, d, J = 7.86), 7.67 (1H, s), 7.54 (2H, d, J=7.80, 7.41(3H, m), 7.22(1H, d, J = 7.50), 7.08(1H, s), 3.98(3H , s), 3.94(3H, s), 3.83(2H, s), 3.62(2H, s (br.)), 3.56(2H, s (br.) ), 2.36 ((2H, s (br.)), 2.2780(2H, s (br.)), 2.21(3H, s). 2-[3'-(6,7-Dimethoxy - quinazoline _4_ylamino)-biphenyl _4_yl]_1_(4-methyl-pyridin-1-yl)-ethanone (9a-7d) 'H NMR (CD3OD) 68.38 (1H, s), 7.96(1H, s), 7.72(1H, d, J=7.82), 7.66 (1H, s), 7.60(2H, d, J=8.16), 7.42(1H, t, J= 7.82), 7.37(1H, d, J=7.82), 7.30(2H, d, J=8.16), 7.07(1H, s), 3.98 (3H, s), 3.94(3H, s), 3.80(2H, s), 3.63 (2H, s (br.)), 3.56 (2H, t, J=4.80), 2.39(2H, t, J=4.99), 2.31(3Η, 2H, t, J=4.80), 2.25 (3H, s). 2-[3'-(6,7-Dimethylmethyl-quinazolin-4-ylamino)-biphenyl-4-yloxy]-1-(4-A基-旅nqqin-1-yl)-acetamidine (9a_7e) !H NMR (CD3OD) 58.41 (1H, s), 7.93(1H, s), 7.77(1H, s), 7.69 (1H, d, J =8.68), 7.61(2H, d, J=8.68), 7.45 (1H, t, 117649.doc -36- 201134816 J=7.83), 7.39 (1H5 d, J=7.83), 7.16(1H, s), 7.05(2H, d, J=8.68), 4.88(2H, s), 4.03(3H, s), 3.99 (3H, s), 3.63 (4H, m), 2.51(2H, t, J=4.89), 2.45(2H, t, J=4.8), 2.32(3H, s).

[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-(4-methyl-piperazin-1-yl)-methanone (9b-7b) 'H-NMRCCDsOD) 88.42 (1H, s), 7.85 (2H, d, J=8.52), 7.74 (3H, d, J=7.07), 7.67 (2H, d, J=8.58), 7.49(2H, d, J=8.17), 7.14(1H, s), 4.02(1H, s), 3.98(1H, s), 3.80(2H, s), 3.55(2H, s), 2.54(2H, s), 2.45(2H, s), 2.34(3H, s). 2-[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-3- 1-(4-indolyl-piperazin-1-yl)-ethanone (9b-7c) ^-NMRCCDsOD) δ8·42 (1Η, s), 7.82 (2H, d, J=8.56), 7.78(1H, s), 7.66(2H, d, J=8.585), 7.56(2H, d, J = 1.805), 7.40(1H, t, J=7.98), 7.23(1H, d, J=7.58) , 7.17(1H, s), 4.04(3H, s), 4.00(3H, s), 3.88(2H, s), 3.60(4H, q, J=5.08), 2.41(2H, t, J=5.095) , 2.28(2H, q, J=13.75), 2.26 (3H, d, J=5.115). 2-[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)- Biphenyl-4-yl]-1-(4-indolyl-piperazin-1-yl)-ethanone (9b-7d) • H-NMRiCDsOD) δ 8.42 (1Η, s), 7.79 (3Η, t, J=8.5), 7.63(4H, q, J=9.07), 7.34(2H, d, J=8.075), 7.17(1H, s ), 4.04(3H, s ), 4.01(3H, s ), 3.84(2H, s), 3.65 (2H, s), 3.59(2H, t, J=4.995), 2.41(2H, t, J=5.005), 2.32(2H} t, J=4.895), 2.28(3H, s). 117649.doc - 37- 201134816 Oxygen 2-[4'-(6,7-Dimethoxy-hatentene _4_ylamino) linkage]-1_(4-methyl-piperazine-i-yl)_ Ethyl ketone (9b7e) 丨 = 5.61), 725), 4.86 J = 4.195), ^-NMR CCDs OD) δ 8.41 (1 Η, s), 7.77 (吒7.59 (4H, q, J=8.76), 7.17 (1H, s), 7.〇5(2H5 (2H, s), 4.04(3H, s), 4.01( 3H, s), 3.64(4Η)^ 2.44 (4H, d, J=4.95), 2.33(3H, s Example Four Preparations According to the method shown in Example 3 and Flowchart 4, the following compounds were used: From {5-[3-(6,7-dimethoxy-quinazoline_4_yl) Amino phenyl group}-(4-methyl-piperazin-1-yl)-methanone (9a7fa) 】 thiophene-2- 丨H NMR (CD3OD) δ8·47(1Η, s), 8.13Πη, s ), 7.82ΠΗ Η J=7.33), 7.48(2Η, m), 7.44(1Η, d J=3 ,, ' J 3·81), 7.42 (1Η, d J=3.81), 7.18(1Η,? ), 4·06(3Η, s), 4, s), 3.85 (4Η, s (br.)), 2·55 (4H, t, J=4.87), 2·37 (3H, s) {5 -[3-(6,7-dimethylhydrazine-quinazolinium-4-ylamino)phenyl]furan-2-yl}-(4-methyl-piperazin-1-yl)-methanone 9a_7g_a) NMR (CD3OD) δ8.44(1Η, s), 8.22(1Η, s), 7.76 (1Η, s), 7.74(1H, d, J=7.83), 7.56(1H, d, J=7.83 ), 7.47(1H, t=7.83), 7.16(1H, s), 7.15(1H, d, J=3.56) , 6.95 (1H, d, J=3.56), 4.04(3H, s), 4.00 (3H , s), 3.89 (4H, s (br.)) 5 2.56 (4H, t, J=5.00 ), 2.35 (3H, s). {5-丨3-(6,7-Dimethoxy-quinoline Oxazoline _4_ylamino)phenyl]-thiophene-2-yl}-(4-"bibrid-1-yl-hexahydropyridinyl)methanone (9a 7f b) -38 - 117649.doc 201134816 'H NMR (CD3OD) δ 8.45 (1Η, s), 8.12 (1Η, s), 7.80(2H, m), 7.44(4H, m), 7.18(2H ,s)5 4.04 ( 3H, s), 4.56 (2H, m), 4.01(3H, s), 3.12(2H, s (br.)), 2.73 (4H, s (br.))5 2.49 (1H, m), 2.10 ( 2H, d, J = 12.32), 1.86 (4H, s (br.)) 5 1.53 (2H, m). {5-[3-(6,7-Dimethoxy-quinazoline-4_yl) Aminophenyl]-thiophen-2-yl}-(2-pyrrolidin-1-ylmethyl-pyrrolidine-i-yl)-methanone (9 A-7f-c) 1h NMR (CD3OD) δ 8.47 (1H, s), 8.16 (1Η, s), 7·81 (2Η, m), 7.63 (1Η, s ( br.) ), 7.49 (3Η, m), 7.20(1Η, s), 4.51(1Η, s), 4.06(3Η, s), 4.03(3Η, s), 3.90 (2Η, s), 2.90(2Η, s (br.) ) 3 2.71(4Η, s (br.) ), 2.13((2H, s (br.)), 2.03(2H, s (br.))5 1.86(4H, s (br.)). 5-[ 3-(6,7-dimethoxy-oxazoline. 4-aminophenyl)- porphin-2-carboxylic acid (2-diethylamino-ethyl)-bristamine (9a- 7f-e) *H NMR (CD3OD) 68.44 (1H, s), 8.11 (1H, s), 7.78 (1H, d, J = 7.59), 7.74 (1H, s), 7.63 (1H, d, J= 3.83), 7.45(2H, m), 7.41(1H, d, J=3.83), 7.14(1H, s), 4.03(3H, s)5 3.98(3H, s), 3.49(2H, t, J= 7.16), 2.73(2H, t, J=7.16), 2.67(4H, q, J=7.15), 1.11(6H, t, J=7.15). 5-[3-(6,7-Dimethoxy) -quinazoline-4-ylaminophenyl]-thiophene-2-carboxylic acid (3-dimethylamino-propyl)·chiral amine (9a-7f-f) lU NMR (CD3OD) 58.44 (1H , s), 8.12(1H, s), 7.78(1H, d, J=7.77), 7.76 (1H, s), 7.63(1H, d, J=3.93), 7.47 (1H, m), 7.42 (1H , d, J=3.93), 7.15(1H, s), 4.03 (3H, s), 3.99(3H, s), 3.40 (2H, t, J=7.25), 2.43(2H, t, J=7.25 ) , 2.28(6H, s), 117649.doc •39· 201134816 1.8129(2H,m). 5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl] -thiophene-2-carboxylic acid (2-diethylamino-ethyl)-methyl-decylamine (9a-7f-h) 'Η NMR (CD3OD) 68.4272 (1H, s), 8.1005 (1H, s ), 7.7875 (1H, d, J = 7.12), 7.7149 (1H, s), 7.4161 (4H, m), 7.1219 (1H, s), 4.0161 (3H, s), 3.9724 (3H, s), 3.6719 ( 2H, s), 3.3099(3H, s), 2.7568(2H, s), 2.6189(4H, s( br.)), 1.0674(6H , s( br.)). 5-[3-(6,7 -dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (4-methyl-piperazin-1-yl)-decylamine (9a-7f-i) *H NMR (CD3〇D) δ 8.47 (1Η, d, J=12.93), 8.21(1H, m), 7.91(2H, m), 7.69 (1H, d, J=3.97), 7.46(3H, m), 7.18 (1H, s), 4.08(3H, s), 4.01(3H, s), 3.10 (2H, d, J=10.62), 2.94(4H, m), 2.61(2H,m), 2.34 (3H,d,J=11.22). 5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-hexa) Hydrogen"pyridin-1-yl-ethyl)-decylamine (9a-7f-j) lH NMR (CD3OD) 58.44 (1H, s), 8.13 (1H, s), 7.78 (1H, d, J = 7.63 ), 7.74(1H, s), 7.64(1H, d, J=3.87), 7.45(2H, m), 7.42(1H, d, J=3.87), 7.14(1H, s), 7.14(1H, s), 4.03(3H , s), 3.99(3H , s), 3.55(2H, t, J=6.85), 2.65(2H, t, J=6.85), 2.59(4H, s (br.)), 1.66 (4H, m), 1.51 (2H, m). 5-[3-(6,7-Dimethoxy) -quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid morpholin-4-yl decylamine (9a-7f-l) !H NMR (CD3OD) 58.46 (1H, d, J =3.85 ), 8.23(1H, m), 117649.doc •40- 201134816 7.89(2H, m), 7.70(1H, d, J=3.50), 7.47(3H, m), 7.18(1H, s), 4.05(3H, s), 4.01(3H, s), 3.82 (2H, m), 2.91(2H, m), 1.29(4H, s (br.)). 5-[3-(6,7-II Methoxy-indolyl-4-ylamino)-phenyl]-bitran-2-pyreic acid (4-methyl-piperazin-1-yl)-nitramine (9a-7g-i) * H NMR (CD3OD) 68.43 (1H, s), 8.21 (1H, s), 7.75 (lH, d, J = 7.89), 7.72 (1H, s), 7.70 (1H, d, J = 7.89), 7.26 ( 1H, d, J=3.56), 7.13(1H, s), 6.94(1H, d, J=3.56), 4.04(3H, s), 3.99(3H, s), 2.98(4H, s (br.) ), 2.66(4H, s (br.)), 2.34(4H, s). 5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)phenyl] Furan-2-carboxylic acid (2-hexahydro"biten-1-yl-ethyl)-decylamine (9a-7g-j) !H NMR (CD3OD) δ8.41(1Η, s), 8.24( 1 , s), 7.68(1Η, s), 7.65(2Η, m), 7.46(1Η, t, J=7.91), 7.15(1H, d, J= 3.29), 7.05 (1H, s), 6.88(1H , d, J=3.29), 4.04(3H, s), 3.98 (3H, s), 3.47(2H, t, J=6.49), 2.58(2H, t, J=6.49), 2.53(4H, m) , 1.59(4H, m), 1.4434(2H, m). 5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)phenyl]-furan-2-carboxylate Acid (2-pyrrolidin-1-yl-ethyl)-chiral amine (9a-7g_k) >H NMR (CD3OD) 68.41(1H, s)5 8.24(1Η, s), 7.69(1Η, s), 7.65(2Η, m), 7.46(1Η, t, J=7.89), 7.15(1H, d, J=3.32), 7.06(1H, s), 6.89 (1H, d, J=3.32), 4.04(3H , s)5 3.98(3H, s), 3.47(2H, t, J=6.49 ), 2.66(2H, t, J=6.49), 1.78(4H, s). {5-[4·(6,7 -dimethoxy-quinazolin-4-ylamino)phenyl]-thiophene-2-117649.doc .41 - 201134816 }}-(4-methyl-piperazin-1-yl)- Ketone (9b-7f-a) 1H-NMR (CD3〇D) δ8.46(1Η, s), 7.71(4H, m), 7.38(2H, q, J=3.81 ), 7.34(1H, d, J =2.045 ), 7.18(1H, s), 4.04(3H, s), 4.01(3H, s), 3.83(4H, s), 2.52(4H, t, J=5.095), 2.35(3H, s). {5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-hexa Pyridin-1-yl)-fluorenone (9b-7f-b) 'H-NMR(CD3〇D) δ8.44(1Η, s), 7.83(2H, d, J=8.555), 7.72(1H, s ), 7.64( 2H, d, J=8.575), 7.32( 2H, q, J=3.775), 7.13(1H, s), 4.02(3H, s), 3.98 (3H, s), 2.64( 4H, s ), 2.36( 1H, d, J = 3.805), 1.82(4H, s), 1.48(2H, q, J=3.695), 1.27(2H, s). {5-[4-(6,7-two Mercapto-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(2-*piro-l-yl-methyl-°*-biti-1·yl)_ Methyl ketone (9b-7f-c) 'H-NMR CCDs OD) 88.46 (1H, s), 7.86 ( 2H, d, 1 = 8.475), 7.75 (1H, s), 7.69 (2H, d, J = 8.56), 7.58(1H, d, J=3.15), 7.38( 1H, d, J=3.915), 7.16(1H, s), 4.04(3H, s), 4.00(3H, s), 2.60(4H, q, J =9.485), 2.1〇(5H, s), 1.82(4H, s). 5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)phenyl]-thiophene _2-carboxylic acid (3-diethylamino-propyl)-bristamine (9b-7f-d) 'H-NMRCCDaOD) 68.42 (1H, s), 7.81 (2H, d, J = 8.565), 7.59(4H, m), 7.32 (1H, d, J=3.84), 7.09(1H, s), 4.00(3H, s), 3.95(3H, s), 3.37(2H, t, J=6.89), 2.55(6H, m), 1.76(2H, q, J=7.005), 1.05( 6H,t,J=7.165). 5-[4-(6,7-Dimethoxyquinazoline_4_ Amine Base) phenylphenylthiophene-2-carboxylate 117649.doc -42- 201134816 Acid (2-diethylamino-ethyl)-decylamine (9b-7f-e) 1H-NMR (CD3〇D) δ8 .44(1Η, s), 7.84(2H, d, J=8.66), 7.75(1H, s), 7.68(2H, d, J=8.695), 7.63(1H, d, J=3.915), 7.37( 1H, d, J=3.91), 7.15(1H, s), 4.02(3H, d, J=6.62), 3.99(3H, s), 3.51(2H, t, J=7.225), 2.73(6H, m ), 1.11(6H, q, J=7.265). 5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid ( 4-Methyl-piperazin-1-yl)-decylamine (9b-7f-i) 'H-NMRCCDaOD) δ 8.45 (1 Η, s), 7.86 (2H, d, J = 5.165), 7.67 (4H , m), 7.38 (1H, d, J=3.905), 7.16(1H, s), 4.04(3H, s), 3.99(3H, s), 2.92(4H, d, J=11.81), 2.34(3H , s). 5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-hexahydropyridin-1-yl) -ethyl)-decylamine (9b-7f-j) ^-NMRCCDsOD) 68.46 (1H, s), 7.86 (2H, d, J=8.6), 7.79 (1H, s), 7.72 (2H, d, J =8.615), 7.65(1H, d, J=3.935), 7.40(1H, d, J=3.87), 7.18(1H, s), 4.04(3H, s), 4.0078(3H, s)5 3.54(2H , t, J=6.92), 2.62(2H, t, J=6.885), 2.57(4H, s), 1.66(4H, d, J=5.615), 1.51(2H , s). 5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl- Ethyl)-decylamine (9b-7f-k) ^-NMR CCDs OD) 68.45 (1H, s), 7.85 (2H, d, J = 8.61), 7.77 (1H, s), 7.70 (2H, d, J = 8.65), 7.65(1H, d, J=3.91), 7.38(1H, d, J=3.865), 7.17(1H, s), 4.04(3H, s), 4.00(3H, s), 3.53(2H, t, J=6.925), 2.72(2H, t, J=6.87), 2.65(4H, s), 117649.doc • 43· 201134816 1.83(4H,m). {5-[4-(6,7- Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-yl}-(4-methyl-tour-1-yl)-methanone (9b-7g-a) 'H-NMRCCDaOD) δ 8.45(1Η, s), 7.88(2H, d, J=8.64), 7.74(3H, t, J=8.685), 7.14(2H, t, J=3.59), 6.88(1H , d, J=3.585), 4.03(3H, s), 3.99(3H, s), 2.56(4H, t, J=4.94), 2.36(3H, s). 5-[4-(6,7- Dimethoxy-«Ί: sinister-4-ylamino)-phenyl]-efu shout-2-deoxy acid (4-methyl-piperazin-1-yl)-decylamine (9b-7g -i) ^-NMRCCDsOD) δ 8.47(1Η, s), 7.92(2H, d, J=7.45), 7.67(4H, m), 7.34(1H, s), 7.19(1H, s), 4.05( 3H, s), 4.01(3H, s), 2.93(4H, s), 2.66(4H, s), 2.31(3H, s). 5-[4-(6,7-Dimethoxy-quinazoline) Porphyrin-4-ylamine )-phenyl]-furan-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl)-decylamine (9b-7g-j) 1H-NMR (CD3〇D) δ 8.45 (1Η, s), 7.85(4H, q, J=8.875), 7.74(1H, s), 7.19(1H, d, J=3.55), 7.14(1H, s), 6.87(1H, d, J=3.56), 4.03(3H, s), 3.98(3H, s), 3.65(2H, s), 2.84(2H, t, J=6.515), 2.76(4H, q, J=8.525), 1.91(6H, s). 5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2·carboxylic acid (2-pyrrolidin-1-yl-ethyl)_ Indoleamine (9b-7g-k) 'H-NMRCCDsOD) δ8.45(1Η, s), 7.86(4H, d, J=9.48), 7.75(1H, s)5 7.18(1H, d, J =3.585 ), 7.15(1H, s), 6.86(1H, d, J=3.605), 4.03(3H, s), 3.99(3H, s), 3.56(2H, t, J=6.8), 2.74(2H, t , J = 6.82), 2.64 (4H, d, J = 5.45), 1.83 (4H, q, U7649.doc -44- 201134816 J=3.12). Example 5 The enzyme inhibition of a representative compound of the present invention was tested according to the following method. Activity: Using Upstate's human EGFR kinase domain, a purified and activated enzyme that directly phosphorylates the receptor. EGFRJ敫ase 涓ij test (Kinase Assay) Bay Q is the use of this enzyme 'simultaneous force σ into the test compound and radioactive (triphenyl acid) (ATP), because the test compound is an ATP competitor, will Competing with radioactive ATP, and finally by screening the strong ATP competitor, that is, a potent EGFR inhibitor, by the strength of the radioisotope on the receptor, the VEGFR Kinase Assay was performed in the same manner. The enzyme inhibitory activities of representative compounds of the present invention are shown in Tables 1 and 2 below: Table 1. Enzyme inhibitory activities of the compounds (9a-7a)-(9a-7e) and (9b-7a)-(9b-7e)

9a-7c 9a-7d 9a-7e

9b-7a 9b-7b 9b-7c 9b-7d 9b-7e compound 9a-7a

Percentage of inhibition at 10 μΜ Compound EGF VEGF

Inhibition in ΙΟμΜ Ζ Percentage of use EGF VEGF 57.6% 4.4% 9b-7a

73.1% 66.2% 117649.doc • 45· 0 201134816 9a-7b 0 91.3% 21.9% 9b-7b jO^O, 47.4% 4.6% 9a-7c 57.9% 27.7% 9b-7c kJ, 88.6% 19.8% 9a-7d 54.0% 12.7% 9b-7d rf 70.0% 8.6% 9a-7e 80.7% 1.0% 9b-7e 74.7% 9.7% 9a-7f-ax!^〇n, 76.1% 24.3% 9b-7f-a is c/ 0 69.1 % 1.7% 9a-7g-a 70.3% 1.8% 9b-7g-a is cr o 65.5% 1.3% PD153035 93.8% 44.7% Table 2. Compounds (9a-7f)-(9a-7g) and (9b-7f) -(9b-7g) enzyme inhibitory activity

X = S 9a-7f X = S 9b-7f X = 0 9a-7g X = O 9b-7g

Inhibition at 10 μΜ, inhibition at 10 μΜ, percentage of W, compound W, percentage, EGF, VEGF, EGF, VEGF

46- Compound 9a-7f-a 117649.doc 201134816 9a-7f-b

, N〇 72.8% -16.4% 9b-7f-b 62.2% -4.3% 9a-7f-c 9a-7f-d 9a-7f-e

9a-7f-f 9a-7f-g9a-7f-h

93.4% 36.0% 60.3% 26.9% 82.1% 40.0% 81.5% 17.5% 78.8% 47.0% 9b-7f-c 9b-7f-d 9b-7f-e 9b-7f-f 56.2% 33.5%

39.5% -65.5% 61.5% -11.5% 92.5% 19.6% YN'o 9b-7f-g 79.7% 31.3% 9b-7f-ho 84.2% 19.5% 9a-7f-i 90.8% 32.8% 9b-7f-i 丫, O' 74.4% 12.9%

9a-7f-j 9a-7f-k 9a-7f-l 9a-7g-a Η

90.5% 60.1% 78.4% 63.8% 80.0% 0.2% 70.3% -2.3% 9b-7f-j 9b-7f-k 9b-7f-l 9b-7g-a H "ιγΝ'^'Ν,

O YN' o YNr 〇66.1% -63.1% 63.8% -23.9% 65.5% 1.3% 117649.doc • 47· 201134816 9a-7g-i 0 Wide N, H 85.5% 17.7% 9a-7g-j People ~o H 83.6% 41.1% 9a-7g-k person ~〇H 85.8% 9.9% PD153035 93.8% 44.7% 9b-7g-i H YN. 〇83.7% 16.6% 9b-7g-j H YN, o 85.0% -10.2% 9b -7g-k H y, ^N0 74.0% 15.9% 48- I17649.doc

Claims (1)

201134816 VII. Patent application scope: 1- a compound of formula (I), Wherein: R is ^-Y-(CH2)n-, wherein X is C=C, 〇 or S, Y is Ο or direct bond, η is 〇, 1, 2 or 3; R1 and R2 are independently selected from: 1 ) Η ; 烧基' can be replaced by _NRsR6, where 尺 5 and 尺6 are independently q.6·alkyl, or R5 and R6 and its subsequent n-form form a 3- to 10-member saturation containing n A heterocyclic ring having at least one anthracene group _(ch2)_ on the ring may be optionally substituted by -Ο-, -(NR7)- or -(CHR8)-, wherein R7 is an alkyl group and R8 is an n-containing group 3- a 10-membered saturated heterocyclic ring, or a Ci6-alkyl group substituted with a 3- to 10-membered saturated heterocyclic ring containing N; and 3) a 3- to 10-membered saturated heterocyclic ring containing N, at least one ring Yttrium _ (CH2)- may be -〇_, substituted; or, R1 and R2 and its subsequent N form a 3- to 10-membered and heterocyclic ring containing at least one methylene group on the ring (CH2)_ may be replaced by (NR7)_ or -(CHR8)-; R3 is Η or C n alkyl group, wherein the alkyl group may optionally be one to three selected from the group consisting of 117649.doc 201134816 Substituted by a substituent: halogen, Ci 4 alkoxy, -n(r9)(r9) and -S〇Rl0 ' wherein r9 is independently H or R10, and Rio is Cl_4 alkane R4 is a group selected from the group consisting of hydrazine hydroxy, amine, carboxyl, amine sulfhydryl, ureido, C14 alkoxyamine, fluorenyl, N-Cm alkylamine fluorenyl, N, N-di(Cw alkyl)amine oxime, trans-amino group, Ci_4 alkoxyamino, C14 alkoxyamino, difluoromethoxy, C!-4 alkyl, Cm alkoxy Or (^_3 alkyldioxy; 2) — [(CK4-alkyl)]amino c24-alkoxy, pyrrolidine-fluorene-based heart-fluorene alkoxy, hexahydroacridinyl C2·4 - alkoxy, morpholinyl alkoxy, piperazin-1-yl-C2_4-alkoxy, 4-CN4-alkylpiperazin-1-yl-c2.4-alkoxy. -1-yl-C2-4·alkoxy, bis[(Ci 4 —alkoxy)-C24_alkyl]-amino-C 2·4-alkoxy, thiomorpholinyl C24-alkoxy , i oxythiomorpholinyl c: 2·4-alkoxy, or 二^dioxythiomorpholinyl C24_ alkoxy] wherein any of the aforementioned groups contains anthracenyl-(CH2)- Not attached to N or deuterium atoms, may be replaced by hydroxyl groups; 3) hydrazine, dentate, hydroxyl, hydroxylamine, carboxyl, nitro, thiol, ureido, cyano, trifluoromethyl or (^ _4 alkyl-W-phenyl, wherein W is a direct bond, hydrazine, S or hydrazine; 4) C?_4 alkyl or R" substituted by a cyano group, or wherein r11 is selected from the group consisting of r10, -OR9, - NR9R9, -C(〇)R12, _NHOR10, -〇C(0)R9, cyano, U and -VR10, wherein r1, Rl0, _〇r9 or _nr9r9, u is selected from the group consisting of ✓, hydrogen, and bite , 淋 基 基, n ratio slightly. Base, 4_r9_ σ bottom 嘻 _ i _ group, imidazol-1-yl, 4-.比 镔 丨 丨 丨 、, Ci 4 alkyl (c 〇 2h), 117649. doc -2- 201134816 phenoxy, phenyl, phenyl sulfoximine, C 2 · 4 alkenyl and Cl-4 Alkyl c(o)nr9r9, V is S, so, S〇2 ' wherein the alkyl group of the alkyl group, -OR9 and -NR9R9 may be substituted by 1 to 3 halogens, and may optionally be 1 to 2 Substituting R", and the alkyl group in R11 may be replaced by halogen or R11, the first of which is: no two heteroatoms on the same carbon, 5) selected from -NHS02R10, quinone imine <^-4 alkylsulfonylamino, benzhydrylamine, benzenesulfonylamino, 3-phenylureido, 2-oxapyrrolidinyl-I-based, 2,5-dioxa Pyrrolidinium-yl group and 1^丨3 (:; 2-4 alkanoylamino group, wherein R13 is selected from the group consisting of halogen, —OR9, c2-4 alkanomethoxy, _C(0)r12 and _NR9R9′ and The defined R4 group may be optionally substituted by one to two groups selected from the group consisting of dentate, Ri〇, cyano, sulfonyl and Ci-4 alkoxy; and 6) two R4 The carbon attached thereto forms a 5- to 8-membered ring containing a hetero atom selected from the group consisting of ruthenium, S and N; and m is 1, 2 or 3; or , a stereoisomer, a prodrug or a pharmaceutically acceptable salt or solvate. 2. A compound of claim 1 which is a compound shown below: R-C-NRR 117649.doc 201134816 wherein R and NWR2 are defined as follows: R NR'R2 3-BrC6H4- -N(CH2CH2)2N-CH3 4-BrC6H4--n(ch2ch2)2n-ch3 3-BrC6H4CH2- -n(ch2ch2)2n-ch3 4-BrC6H4CH2--n(ch2ch2)2n-ch3 4-BrC6H4〇CH2--n(ch2ch2)2n-ch3 3. The compound of claim 1, which is a compound shown below: Wherein R and NWR2 are defined as follows: R NR!R2 3-BrC6H4- -N(CH2CH2)2N-CH3 4-BrC6H4- -N(CH2CH2)2N-CH3 3-BrC6H4CH2- -n(ch2ch2)2n-ch3 4 -BrC6H4CH2- -n(ch2ch2)2n-ch3 4-BrC6H4OCH2--n(ch2ch2)2n-ch3 4. The compound of the claim ,, which is the compound shown below: The definition of NW is as follows: 1l7649.doc 4- 201134816 _NR^2 -N(CH2CH2)2N_CH3 -n(ch2ch2)2c-n(ch2)4 -n(ch2)3chch2-n(ch2)4 -NH(CH2)3N(CH2CH3)2 -nh(ch2)2n( Ch2ch3)2 -nh(ch2)3n(ch3)2_ -nh(ch2)2n(ch3)2 -nh(ch3)(ch2)2n(ch2ch3)2 -nh-n(ch2ch2)2n-ch3 -NH(CH2 2N(CH2)5_-NH(CH2)2N(CH2)4_-nhn(ch2ch2)2o_ 5. The compound of claim 1, which is a compound shown below: Wherein, the definition of NRiR2 is as follows: __NW - N(CH2CH2)2N-CH3 - N(CH2CH2)2C-N(CH2)4 -N(CH2)3CHCH2-N(CH2)4 -nh(ch2)3n(ch2ch3)2 -NH(CH2)2N(CH2CH3)2 -nh(ch2)3n(ch3)2_ -nh(ch2)2n(ch3)2_ nh(ch3)(ch2)2n(ch2ch3)2 -nh-n(ch2ch2)2n -ch3 -NH(CH2)2N(CH2)5-NH(CH2)2N(CH2)4_-NHN(CH2CH2)2〇_ 6. The compound of claim 1 which is a compound shown below: 117649.doc 201134816 Where nWr2 is defined as follows: _NR'R2_ -N(CH2CH2)2N-CH3 -nh-n(ch2ch2)2n-ch3_ -NH(CH2)2N(CH2)5 -NH(CH2)2N(CH2)4_ 7. The compound of claim 1, which is the compound shown below: Where NR1^2 is defined as follows: _NR] R2_ -n(ch2ch2)2n-ch3 -NH-N(CH2CH2)2N-CH3_nh(ch2)2n(ch2)5_ -nh(ch2)2n(ch2)4_ 8 A pharmaceutical composition comprising a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof And a pharmaceutically acceptable diluent, adjuvant or carrier. A pharmaceutical composition for inhibiting abnormal cell growth, which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, adjuvant or carrier. I17649.doc 201134816 i〇. A pharmaceutical composition for the treatment of neoplastic diseases, tumors or cancer, gossip. A compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, adjuvant or carrier. 11. A pharmaceutical composition according to claim 8, 9 or 1 (), which comprises a therapeutic agent which is useful for inhibiting abnormal cell growth or treating neoplastic diseases, tumors or cancer, and is useful for inhibiting Use of another therapeutic agent or therapy for abnormal cell growth or for the treatment of neoplastic diseases, tumors or cancer. 12. The pharmaceutical composition of claim 11, wherein the additional treatment #1 is a microtubule affector, an anti-tumor, an anticancer agent, an anti-angiogenic agent, an EGFR kinase inhibitor, an EGFR inhibitor, a VEGFR kinase inhibitor (4) sigh inhibitors, dual inhibitors of EGFR and VEGFR, or interferon; the therapy is radiotherapy 13 - a compound of the claim ^ for the preparation of a medicament, which causes the coughing agent to act as a dual inhibitor of EGFR and VEGFR 2, such as a compound of the request for the preparation of a medicament, wherein the medicament is used To inhibit abnormal cell growth. 15. A method for the use of a compound according to claim 1 for the treatment of a neoplastic disease, for the use of a medicament, for a tumor or a cancer, wherein the use of the drug is as follows: 16. For the purpose of claim 13, 13 or 15 The agent contains another active ingredient which can be used to inhibit abnormal cell growth or treatment, a disease, a tumor or a cancer, or the agent can be used to inhibit abnormal cell growth or to treat a neoplastic disease, tumor or combination Another therapeutic or therapeutic treatment for sputum cancer 17. The active ingredient or therapeutic agent according to claim 16 is micro-117649.doc 201134816 tube-affecting ingredient or preparation, anti-tumor ingredient or preparation, anti-cancer ingredient or preparation, anti-angiogenic ingredient or preparation, EGFR kinase inhibitory ingredient or preparation An EGFR inhibitory component or formulation, a VEGFR kinase inhibitory component or formulation, a VEGFR inhibitory component or formulation, a dual inhibitory component or formulation of EGFR and VEGFR, or an interferon; the therapy is radiation therapy. 18. A method of preparing a compound of claim 1, which comprises the steps of: (a) using a compound of formula (II) as shown below Wherein R 3 and R 4 and m are as defined in claim 1 and T is halogen or sulfonyl sulfonyl, in the presence of a suitable base and a catalyst, in a suitable solvent, with a suitable Suzuki coupling agent; (b) The compound of the formula (II) obtained by the step (a) and the amide of the formula (VI) of RCONWR2 wherein R, R1 and R2 are reacted as defined in claim 1 in the presence of a suitable base and a catalyst to obtain R, A compound of the formula (I) wherein R1, R2, R3 and R4 correspond to m. 117649.doc 201134816 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: U7649.doc -2-