WO2013064068A1

WO2013064068A1 - Thienopyrimidine and furopyrimidine derivatives, preparation method thereof and medical use thereof

Info

Publication number: WO2013064068A1
Application number: PCT/CN2012/083830
Authority: WO
Inventors: 安晓霞; 别平彦; 刘俊; 杨午立
Original assignee: 上海希迈医药科技有限公司
Priority date: 2011-11-03
Filing date: 2012-10-31
Publication date: 2013-05-10
Also published as: CN103087077A; CN103087077B

Abstract

Disclosed are thienopyrimidine and furopyrimidine derivatives, the preparation method thereof and the medical use thereof. The derivatives have a structure as shown in formula V. The thienopyrimidine and furopyrimidine derivatives provided in the present invention have dominant EGFR inhibiting activity, and some of these compounds also have dominant inhibiting activity against VEGFR; therefore, same can expect to be developed as tyrosine kinase EGFR and/or VEGFR inhibitors, and to be used for preparing the drugs for preventing or treating the diseases related to epidermal growth factor receptor EGFR and/or vascular endothelial growth factor receptor VEGFR. Provided is a new development direction and approach for developing novel tyrosine kinase inhibitor drugs having low drug resistance or able to relieve drug resistance to the inhibitor in the early stages, thereby having extensive application prospects and medical value.

Description

Thienopyrimidine and furopyrimidine derivatives, preparation method thereof and application thereof in medicine

The present invention relates to a pyrimidine derivative, a preparation method and application thereof, and more particularly to a thienopyrimidine and furanopyrimidine derivative having an epidermal growth factor receptor EGFR and/or an angiogenic factor receptor VEGFR inhibitory activity. The invention, the preparation method thereof and the application thereof in medicine belong to the technical field of medicinal chemistry. Background technique

Tumor is one of the most serious diseases that threaten human health. Its treatment mainly includes radiotherapy, chemotherapy and surgery. In recent years, with the development of cell biology and oncology, the chemical treatment of tumors has undergone tremendous changes. Conventional chemotherapeutic drugs are gradually rejected due to non-specific blockade of cell division, which also causes normal cell death while killing tumor cells. At the same time, key node proteins in abnormally activated signaling pathways in tumor cells are targeted. It has been found that high-efficiency, low-toxicity and specific small-molecule inhibitors have become an important direction for the research and development of anti-tumor drugs. Receptor tyrosine kinase (RTK), which is aberrantly expressed in tumors, has become a hot spot in anti-tumor drug research because it plays a key role in tumor development, invasion and metastasis, and chemotherapy resistance.

Epidermal growth factor receptor (EGFR), also known as HER1 or cerbBl, is a member of the HER family, the most widely expressed tyrosine kinase in human cancers. The EGFR structure consists of three regions: the extracellular region, the transmembrane region, and the intracellular region. The amino terminal of the extracellular domain consists of 622 amino acids, with two cysteine-rich segments forming a ligand binding region; the transmembrane region is single (X-helix; the intracellular region includes the kinase region and has many tyrosine The terminal end of the carboxyl group of the acid phosphorylation site. Tyrosine kinase (RTK) transports the gamma phosphate of ATP to the tyrosine residue. After binding to the ligand, homologous or heterodimerization of EGFR occurs. The ΤΚ region is tightly linked. The phosphorylation of the tyrosine phosphorylation site at the carboxyl terminal tail RTK creates a binding site for the enzyme and the linker protein (Y992, Y1068, Y1086, Y1148 and Y11730). It can initiate intracellular signaling reactions. These signals form different cellular responses, including proliferation, differentiation, adhesion and angiogenesis, metastasis, and inhibition of apoptosis.

Studies have shown that EGFR is expressed in non-small cell lung cancer, prostate cancer, breast cancer, colorectal cancer, head and neck cancer, gastric cancer, ovarian cancer, and pancreatic cancer. EGFR activation triggers complex signaling reactions. In different types of solid tumors, EGFR proliferates and overexpresses, leading to the loss of control of downstream signaling leading to the formation of various tumors. Mutations in the ATP-binding site in EGFR affect the RTK activity of the receptor and interfere with the formation of tumorigenic signals. At the same time, EGFR is also closely associated with tumor progression and poor prognosis.

Due to the unique role of EGFR and VEGFR in tumorigenesis, monoclonal antibodies and small molecule inhibitors have become hotspots in the development of targeted anti-tumor drugs. At present, several inhibitors targeting EGFR or VEGFR have been marketed, and nearly 20 drug candidates are in clinical development stages. Among them, gefitinib and erlotinib represent an earlier marketed small molecule inhibitor targeting EGFR. Gefitinib (Gefitinib, also known as ZD1839 or Iressa) as three Single-line therapy is used for non-small cell lung cancer (NSCLC). Erlotinib (also known as OSI774 or Tarceva) is a standard regimen for the treatment of ineffective second- or third-line treatments for advanced NSCLC.

However, with the clinical application of these drugs, it has been found that not all patients with high expression of EGFR are effective against these drugs, and some tumors that initially respond to Gefitinib have a disease several months after treatment. progress. These results indicate that the currently used EGFR inhibitor anti-tumor drugs have natural or secondary drug resistance, therefore, the development of new drugs with low drug resistance or ability to alleviate early inhibitory drug resistance has become tyrosine kinase inhibition. The new development direction of the agent. Summary of the invention

In view of the above problems in the prior art, an object of the present invention is to provide a thienopyrimidine and furan pyrimidine derivative having epidermal growth factor receptor EGFR and/or angiogenic factor receptor VEGFR inhibitory activity, and preparation thereof Method and its application in medicine. In a first aspect of the invention, there is provided a compound of formula V, or a tautomer, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable Accepted solvate,

Wherein, R is selected from: hydrogen, d- alkyl or substituted alkyl of _6, d- ₆ alkyl group (preferably an alkyl group of ¾- _6), C ₃ - ₆ cycloalkyl group (preferably C ₄ - ₆ cycloalkyl group), C ₂ - ₆ alkene group (preferably C ₃ - ₆ alkene group) or a substituted alkene group, an aryl group an acyl group or a substituted aryl group, a sulfonyl group, an amide group or a substituted amide group, a reverse amide group or a substituted reverse amide group, an alkoxy group of - ₈ ;

R ³ is hydrogen, C ₆ alkyl or substituted _-6 alkyl;

Z is nitrogen or CH;

R ¹ is -CH ₂ - or -C(=0)- _;

Ar is selected from the group consisting of: C ₆ _ ₂ . Aryl or substituted C ₆ _ ₂ . Aryl, or C ₄ _ ₂ . Heteroaryl or substituted C ₄ _ ₂ . Miscellaneous

3⁄4:

Q is

, X is oxygen or sulfur, R ² is hydrogen or d- ₆ alkyl or substituted

Ci~6 thiol;

Ar _{2 is} selected from the group consisting of: an aryl group of C ₆ -20 or a substituted C ₆ _ ₂ . Aryl, or C ₄ _ ₂ . Heteroaryl or substituted C ₄ _ ₂ . Miscellaneous Base.

In another preferred embodiment, the compound of formula V is a compound of formula I, formula II, formula III or formula IV:

In the above formula:

X is oxygen or sulfur; Z is nitrogen or carbon;

R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and 2 to 6 Any one of an olefin acyl group or a substituted olefin acyl group of a carbon atom, an aryl acyl group or a substituted aryl acyl group, a sulfonyl group, an amide group or a substituted amide group, a reverse amide group or a substituted reverse amide group;

Ar ¹ is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl, 2- or 3 a -C ₃ alkyl substituted phenyl, thienyl, 3-C ₃ alkyl substituted thienyl, furyl, 3-C ₃ alkyl substituted furanyl, 2 or 3-pyridyl;

Is phenyl, halogen substituted phenyl, d- ₆ alkyl substituted phenyl, biphenyl, halogen substituted biphenyl, naphthyl, pyridyl, thienyl, halogen substituted thienyl, d- ₃ alkane Any one of a thiophenyl group, a furyl group, a halogen-substituted furyl group, and a d- ₃ alkyl-substituted furyl group.

Further, in the formula: X is oxygen or sulfur; Z is nitrogen; Ar ¹ is phenyl; Ar ₂ is phenyl; R is hydrogen, alkyl having 1 to 6 carbon atoms or substituted alkyl, 1 An alkyl acyl group of ~6 carbon atoms, a cycloalkyl acyl group having 3 to 6 carbon atoms, an olefin acyl group having 2 to 6 carbon atoms or a substituted olefin acyl group, an aryl acyl group or a substituted aryl acyl group, a sulfonyl group Any of an acyl group, an amide group or a substituted amide group, a reverse amide group or a substituted reverse amide group.

In another preferred embodiment, R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms. An acyl group, an olefin acyl group having 2 to 6 carbon atoms or a substituted olefin acyl group, an amide group or a substituted amide group;

Ar is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl, 2- or 3- Any one of d- ₃ alkyl substituted phenyl groups; Any one of a phenyl group, a halogen-substituted phenyl group, a d- ₆ alkyl-substituted phenyl group, a biphenyl group, a halogen-substituted biphenyl group, and a naphthyl group.

In another preferred embodiment, the substituted alkyl group is a substituted d- ₆ alkyl group, the substituted olefin acyl group is a substituted C ₃ _-6 olefin acyl group, and the aryl acyl group is C ₆ - ₂ . An aryl acyl group, the substituted aryl acyl group is a substituted C ₆ -20 aryl acyl group, the sulfonyl group is a sulfonyl group of d- ₁₅ , and the amide group is an amide group of d- ₁₅ , The substituted amide group is the substituted amide group of C _i5 .

In another preferred embodiment, the substituted alkyl group, substituted olefin acyl group, substituted aryl acyl group, substituted amide group or substituted reverse amide group, substituted aryl group, or substituted heteroaryl group means substituents selected from the group consisting of: fluoro, chloro, bromo, iodo, cyano, hydroxy, d- ₆ alkyl, C ₃ - ₆ cycloalkyl, d- ₆ alkoxy, amino, d_ ₆ alkoxycarbonyl group , nitro, amino, acyl, amide, sulfonyl, d- ₆ haloalkyl.

In another preferred embodiment, the substituted amide group or substituted reverse amide group refers to a substituent-substituted amide group or a substituted reverse amide group selected from the group consisting of: the substituent is bonded to N in the amide group to form Morpholine, pyrrole, piperazine or piperidine, optionally substituted with a substituent selected from the group consisting of d- ₆ alkyl, d- ₆ alkoxy.

In another preferred embodiment, the compound of the formula V is any one of the compounds listed in Table 1.

Table 1

S 2- {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino}-2-benzene

1 base - ethanol

, N^ human S 2- {6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino} 2-phenyl-ethanol

^ ₌ /. ^H 0-2-{6-[4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino} -2-phenyl-ethanol

~ ^f S ,

O

^ ₌ / ^0H S 2-(6- {4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-phenylthieno[2,3-d]pyrimidine-4- Benzyl}-2-phenyl-ethanol-2-phenyl-2-[6-(4-piperazin-1-ylmethyl-phenyl)-thieno[2,3-d]pyrimidine-4- Amino]-ethanol

,. ^h -(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl )-morpholin-4-yl)-methanone

o~<. . ^H -(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl )-pyrrol-1-yl-ketone

0(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl) -(4-methoxy-piperidin-1-yl)-methanone

Eight _N

Dimethylamino-1 -(4-{4-[4-(2-hydroxy- 1 -phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylper Pyrazin-1-yl)-butyl-2-en-1-one

0(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl) -piperidin-1-yl)-methanone

0(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine -1-

^= human base) -N-ethyl-piperazin-1-yl)-methanone

The pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, and the like; organic acid salts such as formate, acetic acid Salt, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.; alkyl sulfonate, such as methyl sulfonate, ethyl sulfonate Salts and the like; aryl sulfonates such as besylate, p-toluenesulfonate and the like.

The pharmaceutically acceptable solvate includes, without limitation, a solvate of the compound with water, ethanol, isopropanol, diethyl ether, acetone or the like. In a second aspect of the invention, there is provided a process for the preparation of a compound of formula V, comprising: a step of reacting a compound of formula VI VII to obtain a compound of formula V,

VI V

In each formula, ⁴ is a hydroxyl group or a - ₆ alkane

R ⁵ -Q- is

Or, R ⁵ is F, Cl, Br, I;

The definitions of R, Z, R ³ , RX, R ² , Ar and Ar ₂ are as described in the first aspect.

The invention provides a method for preparing a thienopyrimidine and a furanopyrimidine derivative represented by the formula I, which comprises the following step 3 or steps 1 and 3 or steps 2 and 3 or steps 1 to 3:

The preparation method of the thienopyrimidine and furanopyrimidine derivatives represented by the formula of the present invention includes the following Step 5 or Steps 2 and 5 or Steps 4 and 5 or Steps 2 and 4 and 5:

The present invention provides a process for the preparation of a thienopyrimidine and a furanopyrimidine derivative represented by the general formula III, which comprises the following step 7 or steps 1 and 7 or steps 6 and 7 or steps 1 and 6 and 7:

The method for preparing a thienopyrimidine and a furanopyrimidine derivative represented by the formula IV provided by the present invention comprises the following Step 8 or Steps 4 and 8 or Steps 6 and 8 or Steps 4 and 6 and 8:

Further, the thienopyrimidine and the furanopyrimidine derivative represented by the above formula 还 can also be obtained by hydrogenating a thienopyrimidine represented by the formula I and a furand pyrimidine derivative.

Further, the thienopyrimidine and the furanopyrimidine derivative represented by the above formula IV can also be obtained by hydrogenating a thienopyrimidine represented by the formula III and a furanopyrimidine derivative. In a third aspect of the invention, there is provided a compound of formula V, or a tautomer, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable The use of solvates.

The thienopyrimidine and furanopyrimidine derivatives of the present invention have inhibitory activities against epidermal growth factor receptor (EGFR) and/or angiogenic factor receptor (VEGFR), and thus, the thiophene of the present invention And pyrimidine and furan pyrimidine derivatives or tautomers, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable Any one or a mixture of solvates may be used to prepare tyrosine kinase inhibitors, particularly for the preparation of EGFR and/or VEGFR inhibitors.

Further, the inhibitor may be applied to the preparation of a medicament for preventing or treating a disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR, and in particular, for the preparation of a prophylactic or therapeutic agent with epidermal growth factor Receptor EGFR and/or angiogenic factor receptor VEGFR-associated cells with abnormal proliferation, morphological changes, hyperkinesia, angiogenesis, and tumor metastasis.

Furthermore, the inhibitors are useful for the preparation of a medicament for the treatment or prevention of tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.

Furthermore, the active ingredient of the inhibitor is preferably a compound shown in Table 1 or a tautomer, a racemate, an enantiomer, a diastereomer, or a pharmaceutically acceptable compound of the indicated compound. Any one or a mixture of the accepted salts, pharmaceutically acceptable solvates. According to a fourth aspect of the present invention, there is provided a tyrosine kinase inhibitor, the compound of the formula V according to the first aspect, or a tautomer thereof, a racemate, an enantiomer, a diastereomer A mixture of any one or a mixture of an isomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate is prepared. The tyrosine kinase inhibitor refers to an EGFR and/or VEGFR inhibitor. According to a fifth aspect of the invention, the use of the tyrosine kinase inhibitor of the fourth aspect, for the preparation of:

(i) a drug that prevents or treats diseases associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR;

(ii) a drug that prevents or treats abnormal cell proliferation, morphological changes, hyperkinesia, angiogenesis, and metastatic disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR;

(iii) Drugs for preventing or treating tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR. According to a sixth aspect of the invention, a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound of the formula V according to the first aspect, or a tautomer thereof, a racemate, an enantiomer A diastereomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. In the present invention, the pharmaceutically acceptable salt includes, without limitation, a mineral acid salt such as a hydrochloride, a hydrobromide salt, a nitrate salt, a sulfate salt, a phosphate salt or the like; an organic acid salt such as formic acid. a salt, an acetate, a propionate, a benzoate, a maleate, a fumarate, a succinate, a tartrate, a citrate, etc.; an alkylsulfonate such as a methylsulfonate, Ethyl sulfonate or the like; aryl sulfonate such as benzenesulfonate, p-toluenesulfonate and the like.

The pharmaceutically acceptable solvate includes, without limitation, a solvate of the compound with water, ethanol, isopropanol, diethyl ether, acetone or the like. Compared with the prior art, the thienopyrimidine and furanopyrimidine derivatives provided by the present invention have novel structures, have obvious EGFR inhibitory activity, and some compounds have significant inhibitory activity against VEGFR, and are expected to be developed as tyrosine. Kinase EGFR or/and VEGFR inhibitors for the prevention or treatment of abnormal cell proliferation, morphological changes, hyperkinesia, and angiogenesis associated with epidermal growth factor receptor EGFR and/or angiogenic factor receptor VEGFR Or a drug for tumor metastasis-related diseases, especially for the preparation of a drug for treating or preventing tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR, for the development of novel low drug resistance Or tyrosine kinase inhibitor drugs that can alleviate the resistance of early inhibitors provide new development directions and approaches, and have broad application prospects and medicinal value. detailed description

the term

As used herein, "d- ₆ " means having 1 to 6 carbon atoms, and similarly, "C ₃ - ₆ " means having _{3 to} ₆ carbon atoms; "C ₂ - ₆ " Means having 2 to 6 carbon atoms; "C ₂ - ₈ " means having _{2 to} ₈ carbon atoms.

"Alkyl" means a chain-saturated organic functional group containing only carbon and hydrogen atoms, including branched and linear alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, and iso- Butyl, sec-butyl, tert-butyl and the like.

"Cycloalkyl" means a cyclic organic functional group containing two atoms of carbon and hydrogen, such as cyclopropyl, cyclobutane and the like. "Acyl" means a functional group having -C (=0) -.

"Alkyl acyl" means a group formed by linking an alkyl group to -C(=0)-, and alkyl acyl group of d- _{6 is} a group formed by linking an alkyl group of ^ ₆ to -C(=0)-. group.

"Cycloalkyl acyl" means a group formed by linking a cyclic organic functional group containing two atoms of carbon and hydrogen to -C (=0) -. C ₃ - ₆ cycloalkyl group refers to a C ₃ - ₆ cycloalkyl and -C (= 0) - group is attached is formed

"Olefinyl" means an unsaturated organic functional group consisting of carbon and hydrogen containing C=C and -C (=0)

- a group formed by association. The olefin acyl group of C ₂ - ₆ means a group formed by linking an unsaturated organic functional group composed of two atoms of carbon and hydrogen having C=C and -C (=0) - having _{2 to} ₆ carbon atoms.

"Aryl" means a hydrocarbyl moiety containing one or more aromatic rings. The aryl group in the invention preferably has 6 to 20 carbon atoms, and examples of the aryl moiety include a phenyl group, a phenylene group, a naphthyl group, a naphthylene group, an anthracenyl group, an anthracenyl group and a phenanthryl group.

"Heteroaryl" means a moiety which contains one or more aromatic rings having at least one hetero atom (e.g., N, 0 or S). The heteroaryl group in the present invention preferably has 4 to 20 carbon atoms, and examples of the heteroaryl group include furyl, furanyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, Pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and fluorenyl.

The "aryl acyl group" means a group formed by linking an aryl group to -C (=0) -, preferably a group formed by linking an aryl group having 6 to 20 carbon atoms to -C (=0) -.

"Sulfonyl" means a functional group after a sulfonic acid has lost a hydroxyl group, and can be written as R'-S(=0) ₂ -, such as R' is a methyl group, an ethyl group, a phenyl group, a p-tolyl group or the like.

"Amido" means a functional group having an amide bond -CONH-. "Reverse amide group" means a functional group having a reverse amide bond -NHCO-.

"Alkoxyacyl" means a group formed by linking -C(=0)- with an oxygen on an alkoxy group, and alkoxy means a group formed by linking an alkyl group to an oxygen atom, such as a methoxy group, Ethoxylate and the like. C ₂ - ₈ alkoxy group refers to a C ₂ - ₈ alkoxy and -C (= 0) - group attached is formed.

"Amino" means NH ₂ -.

"Amine" refers to one or more Cw. A hydrocarbyl-substituted amino group such as (CH ₃ ) ₂ N -, (CH ₃ CH ₂ ) ₂ N- (CH ₃ )(CH ₃ CH ₂ )N-CH ₃ NH -, CH ₃ CH ₂ NH-, and the like.

In the present invention, an alkyl group, a cycloalkyl group, an olefin acyl group, an aryl group, a heteroaryl group, an aryl acyl group, an amide group or a reverse amide group includes both substituted and unsubstituted moieties. Possible substituents on an alkyl, cycloalkyl, olefin acyl, aryl, heteroaryl, aryl acyl, amide or reverse amide group include, but are not limited to: fluorine, chlorine, bromine, iodine, nitrile, hydroxy , d- ₆ alkyl, C ₃ _-6 cycloalkyl, d- ₆ alkoxy, amino, d- ₆ alkoxy, nitro, amino, acyl, Amido group, sulfonyl group. Preparation

The compound of the formula V of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.

The process comprises the step of a condensation reaction of a compound of formula VI with a compound of formula VII to obtain a compound of formula V.

In the formulas, R ⁴ , R ⁵ -Q -, R, Z, R ³ , RX, R ² , Ar and Ar ₂ are as defined above.

Usually, the reaction is carried out in an inert solvent at a temperature of from 10 ° C to a reflux temperature (e.g., 100 ° C) for 0.1 to 72 hours. Representative solvents include, but are not limited to: acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, acetonitrile or a mixture of two or more . Pharmaceutical composition

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

"Compound of the invention" means a compound of formula V (including a compound of formula I, formula π, formula m or formula IV), or a tautomer thereof, a racemate, an enantiomer, a diastereomer A pharmaceutically acceptable salt or a pharmaceutically acceptable solvate.

Since the compound of the present invention has an inhibitory activity against epidermal growth factor receptor (EGFR) and/or vascular growth factor receptor (VEGFR), the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the preparation of prophylaxis or A medicament for treating a disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.

A safe and effective amount of a compound of the invention is included in the pharmaceutical compositions of the invention, wherein "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or a tablet. A "pharmaceutically acceptable carrier" can be one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. Application method

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, nasal inhalation, rectal, and parenteral (intravenous, intramuscular, or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as cisplatin. When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is applied to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. The structures of the compounds prepared in the following examples were determined by nuclear magnetic resonance (HNMR) and mass spectrometry (MS). The 1H NMR shift (δ) is given in parts per million (ppm). The 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC1 ₃ ), internal standard was tetramethylsilane (TMS), and the chemical shift was to give ^10-6 as a unit.

The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

IC ₅ . The value was determined using a NovoStar plate reader (BMG, Germany).

The thin layer of silica gel is made of Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.

Silica gel column chromatography was carried out using Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

The HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).

The microwave reaction was performed using a CEM Discover-S Model 908860 microwave reactor.

Further, the following examples were not specifically described, and the reactions were all carried out under a nitrogen atmosphere.

The argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 liter.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

Unless otherwise specified in the following examples, the solution in the reaction means an aqueous solution. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. Various modifications and alterations of the present invention will be apparent to those skilled in the <RTIgt; The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight. -1 and compound II -1

II -1

The first step:

P-carboxyphenyl boronic acid pinacol ester (lg, 4.03 mmol) was dissolved in dichloromethane (10 ml, 0.16 mol) at room temperature N-ethylpiperazine (0.6 ml, 4.8 mmol) was added to N,N-dimethylformamide (1 ml, 13.0 mmol), and 1-ethyl-(3-dimethylaminopropyl group was added sequentially. Carbodiimide hydrochloride (0.93 g, 4.8 mmol), N-hydroxybenzotriazole (0.66 g, 4.8 mmol), triethylamine (0.84 ml, 6.04 mmol), stirred at room temperature until TLC The reaction was completed, and 10 ml of water was added to the reaction mixture, and the mixture was stirred for 30 minutes, extracted with dichloromethane (50 ml*3), and washed with saturated sodium chloride (50 ml*2). Filtration and concentration under reduced pressure afforded: (4-ethyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron Cyclo-2-yl)-phenyl]-methanone (1.4 g, pale yellow solid) was used directly in the next step.

The second step:

Among them, 6-bromo-4-chlorothiophene [2,3-d]pyrimidine was prepared according to the method described in WO 2007/059257.

The compound 6-bromo-4-chlorothiophene [2,3-d]pyrimidine (lg, 4.0 mmol) and L-phenylglycinol (lg, at room temperature)

7.2 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.259 mol), 1 ml of triethylamine (363 mg, 7.19 mmol) was added dropwise, and stirred at room temperature until the reaction was completed by TLC. After suction filtration, the filter cake was washed with water (100 ml*2) to give: Compound 2-(6-bromo-thiophen[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (1.3 g, light Yellow solid), Yield: 93%.

MS m/z (ESI): 351 [M+l].

1HNMR (400MHz, DMSO-d ₆ ): 8.24 (s, 1H), 8.16 (d, J=8.1Hz, 1H), 8.02 (s,lH), 7.38-7.40 (m, 2H), 7.23-7.32 (m , 2H), 7,20-7.22(m, 1H), 5.39(m, 1H), 4.98(t, J=8.1Hz, lH),

third step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (500 mg, 1.43 mmol) and (4-ethyl-piperazine) 1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (982 mg, 2.86 mmol Dissolved in N,N-dimethylformamide (15 ml, 0.194 mol), sequentially added tetrakistriphenylphosphine palladium (164 mg, 0.143 mmol), sodium carbonate solution (1 mol/L, 2.8 ml), protected with nitrogen, heated The reaction was completed until 80 ° C until the TLC was monitored. The mixture was washed with water (100 ml*3), and extracted with ethyl acetate (250 ml*l). The organic phase was washed with saturated brine (100 ml*2). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated, evaporated]]]]]]]] -Ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenylmethanone (1-1) (440 mg, pale yellow solid), yield: 63%.

MS m/z (ESI): 495 [M + 1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.30 (d, 2H), 8.19 (d, 1H), 7.79 (d, 2H), 7.51-7.20 (m, 7H), 5.46 (m, 1H), 5.01 ( t,,1H), 3.75 (m, 2H), 3.55 (m, 4H), 2.35 (m, 6H), 0.99 (t, J = 8.0 Hz, 3H).

the fourth step:

Lithium tetrahydroaluminum (27.3 mg, 0.718 mmol) and anhydrous tetrahydrofuran (8 ml, 98.63 mmol) were stirred and stirred at room temperature, and the compound I-I (140 mg, 0.287 mmol) of tetrahydrofuran (10 ml, 0.123mol), the reaction was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC. The reaction was cooled to room temperature. 20 ml of water was added to the reaction mixture, and extracted with ethyl acetate (100 ml*3). The mixture was washed with a saturated aqueous solution of sodium chloride (100 ml?). (4-ethyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino}-2-phenyl-ethanol (Π -1) ( 15 mg , pale yellow solid), Yield: 11.0%.

MS m/z (ESI): 473 [M+1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.23-8.18 (m,3H), 7.66 (d, 2H), 7.42-7.23 (m,7H), 5.44 (m, 1H), 5.03 (t,,1H) , 3.76 (m, 2H), 3.55 (m, 6H), 2.4 l (m, 6H), 0.98 (t,, 3H).

Example 2: Preparation of Compound I-2 and Compound II-2

The first step:

The p-carboxyphenylboronic acid pinacol ester (3 g, 12.10 mmol) was dissolved in dichloromethane (27 ml, 0.422 mol) and N,N-dimethylformamide (9 ml, 0.116 mol) at room temperature, and N-A was added. Piperazine (1. 45 g, 14.5 mmol), and sequentially added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.79 g, 14.4 mmol), N-hydroxybenzo Triazole (1.98 g, 12.9 mmol), triethylamine (2.5 ml, 17.99 mmol), the reaction was stirred at room temperature until the reaction was completed by TLC. 30 ml of water was added to the reaction mixture, stirred for 30 minutes, with dichloromethane (100 ml) *3) The extract is washed with a saturated sodium chloride solution (100 ml*2), and the organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (4-methyl-piperazin-1-yl) - [4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.5 g, white solid), Rate: 37.6%.

The second step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (100 mg, 0.2857 mmol) and (4-methyl-piperazine- L-yl)-[4-(4, 4, 5, 5_tetramethyl-[ 1, 3, 2]dioxaborolan-2-yl)-phenyl]-methanone (188 mg, 0.5714 mmol) Dissolved in N, N-dimethylformamide (4 ml, 51.7 mmol), sequentially added tetrakistriphenylphosphine palladium (33 mg, 0.0286 mmol), sodium carbonate solution (1 mol/L, 0.6 ml), nitrogen-protected, heated The reaction was completed until 80 ° C until TLC was monitored. The mixture was washed with water (100 ml*3), and extracted with ethyl acetate (250 ml*l). The organic phase was washed with saturated brine (100 ml*2). The organic phase was dried over anhydrous MgSO.sub.sub.subsubsubsubsubsubsubsub Hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (I - 2) (71 mg, white solid), Yield: 52.6%.

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.30 (d, 2H), 8.19 (d, 1H), 7.75 (d, 2H), 7.51-7.21 (m, 7H), 5.46 (m, 1H), 5.02 ( t,,1H), 3.75 (m, 2H), 3.55 (m, 4H), 2.35 (m, 4H), 2.19 (s, 3H).

third step:

Lithium tetrahydrogenate (100 mg, 2.640 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound I-2 (500 mg, 1.056 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture. The solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC. The reaction was cooled to room temperature, then 20 ml of water was added to the mixture and extracted with ethyl acetate (100 ml*3) The sodium solution (100 ml * 2) was washed, and the obtained organic layer was dried (jjjjjjjjjj (4-methyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino-2-phenyl-ethanol(II-2) (42 mg, light Yellow solid), Yield: 8.7%.

MS m/z (ESI): 460 [M+1].

1H NMR (400 Hz, DMSO-d ₆ ): 8.30 (d, 2H), 8.19 (d, 1H), 7.75 (d, 2H), 7.51-7.21 (m, 7H),

5.46 (m, 1H), 5.02 (t, 1H), 3.75 (m, 2H), 3.55 (m, 6H), 2.35 (m, 4H), 2.19 (s, 3H).

Example 3: Preparation of Compound I -3 and Compound II -3

Second step

The first step:

The p-carboxyphenylboronic acid pinacol ester (3 g, 12.10 mmol) was dissolved in dichloromethane (27 ml, at room temperature).

Into 0.42 mol) and N,N-dimethylformamide (9 ml, 0.116 mol), 1-cyclopropylmethylpiperazine (2.3 g, 14.9 mmol) was added, followed by 1-ethyl-(3- Dimethylaminopropyl)carbonyldiimide hydrochloride (2.79 g, 14.4 mmol), N-hydroxybenzotriazole (1.98 g, 12.9 mmol), triethylamine (2.5 ml, 17.99 mmol), The reaction was stirred at room temperature until the reaction of the starting material was completely monitored by TLC. 30 ml of water was added to the reaction mixture, stirred for 30 minutes, extracted with dichloromethane (100 ml*3), and washed with saturated sodium chloride solution (100 ml*2). Drying over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure afforded: <RTIgt; (4-cyclopropylcarbonyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1, 3, 2] Dioxaborolan-2-yl)-phenyl]-methanone (3.5 g, white solid), yield 61.4%, used for the next reaction. The second step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (500 mg, 1.43 mmol) and (4-cyclopropylcarbonyl-perfluoro) Pyrazin-1-yl)-[4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxaborolan-2-yl)-phenyl]-methanone (1.099g , 2.86 mmol) dissolved in N, N-dimethylformamide (15 ml, 0.194 mol), followed by tetrakistriphenylphosphine palladium (164 mg, 0.143 mmol), sodium carbonate solution (1 mol/L, 2.8 ml), nitrogen The mixture was heated to 80 ° C until TLC was used to monitor the reaction of the starting material. The mixture was cooled to room temperature, washed with water (100 ml*3), extracted with ethyl acetate (250 ml*l), and the organic phase was washed with saturated brine (100ml*2) The obtained organic phase was dried (MgSO4) {4-[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenyl}-methanone (I -3) (300 mg, Light yellow solid), Yield: 60%.

MS m/z (ESI): 528 [M+1].

¹ H NMR (400 Hz, DMSO-d ₆ ): ¹ H NMR (400 Hz, DMSO-d ₆ ): 8.44m, 2H), 8.26 (s, lH), 7.75 (d, 2H), 7.52-7.28 (m, 7H) , 5.48(m,lH), 5.20(t,lH), 3.87(m,lH), 3.68(s,2H), 3.09(m, 8H), 1.23(m,lH), 0.68(m,2H), 0.44 (m, 2H).

third step:

Lithium tetrahydrogenate (90 mg, 2.369 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound 1-3 (250 mg, 0.474 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture. The solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC. The reaction was cooled to room temperature, then 20 ml of water was added to the mixture and extracted with ethyl acetate (100 ml*3) The sodium solution (100 ml * 2) was washed, and the obtained organic layer was dried (jjjjjjjjjj (4-cyclopropylmethyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino}-2-phenyl-ethanol (Π-3 (42 mg, off-white solid), Yield: 4.3%.

MS m/z (ESI): 500 [M + 1].

1H NMR (400 Hz, DMSO-d ₆ ): 8.43 (m, 2H), 8.26 (s, lH), 7.75 (d, 2H), 7.52-7.28 (m, 7H),

5.48(m,lH), 5.20(t,lH), 3.87(m,lH), 3.68(s,2H), 3.09(m, 10H), 1.23(m,lH), 0.68(m,2H),

Example 4: Preparation of Compound I-4 and Compound II-4

The first step:

The p-carboxyphenyl boronic acid pinacol ester (3 g, 12.10 mmol) was dissolved in dichloromethane (27 ml, 0.422 mol) and N,N-dimethylformamide (9 ml, 0.116 mol) at room temperature, and N-hydroxyl was added. Ethyl piperazine (2 g, 15.36 mmol), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.79 g, 14.4 mmol), N-hydroxybenzo Triazole (1.98 g, 12.9 mmol), triethylamine (2.5 ml, 17.99 mmol), stirred at room temperature until TLC The reaction of the starting material was monitored. To the reaction mixture was added 30 ml of water, stirred for 30 minutes, extracted with dichloromethane (100 ml*3), washed with saturated sodium chloride solution (100 ml*2) and dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure gave: (4-hydroxyethyl-piperazin-1-yl)-[4-(4, 4, 5, 5-tetramethyl-[1, 3, 2]diox Borapentan-2-yl)-phenyl]-methanone (3.0 g, white solid), yield 68.8%, used for the next step.

The second step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (500 mg, 1.43 mmol) and (4-hydroxyethyl-piperazine) -1-yl)-[4-(4, 4, 5, 5-tetramethyl-[ 1, 3, 2]dioxaborolan-2-yl)-phenyl]-methanone (1.029 g, 2.86mmol) dissolved in N, N-dimethylformamide (15ml, 0.194mol), then added tetrakistriphenylphosphine palladium (164mg, 0.143mmol), sodium carbonate solution (lmol / L, 2.8ml), nitrogen protection The mixture was heated to 80 °C until the reaction was completed by TLC. The mixture was washed with water (100 ml*3), and then extracted with ethyl acetate (250 ml*1). The organic phase was washed with saturated brine (100ml*2). The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated,462462462462462462462462462462462462462462462462462462462462 -{4-[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenyl}-methanone (I -4) ( 300 mg, pale yellow solid), Yield: 41.7%.

MS m/z (ESI): 504 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37-8.27 (m, 3H), 7.77 (d, 2H), 7.51-7.22 (m, 7H), 5.45 (m, lH), 5.14 (t, lH), 4.46(m,lH), 3.75(m,2H), 3.61(m,2H), 3.49(m,2H), 3.36(m,4H), 2.43(m,4H

third step:

Lithium tetrahydroaluminum (90 mg, 2.369 mmol) and anhydrous tetrahydrofuran (10 ml) were stirred and stirred at room temperature, and a solution of compound 1-4 (250 mg, 0.496 mmol) in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise at room temperature. The reaction was stirred for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC. The mixture was cooled to room temperature, and 20 ml of water was added to the reaction mixture, and extracted with ethyl acetate (100 ml*3), and then saturated sodium chloride solution ( After washing with 100 ml of 2), the obtained organic layer was dried (jjjjjjjjjjjj Hydroxy-ethyl)-piperazin-1-ylmethyl]-phenyl}"cepheno[2,3-d]pyrimidin-4-ylamine } -2-phenyl-ethanol (Π-4) (48 mg, off-white solid), Yield: 4.3%.

MS m/z (ESI): 490 [M+1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37-8.29 (m, 3H), 7.77 (d, 2H), 7.51-7.22 (m, 7H) _: 5.45 (m, lH), 5.14 (t, lH), 4.46(m,lH), 3.75(m,2H), 3.68(s,2H), 3.61(m,2H), 3.49(m,2H) 3.36(m,4H),2.43(m,4H)o

Example 5: Preparation of Compound I-5 and Compound II-5

The first step:

P-carboxyphenyl boronic acid pinacol ester (0.894 g, 4.8 mmol) was dissolved in dichloromethane (10 ml, at room temperature).

N-Boc piperazine (lg, 4.03 mmol) was added to N,N-dimethylformamide (1 ml, 17.78 mmol), and 1-ethyl-(3-dimethylaminopropyl) was added sequentially. Carboxylideneimide hydrochloride (0.93 g, 4.8 mmol), N-hydroxybenzotriazole (0.66 g, 4.8 mmol), triethylamine (0.84 ml, 6.04 mmol), stirred at room temperature until TLC The reaction of the starting material was monitored. To the reaction mixture was added 30 ml of water, stirred for 30 minutes, extracted with dichloromethane (100 ml*3), washed with saturated sodium chloride solution (100 ml*2) and dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure afforded: 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxyboron 2_yl)benzoyl-]-piperazin-1- tert-Butyl ester (1.6 g, white solid), yield 95.4%.

The second step:

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (500 mg, 1.428 mmol) and 4-[4-(4,4) ,5,5-tetramethyl-[1,3,2]dioxaboron 2_yl)benzoyl-]-piperazine-1-tert-butyl ester ( 1.189 g, 2.857 mmol) dissolved in N, N-dimethyl Formamide (20ml, 0.65mol), then added tetrakistriphenylphosphine palladium (161.8mg, 0.14mmol), sodium carbonate solution (lmol / L, 2.5ml), nitrogen protection, heated to 85 ° C until TLC monitoring of raw material reaction The mixture was washed with EtOAc (100 mL EtOAc) (EtOAc)EtOAc. The residue was purified by silica gel chromatography eluting elut elut elut elut elut MS m/z (ESI): 560 [M+l]. third step:

The product (168 mg, 0.3 mmol) was dissolved in dichloromethane (8 ml, 0.125 mol), and then trifluoroacetic acid (0.45 ml, 0.6 mmol). The mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane (50ml*3). The organic layer was washed with saturated brine (50ml*3), concentrated under reduced pressure, and slabs were obtained to obtain: -{4-[ 4-(2-hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenylpiperazin-1-yl-methanone-5) (50 mg, white Solid), Yield: 36%.

MS m/z (ESI): 460 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.40 (m, 1H), 8.24 (m, 2H), 7.79 (d, 2H), 7.45 (m, 4H), 7.21 (m, 3H), 5.45 (m, lH), 5.04 (t, lH), 3.55 (s, 2H), 2.74 (m, 4H), 2.39 (m, 4H).

the fourth step:

Lithium tetrahydroaluminum (51.5 mg, 1.355 mmol) and anhydrous tetrahydrofuran (25, 0.308 mol) were stirred and stirred at room temperature, and the compound 1-5 (500 mg, 0.451 mmol) of tetrahydrofuran (25 ml, 0.308 mol) was added dropwise to the reaction mixture. The solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction of the starting material was completely monitored by TLC. The mixture was cooled to room temperature, and 20 ml of water was added to the reaction mixture, and ethyl acetate (50 ml*3) was used for extraction. The sodium chloride solution (100 ml * 2 ) was washed, and the obtained organic layer was dried (jjjjjjjjjj (4-piperazin-1-ylmethyl-phenyl)-thieno[2,3-d]pyrimidin-4-ylamino]-ethanol (Π -5) (100 mg, white solid), Yield: 20.7 %

MS m/z (ESI): 446 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.41 (m, 1H), 8.26 (m, 2H), 7.78 (d, 2H), 7.46 (m, 4H), 7.22 (m, 3H), 5.48 (m, lH), 5.06 (t, lH), 3.84 (m, 2H), 3.57 (s, 2H), 2.76 (m, 4H), 2.40 (m, 4H).

6: Preparation of compound II -6

first step:

The morpholine (5 ml, 57.405 mmol) was dissolved in dichloromethane (40 ml), and N,N-diisopropylethylamine (9.5 ml, 57.405 mmol) The triphosgene (6g, 20.69mmol) in 30ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ± 3 °C for 1 hour. Add N-Boc piperazine under ice bath at 0 °C. ( 11.8 mg, 63.15 mmol) and N,N-diisopropylethylamine (9.5 ml, 57.405 mmol). The reaction was stirred at room temperature until the reaction was completed by TLC, and concentrated under reduced pressure. The crude product was dissolved in 30 ml of dichloromethane. The mixture was stirred at room temperature under trifluoroacetic acid (14 ml, 18.7 mmol). The mixture was extracted with methylene chloride (EtOAc (EtOAc) (EtOAc). m/z (ESI): 200 [M+1].

The second step:

The morpholinyl piperazinyl urea (500 mg, 2.51 mmol) and the B 4-formylbenzeneboronic acid (396 mg, 2.64 mmol) were dissolved in 20 ml of tetrahydrofuran, and the acetic acid solution (0.5 ml, 8.75 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After adding sodium triacetoxyborohydride (798 mg, 3.77 mmol), the mixture was heated to 60 ° C, and the reaction was stirred until the reaction was completed by TLC, and the residue was evaporated. Benzyl-piperazin-1-yl)-morpholin-1-yl-methanone-boronic acid (330 mg, pale-yellow solid), yield: 23%, MS m/z (ESI): 334[M+1] .

third step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (189 mg, 0.540 mmol) and (4-benzyl-piperazine small) - morpholine ketone- ketone-boric acid (150 mg, 045 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.65 mol), followed by tetratriphenylphosphine palladium (52 mg, 0.045 mmol). Sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2), the organic phase is saturated The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. 2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-morpholin-4-yl)-methanone (II-6) (15 mg, white solid), Yield: 6%.

MS m/z (ESI): 559 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.28-8.20 (m, 3H), 7.69 (d, 2H), 7.46-7.23 (m, 7H), 5.45 (m, lH), 5.05 (t, lH), 3.76 (m, 2H), 3.55 (m, 6H), 3.25-3.08 (m, 8H), 2, 39 (m, 4H).

Example 7: Preparation of Compound II-7

first step: Tetrahydropyrrole (600 mg, 8.436 mmol) was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.4 ml, 8.436 mmol) was added in an ice bath at 0 ° C and dissolved in dichloromethane. The triphosgene (801mg, 2.70mmol) in (5ml) was slowly added dropwise. The temperature of the addition process was kept at 0±3°C for 1 hour. N-Boc piperazine (1.57g, was added to the ice bath at 0°C. 8.436 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.436 mmol). The reaction was stirred at room temperature until the reaction was completed by TLC. The crude material was dissolved in 20 ml of dichloromethane and trifluoroacetic acid (10 ml, The mixture was stirred at room temperature until the reaction was completed with EtOAc (EtOAc) (EtOAc). The residue obtained was purified by chromatography to give: <RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;

MS m / z (ESI): 184 [M + 1].

1H NMR (400 Hz, DMSO-d ₆ ): 3.23 (t, 5H), 3.05 (t, 4H), 2.64 (t, 4H), 1.72 (m, 4H) o

Tetrahydropyrrolyl piperazinyl urea (370 mg, 2.022 mmol) and 4-formylbenzeneboronic acid (334 mg, 2.224 mmol) were dissolved in 10 ml of tetrahydrofuran and 10 ml of methanol, and acetic acid solution (0.5 ml, 8.75 mmol) was added and stirred at room temperature. After reacting for 1 hour, sodium triacetoxyborohydride (1. lg, 5.055 mmol) was added, and the mixture was heated to 60 ° C. The reaction was stirred until the reaction was completed by TLC. Yield: (4-Benzyl-piperazin-1-yl)-tetrahydropyrrole-1-yl-methanone-boronic acid (210 mg), Yield: 33%.

¹ H NMR (400 Hz, DMSO-d ₆ ): 7.99 (s, 2H), 7.74 (d, 2H), 7.25 (d, 2H), 3.47 (s, 2H), 3.23 (m, 4H), 3.16 (m, 4H), 2.33 (m, 4H), 1.72 (m, 4H).

third step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (317 mg, 0.906 mmol) and (4-benzyl-piperazine small) Tetrahydropyrrolidinyl-ketone-boric acid (200 mg, 0.604 mmol) was dissolved in N,N-dimethylformamide (5 ml, 65 mmol), then tetratriphenylphosphine palladium (70 mg, 0.0604 mmol) , Sodium carbonate solution (lmol / L, lml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with dichloromethane (3 * 100ml), organic phase The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. [4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine small group)-pyrrolidino-ketone (Π - 7) (67mg, white solid), Yield: 20% o

MS m/z (ESI): 543 [M+l].

1H NMR (400 Hz, DMSO-d ₆ ): 8.28-8.19 (m, 3H), 7.69 (d, 2H), 7.46-7.23 (m, 7H),

5.45(m,lH), 5.05(t,lH), 3.76(m,2H), 3.53(s,2H), 3.25-3.08(m,8H), 2,39(m, 4H), 1.74(s, 4H).

Example 8: Preparation of Compound II-8

first step: Tetramethoxypiperidine (500 mg, 4.314 mmol) was dissolved in 10 ml of dichloromethane. N,N-diisopropylethylamine (0.72 ml, 4.314 mmol) The triphosgene (412mg, 1.389mmol) in dichloromethane (5ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ± 3 °C for 1 hour. N-Boc piperazine was added to the ice bath at 0 °C. 809 mg, 4.341 mmol) and N,N-diisopropylethylamine (0.72 ml, 4.341 mmol). The reaction mixture was stirred at rt. Trifluoroacetic acid (10 ml, 0.135 mol) was added and the reaction was stirred at room temperature until the reaction was completed by TLC. The mixture was concentrated under reduced pressure, washed with saturated sodium carbonate (50ml*3) and extracted with dichloromethane (50ml*5). The mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj 228 [M+1].

The second step:

4-methoxypiperidylpiperazinyl urea (414 mg, 1.824 mmol) and 4-formylbenzeneboronic acid (287 mg, 1.915 mmol) were dissolved in 5 ml of tetrahydrofuran and 5 ml of methanol, and then acetic acid solution (0.2 ml, 3.5 mmol) The reaction was stirred at room temperature for 1 hour, sodium triacetoxyborohydride (580 mg, 2.726 mmol) was added, and the mixture was heated to 60 ° C. The reaction was stirred until the reaction was completed by TLC, and concentrated under reduced pressure. Of (4-benzyl-piperazin-1-yl)-4-methoxypiperidin-1-yl-methanone-boronic acid (251 mg, pale-yellow solid), yield: 38.1%, MS m /z(ESI): 362[M+1].

third step:

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (181 mg, 0.520 mmol) and (4-benzyl-piperazine- 1-yl)-4-methoxypiperidin-1-yl-methanone-boronic acid (125 mg, 0.346 mmol) dissolved in N,N-dimethylformamide (20 ml, 0.65 mol). Palladium phosphine (40mg, 0.035mmol), sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting material, naturally cooled to room temperature, washed with 100ml of water, with ethyl acetate ( The organic phase is washed with a saturated aqueous solution of sodium sulfate (MgSO4), EtOAcjjjjjjjjjjjjjjjjjjj -{4-[4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-(4 -Methoxy-piperidinyl)-methanone (Π-8) (36 mg, pale yellow solid), Yield: 17.7%. MS m/z (ESI): 587 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.31-8.19 (m, 3H), 7.67 (d, 2H), 7.46-7.44 (m, 4H) 7.35-7.22 (m, 3H), 5.46 (m, lH) , 5.06(t,lH), 3.77(m,2H), 3.52(s,2H), 3.35(m, 7H), 3.20(s,3H) 2.89(m,2H), 2.44(m,4H), 1.81 (m , 2H) , 1.35 (m, 2H).

-9

The compound Π-5 (100 mg, 0.225 mmol) was dissolved in N,N-dimethylformamide (5 ml) at room temperature, and 4-bromocrotonic acid (37.2 mg, 0.225 mmol) and N-(3-di) were added. Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.0 mg, 0.225 mmol). The reaction was stirred at room temperature until the reaction was completed by TLC, and concentrated under reduced pressure. THF (30 ml, 0.37 mol) Methylamine (0.5 ml, 3.66 mmol) was stirred at room temperature until the reaction was taken from EtOAc (EtOAc) (EtOAc) Filtration, concentration under reduced pressure, and the residue obtained by silica gel column chromatography to give: -4-dimethylamino-1-(4-{4-[4-(2-hydroxy-1-phenyl-ethyl) Amino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine-1-yl)-butyl-2-enione (Π-9) (40 mg, off-white solid) Yield: 32%.

MS m/z (ESI): 557 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.36-8.30 (m, 3H), 7.74 (d, 2H), 7.53 - 7.29 (m, 7H), 6.87 (d, lH), 6.64 (dd, 1H), 5.52 (m, lH), 5.12 (t, 1H), 3.83 (m, 2H), 3.60 (s, 2H), 3.58 (m, 6H), 2.60 (s, 6H), 2.45 (m, 4H).

Example 10: Preparation of Compound II -10

The first step:

The piperidine (1 g, 11.752 mmol) was dissolved in dichloromethane (10 ml). N,N-diisopropylethylamine (2 ml, 11.752 mmol) The triphosgene (l.lg, 3.761mmol) was slowly added dropwise. The temperature of the addition process was kept at 0 ± 3 °C for 1 hour. Add N-Boc piperazine under ice bath at 0 °C. (2.2 g, 11.752 mmol) and N,N-diisopropylethylamine (2 ml, 11.752 mmol). The reaction was stirred at rt. Trifluoroacetic acid (20 ml, 0.27 mol) was added and the reaction was stirred at room temperature until the reaction was completed by TLC, concentrated under reduced pressure, and washed with saturated sodium carbonate (50ml*3), with dichloromethane (50ml*5) The extract was concentrated under reduced pressure. EtOAcjjjjjjj

MS m/z (ESI): 198 [M+1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 3.59 (brs, 1H), 3.09 (m, 8H), 2.78 (m, 4H), 1.48 (m, 6H). The second step:

Piperidinyl piperazinyl urea (1.25 g, 6.336 mmol) and B 4-formylbenzeneboronic acid (1.05 g, 6.969 mmol) were dissolved in 15 ml of tetrahydrofuran and 15 ml of methanol, and acetic acid solution (0.7 ml, 12.67 mmol) was added. The reaction was stirred at room temperature for 1.5 hours, sodium triacetoxyborohydride (3.36 g, 15.84 mmol) was added, and the mixture was warmed to 60 ° C. The reaction was stirred until the reaction was completed by TLC, and concentrated under reduced pressure. Yield: (4-Benzyl-piperazin-1-yl)-piperidin-1-yl-methanone-boronic acid (1.25 g, pale-yellow solid). Yield: 60%.

MS m/z (ESI): 332 [M+1].

1H NMR (400 Hz, DMSO-d ₆ ): 7.97 (s, 2H), 7.74 (d, 2H), 7.25 (d, 2H), 3.47 (s, 2H),

3.09 (m. 8H), 2.33 (m, 4H), 1.45 (m, 6H).

third step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (317 mg, 0.906 mmol) and (4-benzyl-piperazine small) -Piperidine ketone-ketone-boric acid (200 mg, 0.604 mmol) was dissolved in N,N-dimethylformamide (10 ml, 0.325 mol), then tetratriphenylphosphine palladium (70 mg, 0.0604 mmol) , sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until the TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2), organic phase The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered, evaporated,lululululululululululululululululu 1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine small group)-piperidinyl)-methanone (Π-10) (67 mg, Off-white solid), Yield: 20%.

MS m/z (ESI): 557 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.28 (m, 3H), 7.68 (d, 2H), 7.44 (d, 4H), 7.31-7.24 (m, 3H), 5.45 (m, lH), 5.06 ( t, lH), 3.80 (m, 2H), 3.54 (s, 2H), 3.12 (m, 8H), 2.39 (m, 4H), 1.19 (m, 6H).

Example 11: Preparation of Compound II -11

The first step:

N-Ethylpiperazine (1 g, 8.77 mmol) was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.5 ml, 8.77 mmol) was added in an ice bath at 0 ° C, dissolved in The triphosgene (833mg, 2.81mmol) in dichloromethane (10ml) was slowly added dropwise, the temperature of the addition process was kept at 0 ± 3 °C, the reaction was carried out for 1 hour, and the mixture was added at 0 °C in an ice bath. N-Boc piperazine (1.63 g, 8.77 mmol), EtOAc, EtOAc (EtOAc:EtOAc. In dichloromethane (30 ml), trifluoroacetic acid (10 ml, 0.135 mol) was added and the reaction was stirred at room temperature until the reaction was completed by TLC, concentrated under reduced pressure, and washed with saturated sodium carbonate (50ml*3). Methane (50 ml * 5 ) was extracted, concentrated under reduced pressure, and purified to silica gel column chromatography to afford: N-ethyl piperazine piperazine ( lg, pale yellow liquid), yield: 34.97%, MS m/z (ESI): 227 [M + 1].

The second step:

N-Ethyl piperazinyl piperazine urea (1 g, 4.40 mmol) and 4-formylbenzeneboronic acid (729 mg, 4.86 mmol) were dissolved in 10 ml of tetrahydrofuran and 10 ml of methanol, and acetic acid solution (0.7 ml, 12.67 mmol) was added. The reaction was stirred at room temperature for 1.5 hours, sodium triacetoxyborohydride (2.33 g, l l mmol) was added, and the mixture was warmed to 60 ° C. The reaction was stirred until the reaction was completed by TLC, and concentrated under reduced pressure. , (4-benzyl-piperazin-1-yl)-N-ethylpiperazin-1-yl-methanone-boronic acid (125 mg, pale yellow solid), yield: 8.0%, MS m/z (ESI): 361 [M+1].

third step:

The compound 2-(6-bromo-thiophene[2,3-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (181.8 mg, 0.520 mmol) and (4-benzyl-piperazine) -N-ethylpiperazine-based-ketone-boric acid (125 mg, 0.346 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.65 mol), then tetratriphenylphosphine palladium ( 40mg, 0.035mmol), sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added to 100ml water wash, with ethyl acetate (100ml * 2) The organic phase is washed with saturated brine (50 ml*3), EtOAcjjjjjjjjjj P-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine small group)-N-ethyl-piperazine small group)-A Ketone (Π - 11) (120 mg, white solid), Yield: 59%.

MS m/z (ESI): 587 [M+l] o

1H NMR (400 Hz, DMSO-d ₆ ): 8.38 (m, 2H), 8.27 (s, lH), 7.70 (d, 2H), 7.47 (m, 4H), 7.26(m,3H), 5.45(m,lH), 5.13(t,lH), 3.80(m,2H), 3.60(s,2H), 3.40-3.05(m,14H), 2.43(m,4H)

Example 12: Preparation of Compound ΙΠ-1 and Compound IV-1

first step:

Among them, 6-bromo-4-chlorothiophene [ 3,2-d] pyrimidine was prepared according to the method described in WO 2009/007421.

The compound 6-bromo-4-chlorothiophene [3,2-d]pyrimidine (2 g, 8.01 mmol) and L-phenylglycine ( 1.65 g, 12.02 mmol) were dissolved in N, N-dimethylmethyl at room temperature. In amide (25 ml, 0.32 mol), 2.8 ml of triethylamine (2.03 g, 20.025 mmol) was added dropwise, and the mixture was heated to 60 ° C until the reaction was completed by TLC, and then cooled to room temperature, washed with 100 ml of water, with dichloromethane (3*100 ml), the organic phase was washed with saturated brine (100 ml*2). 3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (1.7 g, pale yellow solid), yield: 61%.

MSm/z (ESI): 351 [M+l] o

1H NMR (400 Hz, DMSO-d ₆ ): 8.39 ( s, lH ), 8.230 (d, 1H), 7.60 (d, 1H), 7.46 (m, 2H), 7.24

(m, 3H), 5.48 (m, 1H), 5.03 (t, lH), 3.78 (m, 2H).

The second step:

Wherein (4-ethyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene The preparation method of the base]-methanone was the same as that of the first step of Example 1.

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (1.2 g, 3.43 mmol) and (4-ethyl-piperazine) -1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (2.36 g, 6.86mmol) dissolved in N, N-dimethylformamide (36ml, 0.465mol), sequentially added tetrakistriphenylphosphine palladium (0.4g, 0.343mmol), sodium carbonate solution (lmol / L, 7ml), nitrogen protection The mixture was heated to 85 °C until TLC was used to monitor the reaction. The mixture was washed with 100 ml of water, cooled to room temperature, extracted with dichloromethane (3*100 ml), and the organic phase was washed with saturated brine (100 ml*2). Drying over anhydrous magnesium sulfate, filtration, and concentrated under reduced pressure afforded IJ: (S)-(4-ethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-benzene -ethylamine)-thiophene [3,2-d]pyrimidin-6-yl]-phenylmethanone (III-1) (500 mg, yellow solid) Yield: 30% o MSm/z (ESI): 487 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.42 ( s, lH), 8.22 (d, 1H), 7.89 (d, 2H), 7.85 (s, 1H), 7.82 (m, 4H), 7.20-7.46 ( m,3H), 5.48(m, 1H), 5.00(t,lH), 3.83(m,2H), 3.40(m,4H), 2.45(m, 4H), 2.27(q, 2H), 0.99(t , 3H).

third step:

Lithium tetrahydroaluminum (75 mg, 1.95 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and (4-ethyl-piperazin-1-yl)-{4-[ 4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2,d]pyrimidin-6-yl]-phenylmethanone (370 mg, 0.78 mmol) in tetrahydrofuran (10 ml, 0.123 mol The solution was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC. 20 ml of water was added to the reaction mixture under ice-cooling at 0 ° C, extracted with ethyl acetate (50 ml * 2 ), and then saturated. The sodium chloride solution (50 ml * 3 ) was washed and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3,2-d]pyrimidin-4-ylamino}-2-phenyl-ethanol (IV-1) (17 mg, pale yellow solid), yield: 18.4%.

MSm/z (ESI): 473[M+l

1H NMR (400 Hz, DMSO-d ₆ ): 8.37 ( s, lH), 8.19 (d, 1H), 7.82 (d, 2H), 7.79 (s, 1H), 7.82

(m, 4H), 7.20-7.46(m,3H), 5.47(m, 1H), 5.00(t,lH), 3.83(m,2H), 3.52(s,2H), 2.40(brs, 8H), 2.27 (q, 2H), 0.98 (t, 3H).

Example 13: Preparation of Compound ΙΠ-2 and Compound IV-2

first step:

(4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl The preparation method of the -methanone is the same as the first step of the embodiment 2.

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (200 mg, 0.57 mmol) and (4-methyl-piperazine- 1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (226 mg, 0.684 mmol Dissolved in N,N-dimethylformamide (10 ml, 0.13 mol), and then added tetrakistriphenylphosphine palladium (66 mg, 0.057mmol), sodium carbonate solution (lmol / L, 0.5ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting material, naturally cooled to room temperature, added with 100ml of water, extracted with dichloromethane (3 * 100ml) The organic phase was washed with saturated brine (100 ml*2). EtOAcjjjjjjjjjjjjjj Phenyl-ethylamine)-thieno[3,2-d]pyrimidin-6-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (III-2) (100 mg , yellow solid), Yield: 37%

MS m/z (ESI): 473 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.41 (s,lH), 8.30 (d, 1H), 7.87 (d, 2H), 7.84 (s, 1H), 7.50 (m, 4H), 7.27-7.39 ( m, 3H), 5.49 (m, 1H), 5.10 (t, lH), 3.83 (s, 2H), 3.65-3.60 (m, 4H), 2.40 (m, 4H), 2.25 (s, 3H).

The second step:

Lithium tetrahydroaluminum (20.14 mg, 0.53 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and a solution of the compound ΙΠ-2 in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature. After 1 hour, the temperature was raised to 55 °C until the reaction of the starting material was completely monitored by TLC. 20 ml of water was added to the reaction solution under ice bath at 0 ° C, extracted with ethyl acetate (50 ml * 2), and then saturated sodium chloride solution (50 ml) *3) Washing, drying over anhydrous sodium sulfate, evaporation of solvent under reduced pressure, and the residue obtained from silica gel column chromatography to give: ( -2-{6-[4-(4-methyl-piperazine-1-) Methyl)-phenyl]-thieno[3,2-d]pyrimidin-4-ylamino 2-phenyl-ethanol (IV-2) (30 mg, pale yellow solid), yield: 31%.

MSm/z (ESI): 458 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.42 ( s, lH), 8.31 (d, 1H), 7.87 (d, 2H), 7.85 (s, 1H), 7.50 (m, 4H), 7.27-7.39 ( m,3H), 5.49(m, 1H), 5.10(t,lH), 3.78(m,2H), 3.63(s,2H),2.84-2.62(m, 4H), 2.45(s, 3H), 2.52 -2.56 (m, 4H).

Example 14: Preparation of Compound ΙΠ-3 and Compound IV-3

first step: Wherein (4-cyclopropylcarbonyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl The preparation method of -phenyl]-methanone is the same as the first step of Example 3.

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (600 mg, 1.72 mmol) and (4-cyclopropylcarbonyl-piperone) Pyrazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (892 mg, 2.32 mmol) was dissolved in N,N-dimethylformamide (10 ml, 0.13 mol), then tetratriphenylphosphine palladium (100 mg, 0.086 mmol), sodium carbonate solution (1 mol/L, 2 mL), The mixture was heated to 85 ° C until TLC was used to monitor the reaction of the starting material. The mixture was cooled to room temperature, washed with 100 ml of water, extracted with dichloromethane (3*100 ml), and the organic phase was washed with saturated brine (100 ml*2). Drying over anhydrous magnesium sulfate, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -Phenyl-ethylamine)-thieno[3,2-d]pyrimidin-6-yl]-phenylmethanone (III-3) (862 mg, yellow solid), yield: 95%.

MS m/z (ESI): 528 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.39 (s,lH), 8,17 (d, 1H), 7.84-7.78 (m, 3H), 7.47-7.43 (m, 4H), 7.34-7.22 (m ,3H), 5.46(m, 1H), 5.00(t,lH), 3.80-3.76 (m,2H), 3.61-3.50 (m, 8H), 2.0(m, 1H), 0.70(m,4H) o

The second step:

Lithium tetrahydroaluminum (54 mg, 1.423 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and a solution of the compound ΙΠ-3 OOO mg, 0.57 mmol) in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC. 100 ml of water was added to the reaction mixture under ice bath at 0 ° C, extracted with ethyl acetate (100 ml * 2), and then chlorinated with saturated The sodium solution (50 ml * 3 ) was washed, and the residue obtained was purified to silica gel column chromatography to afford ( -2-{6-[4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)- Phenyl]-thieno[3,2-d]pyrimidin-4-ylamino}-2-phenyl-ethanol (IV-3) (5 mg, white solid), yield: 1.76%.

MS m/z (ESI): 499 [M+1].

1H NMR (400 Hz, DMSO-d ₆ ): 8.39 (s,lH), 8,17 (d, 1H), 7.84-7.78 (m, 3H), 7.47-7.43 (m,

(4H), 7.

0.90 (m, lH), 0.5 (m, 4H).

Example 15: Preparation of Compound ΙΠ-4 and Compound IV-4

H

first step:

Wherein (4-hydroxyethyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl) The preparation method of -phenyl]-methanone was the same as that of the first step of Example 4.

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (340 mg, 0.97 mmol) and (4-hydroxyethyl-piperazine) -1-yl)-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (454 mg, 1.26 Ment) dissolved in N, N-dimethylformamide (10 ml, 0.13 mol), sequentially added tetrakistriphenylphosphine palladium (112 mg, 0.097 mmol), sodium carbonate solution (1 mol/L, 1 ml), nitrogen-protected, heated The reaction was completed until 8 °C until TLC, and the mixture was washed with 100 ml of water, cooled to room temperature, extracted with dichloromethane (3*100 ml), and the organic phase was washed with saturated brine (100 ml*2). The residue was dried over MgSO.sub.subsubsubsubsubsubsubsubsub. -[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[3,2-d]pyrimidin-6-yl]-phenylmethanone (EI-4) (45 mg, yellow solid) Yield: 9.2%.

MS m/z (ESI): 503 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.43 ( s, lH ), 8.21 (d, 1H), 7.92 (m, 3H), 7.43 (m, 4H), 7.26 (m, 3H), 5.49 (m, 1H), 5.02(t,lH), 3.83(m,4H), 3.56(s,2H), 3.10-3.01 (m, 6H), 2.78(m, step 2:

Lithium tetrahydroaluminum (41.8 mg, 1.1 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound III-4 (220 mg, 0.44 mmol) of tetrahydrofuran (10 ml, 0.123) was added dropwise to the reaction mixture. Mol) solution, stir the reaction at room temperature for 1 hour, warm to 55 ° C reaction until TLC monitoring the reaction of the starting material is complete, add 100 ml of water to the reaction solution under ice bath at 0 ° C, extract with ethyl acetate (100 ml * 2), and then use The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered, evaporated, evaporated. {4-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-phenylthieno[3,2-d]pyrimidin-4-ylamino 2-phenyl-ethanol CIV- 4) (30 mg, pale yellow solid), Yield: 14%.

MS m/z (ESI): 490 [M + 1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37 ( s, lH ) , 8.20 (d, 1H), 7.90 (m, 3H), 7.45 (m, 4H), 7.25 (m, 3H), 5.48 (m, 1H), 5.01 (t, lH), 3.85 (m, 4H), 3.58 (s, 2H), 3.10 (m, 8H), 2.80 (m, 2H).

Example 16: Preparation of Compound ΙΠ-5 and Compound IV-5

IV-5

The first step:

The synthesis of 6-bromo-4-chlorofuran [ 3,2-d ] pyrimidine is based on the preparation of 6-bromo-4-chlorothiophene [ 3,2-d ] pyrimidine and WO 2008/073785.

Compound 6-bromo-4-chlorofuran[3,2-d]pyrimidine (lg, 4.29 mmol) and L-phenylglycine (0.83 g, 6.06 mmol) were dissolved in N, N-dimethylmethyl at room temperature. To the amide (25 ml, 0.32 mol), 1.5 ml of triethylamine was added dropwise, and the mixture was heated to 60 ° C until the reaction was completed by TLC. The mixture was cooled to room temperature, washed with 100 ml of water and extracted with dichloromethane (3*80 ml). The organic phase was washed with brine (EtOAc (EtOAc) (EtOAc) 4-Aminoamine)-2-Phenyl 1-ethanol (0.7 g, pale yellow solid), Yield: 49%, MS m/z (ESI): 335[M+1]

The second step:

The compound 2-(6-bromo-furan[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (1.2 g, 3.59 mmol) and (4-ethyl-piperazine) -1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (2.36 g, 6.86mmol) dissolved in 36ml N,N-dimethylformamide, added tetrakistriphenylphosphine palladium (0.41g, 0.359mmol), sodium carbonate solution (lMol / L, 7ml), nitrogen protection, heated to 85 ° C. The reaction of the starting material was completed until TLC, and the organic phase was washed with dichloromethane (3*80 ml) and the organic phase was washed with saturated brine (80 ml*2). Drying, filtration and concentration under reduced pressure afforded: (4-ethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-furo[3 , 2,d]pyrimidin-6-yl]-phenyl}-methanone (ΙΠ-5) (475 mg, yellow solid), Yield: 28%.

MS m/z (ESI): 472 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.40 ( s, lH), 8.22 (d, 1H), 7.89 (d, 2H), 7.48 (s, 1H), 7.82 (m, 4H), 7.20-7.46 ( m,3H), 5.48(m, 1H), 5.01(t,lH), 3.83(m,2H), 3.40(m,4H), 2.45(m, 4H), 2.27(q, 2H), 1.03(t , 3H).

third step:

Lithium tetrahydrogen aluminum (75 mg, 1.95 mmol) and 5 mL of anhydrous tetrahydrofuran were mixed and stirred at room temperature to the reaction. A solution of compound III-5 (355 mg, 0.75 mmol) in tetrahydrofuran (10 mL, 0.123 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, and then warmed to 55 ° C until the reaction was completed by TLC. 20 ml of water was added to the reaction mixture, which was extracted with ethyl acetate (50 ml*2), and then washed with saturated sodium chloride (50 ml*3) and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified to silica gel column chromatography to [3,2-d]Pyridine-4-ylamino}-2-phenyl-ethanol (IV-5) (48 mg, pale yellow solid), Yield: 14%.

MS m/z (ESI): 458 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.38 ( s, lH), 8.20 (d, 1H), 7.82 (d, 2H), 7.47 (s, 1H), 7.82 (m, 4H), 7.23-7.47 ( m,3H), 5.46(m, 1H), 5.01(t,lH), 3.83(m,2H), 3.52(s,2H), 2.40(brs, 8H), 2.28(q, 2H), 0.99(t , 3H).

Example 17: Preparation of compound ΙΠ-6 and compound IV-6

The first step:

The compound 2-(6-bromo-furan[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (198 mg, 0.59 mmol) and (4-methyl-piperazine- 1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (226 mg, 0.684 mmol Dissolved in 10 mL of N, N-dimethylformamide, and then added tetrakistriphenylphosphine palladium (66 mg, 0.057 mmol), sodium carbonate solution (1 mol / L, 0.5 ml), protected with nitrogen, heated to 85 ° C until The reaction was carried out with TLC. The organic phase was washed with EtOAc (EtOAc) (EtOAc). Filtration and concentration under reduced pressure afforded: <-""""""""""""" -(4-Methyl-piperazin-1-yl)-methanone (ΙΠ-6) (95 mg, yellow solid) Yield: 35.8%.

MS m/z (ESI): 458 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.43 ( s, lH) , 8.30 (d, 1H), 7.88 (d, 2H), 7.48 (s, 1H), 7.50 (m, 4H), 7.27-7.41 ( m, 3H), 5.50 (m, 1H), 5.03 (t, lH), 3.83 (s, 2H), 3.65-3.60 (m, 4H), 2.40 (m, 4H), 2.27 (s, 3H).

The second step:

Lithium tetrahydroaluminum (20.14 mg, 0.53 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and the compound III-6 (90 mg, 0.19 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture. The solution was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC. 20 ml of water was added to the reaction mixture under ice bath at 0 ° C, extracted with ethyl acetate (40 ml * 2 ), and then saturated. Sodium chloride solution (40ml*3) Washed and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified mjjjjjjjjjj 3,2-d]pyrimidin-4-ylamino}-2-phenyl-ethanol (IV-6) (25 mg, pale yellow solid), yield: 28.7%.

MS m/z (ESI): 444 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.43 ( s, lH ) , 8.32 (d, 1H), 7.87 (d, 2H), 7.49 (s, 1H), 7.50 (m, 4H), 7.27-7.39 ( m,3H), 5.49(m, 1H), 5.11(t,lH), 3.78(m,2H), 3.63(s,2H),2.84-2.62(m, 4H), 2.47(s, 3H), 2.52 -2.56 (m, 4H).

-7 and compound IV-7

The first step:

The compound 2-(6-bromo-furan[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (290 mg, 0.868 mmol) and (4-cyclopropylcarbonyl-piperone) Pyrazin-1-yl)-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (445 mg, 1.16mmol) was dissolved in 5mL of N,N-dimethylformamide, then added tetrakistriphenylphosphine palladium (50mg, 0.043mmol), sodium carbonate solution (lmol / L, 2mL), nitrogen protection, heated to 85 ° C. The reaction of the starting material was completed until TLC, and the mixture was cooled to room temperature, and then washed with 80 mL of water, and extracted with dichloromethane (3*80 mL). The organic phase was washed with saturated brine (80 ml*2) Drying, filtration, and concentration under reduced pressure. EtOAcjjjjjjjjj Phenyl-ethylamine)-furo[3,2-d]pyrimidin-6-yl]-phenylmethanone (ΙΠ-7) (350 mg, yellow solid), yield: 79%.

MS m/z (ESI): 512 [M+l].

1H NMR (400 Hz, DMSO-d ₆ ): 8.41 (s,lH), 8.19 (d, 1H), 7.86-7.75 (m, 3H), 7.49-7.40 (m,

4H), 7.36-7.22 (m, 3H), 5.48 (m, 1H), 5.01 (t, lH), 3.80-3.78 (m, 2H), 3.67-3.52 (m, 8H), 2.01 (m _:

The second step:

Lithium tetrahydrogenate (60 mg, 1.578 mmol) and 10 mL of anhydrous tetrahydrofuran were stirred and stirred at room temperature, and a solution of compound III-7 (290 mg, 0.567 mmol) in 10 mL of tetrahydrofuran was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was carried out at 55 ° C until the reaction of the starting material was completely monitored by TLC. 80 ml of water was added to the reaction mixture under ice bath at 0 ° C, extracted with ethyl acetate (90 ml * 2 ), and washed with saturated sodium chloride solution (60 ml * 3 ) The residue obtained is purified by silica gel column chromatography to give: </ </RTI> </RTI> </RTI> </RTI> 2-{6-[4-(4-cyclopropylmethyl-piperazine-1-methyl)-phenyl]-furo[3,2- d]pyrimidine-4-amino}-2-phenyl-ethanol (IV-7) (75 mg, white solid), yield: 27.4%.

MS m/z (ESI): 484 [M+1]. ¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37 ( s, lH), 8.17 (d, 1H), 7.83-7.78 (m, 3H), 7.47-7.43 (m 4H), 7.34-7.19 (m, 3H) , 5.45(m, 1H), 5.02(t,lH), 3.81-3.76(m,2H), 3.56(brs,2H), 2.59(m _: 10H), 2.02(m, lH),0.68(m, 4H ).

Example 19: Preparation of a compound ΙΠ-8

first step:

The p-carboxyphenylboronic acid pinacol ester (2.8 g, 11.3 mmol) was dissolved in dichloromethane (27 ml, 0.422 mol), hydrazine, dimethyl-dimethylformamide (9 ml, 0.116 mol), and added -Boc-3-methylpiperazine (2.9 g, 14.52 mmol), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 2.79 g, 14.55 mmol). N-hydroxybenzotriazole (1.98 g, 14.66 mmol), triethylamine (2.5 ml, 17.99 mmol), stirred at room temperature until the reaction was completed by TLC, 30 ml of water was added to the reaction mixture, and stirred for 30 minutes. Dichloromethane (100 ml * 3 ) was extracted and washed with a saturated sodium chloride solution (100 ml * 2 ). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give: g, white solid), yield 85.4%.

MS m/z (ESI): 431 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 7.79 (d, 2H), 7.43 (d, 2H), 3.79 (m, 3H), 3.36 (m, 4H), 1.52 (s, 9H), 1.40 (s, 12H), 1.18(d, 3H).

The second step:

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (700 mg, 2.0 mmol) and the phenylboronic acid pinacol obtained in the previous step. The ester (1290 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (10 ml, 0.129 mol), then tetratriphenylphosphine palladium (115 mg, 0.1 mmol), sodium carbonate solution (lmol/L, 2 ml) ), nitrogen protection, heating to 80 ° C until TLC monitoring of the reaction of the starting material is complete, naturally cooled to room temperature to add water (100ml * 3) The mixture was washed with EtOAc (EtOAc (EtOAc) (EtOAc) The residue obtained gives: -4-(4-(4-(2-hydroxy-1-phenylethylamine)-thiophene[3,2-d]pyrimidin-6-yl)benzoyl)-3-yl Tert-butyl peptazin-1-carboxylate (ΙΠ-8) (900 mg, pale yellow solid), Yield: 78%

MS m/z (ESI): 574 [M+l

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.39 (s, lH), 8.24 (d, 1H), 7.92 (m, 3H), 7.54 (d, 2H), 7.45 (d, 2H), 7.25 (m, 3H), 5.46 (m, lH), 4.99 (t, lH), 3.82 (m, 2H), 3.20-2.90 (m, 7H), 1.42 (s, 9H), 1.16 (d, 3H).

Example 20: Preparation of a compound ΙΠ-9

4-(4-(4-(2-hydroxy-1-phenylethylamine)-thiophene[3,2-d]pyrimidin-6-yl)benzoyl)-3-methylpiperazine at room temperature 1-carboxylic acid tert-butyl ester (ΙΠ-8) (900 mg, 1.57 mmol) was dissolved in dichloromethane (10 ml, 0.156 mol), trifluoroacetic acid (2.4 ml, 31.4 mmol), and stirred at room temperature until TLC The reaction was completed, concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted with dichloromethane (50ml*3). The organic layer was washed with saturated brine (50ml*3), concentrated under reduced pressure ,: 3⁄4H4-K-2-hydroxy-1-phenylethylamine)-thiophene[3,2-d]pyrimidin-6-yl)phenyl)(2-methylpiperazin-1-yl)methanone ( ΙΠ-9) (550 mg, white solid), Yield: 74%.

MS m/z (ESI): 474 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.44 (s, lH), 8.32 (d, 1H), 8.00 (m, 3H), 7.65 (d, 2H), 7.49 (d, 2H), 7.34 (m, 3H), 5.51 (m, lH), 5.06 (t, lH), 3.84 (m, 2H), 3.44-3.08 (m, 7H), 1.41 (d, 3H).

Example 21: Preparation of Compound IV-8

Lithium tetrahydroaluminum (132 mg, 3.479 mmol) and anhydrous tetrahydrofuran (30 ml, 0.369 mol) were stirred and stirred at room temperature, and -(4-(4-(2-hydroxy-1-phenylethylamine)) was added dropwise to the reaction mixture. - thiophene [3,2-d]pyrimidin-6-yl)phenyl)(2-methylpiperazin-1-yl)methanone (III-9) (550 mg, 1.16 mmol) in tetrahydrofuran (30 ml, 0.369) Mol) solution, room The reaction was stirred for 1 hour, and the temperature was raised to 50 ° C until the reaction of the starting material was completely monitored by TLC. The mixture was cooled to room temperature, and 20 ml of water was added to the reaction mixture, and extracted with ethyl acetate (100 ml*3), and then saturated sodium chloride solution was used. (100 ml * 2 ) After washing, the obtained organic layer was dried (MgSO4jjjjjjjj -methyl-piperazine-1 -methyl)-phenyl]-thiophene [3,2-d]pyrimidine-4-amino-2-phenyl-ethanol (IV-8) (142 mg, white solid) Rate: 26.7%.

MS m/z (ESI): 460 [M+1].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37 (s, lH), 8.34 (d, lH), 7.83 (m, 3H), 7.47 (m, 4H), 7.25 (m, 3H), 5.44 (m, 1H), 5.14(t, lH), 3.78 (m, 2H), 3.56 (brs, 2H), 3.44-3.08 (m, 7H), 1.32 (d, 3H).

Example 22: Preparation of Compound IV-9

Among them, the preparation method of (4-benzyl-piperazin-1-yl)-tetrahydropyrrole-1-yl-methanone-boronic acid is as described in Example 7. The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (174 mg, 0.497 mmol) and (4-benzyl-piperazine small) Tetrahydropyrrole small-ketone-boronic acid (105 mg, 0.331 mmol) was dissolved in N,N-dimethylformamide (5 ml, 65 mmol), then tetratriphenylphosphine palladium (38 mg, 0.033 mmol) , sodium carbonate solution (lmol / L, lml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with dichloromethane (3 * 100ml), organic phase The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. -hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-pyrrol-1-yl-methanone (IV- 9) (7mg, white solid), Yield: 3.9% o

MS m/z (ESI): 543 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.36 (s, lH), 8.15 (d, lH), 7.83-7.77 (m, 3H), 7.47-7.42 (m, 4H), 7.24-7.21 (m, 3H) ), 5.44 (m, 1H), 4.97 (t, 1H), 3.75 (m, 2H), 3.54 (s, 2H), 3.25-3.17 (m, 8H), 2.40-2.38 (m, 4H), 1.75 ( m, 4H).

Example 23: Preparation of Compound IV-10

Among them, the preparation method of (4-benzyl-piperazin-1-yl)-4-methoxypiperidin-1-yl-methanone-boronic acid is the same as that described in Example 8.

The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (181 mg, 0.520 mmol) and (4-benzyl-piperazine- 1-yl)-4-methoxypiperidin-1-yl-methanone-boronic acid (125 mg, 0.346 mmol) dissolved in N,N-dimethylformamide (20 ml, 0.65 mol). Palladium phosphine (40mg, 0.035mmol), sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting material, naturally cooled to room temperature, washed with 100ml of water, with ethyl acetate ( The organic phase is washed with a saturated aqueous solution of sodium sulfate (MgSO4), EtOAcjjjjjjjjjjjjjjjjjjj -{4-[4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-(4 -Methoxy-piperidin-1-yl)-methanone (IV-10) (28 mg, white solid), Yield: 13.8%.

MS m/z (ESI): 587 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37 (s,lH),8,18 (d, 1H), 7.84-7.79 (m, 3H), 7.47-7.44 (m, 4H), 7.32-7.22 (m , 3H), 5.45(m, 1H), 4.99(t,lH), 3.81-3.72(m,2H), 3.52(s,2H), 3.37(s,lH), 3.35(s, 3H), 3.14( m, 4H), 2.90 (m, 2H), 2.40 (m, 4H), 1.80 (m, 2H), 1.36 (m, 4H).

Example 24: Preparation of Compound IV-11

Among them, the preparation method of (4-benzyl-piperazin-1-yl)-morpholin-1-yl-methanone-boronic acid is the same as that described in Example 6. The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (189 mg, 0.540 mmol) and (4-benzyl-piperazine small) - morpholine ketone- ketone-boric acid (150 mg, 045 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.65 mol), followed by tetratriphenylphosphine palladium (52 mg, 0.045 mmol). Sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2), the organic phase is saturated The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. 2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzyl}-piperazin-1-yl)-morpholin-4-yl)- Methyl ketone (IV-11) (25 mg, white solid), Yield: 14%.

MS m/z (ESI): 559 [M+l].

^{1 HNMR (400Hz, DMSO-d} 6): 8.37 (s, lH), 8.21 (d, 1H),

7.84-7.79(m,3H), 7.45-7.41(m,4H), 7.29-7.22(m,3H), 5.42(m,lH), 5.00(t, 1H), 3.78(m, 2H), 3.53( m. 6H), 3.20-3.10 (m, 8H), 2.41-2.39 (m, 4H). Example 25: Preparation of Compound IV-12

The preparation method of (4-benzyl-piperazin-1-yl)-piperidin-1-yl-methanone-boronic acid is as described in Example 10. The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (317 mg, 0.906 mmol) and (4-benzyl-piperazine small) -Piperidine ketone-ketone-boric acid (200 mg, 0.604 mmol) was dissolved in N,N-dimethylformamide (10 ml, 0.325 mol), then tetratriphenylphosphine palladium (70 mg, 0.0604 mmol) , sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until the TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2), organic phase The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjj -hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazine small group)-piperidinyl)-methanone (IV-12) (25 mg, off-white solid), Yield: 7.5%.

MS m/z (ESI): 557 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.37 (s,lH), 8.16 (d,lH), 7.84-7.78 (m, 3H), 7.47-7.22 (m, 7H), 5.45 (m, lH), 4.97(t, 1H), 3.7 (m, 2H), 3.55 (s, 2H), 3.11 (m, 8H), 2.39 (m, 4H), 1.49 (m, 6H).

Example 26: Preparation of Compounds IV-13

The preparation method of (4-benzyl-piperazin-1-yl)-N-ethylpiperazin-1-yl-methanone-boronic acid is the same as that described in Example 11. The compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (181.8 mg, 0.520 mmol) and (4-benzyl-piperazine) -N-ethylpiperazine-based-ketone-boric acid (125 mg, 0.346 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.65 mol), then tetratriphenylphosphine palladium ( 40mg, 0.035mmol), sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added to 100ml water wash, with ethyl acetate (100ml * 2) The organic phase is washed with saturated brine (50 ml*3), EtOAcjjjjjjjjjj (2-hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-N-ethyl-piperazine-1 -yl)-methanone (IV-13) (HOmg, white solid), Yield: 54%. MS m/z (ESI): 587 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.38 (s, lH), 8.22 (m, lH), 7.85 (m, 3H), 7.50 (m, 4H), 7.31 (m _: 3H), 5.47 (m, lH), 5.00(m,lH), 3.78(m,2H), 3.59(s,2H), 3.40-2.95(m,14H), 2.43(m,4H) 1.25(m,3H) o

Example 27: Preparation of Compound IV-14

IV-14

The first step:

The hydrazine-methylpiperazine (1.5 g, 10 mmol) was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.65 ml, 10 mmol) was added to the ice bath at 0 ° C, which was dissolved in two The triphosgene (950mg, 3.2mmol) in methyl chloride (10ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ± 3 °C for 1 hour. N-Boc piperazine was added to the ice bath at 0 °C (1.9). g, lOmmol) and N,N-diisopropylethylamine (1.65 ml, 10 mmol), the reaction was stirred at rt. Trifluoroacetic acid (10 ml, 0.135 mol) was added and the reaction was stirred at room temperature until the reaction was completed by TLC. EtOAc was evaporated. The mixture was concentrated under reduced pressure. EtOAcjjjjjjj

MS m/z (ESI): 213 [M+1].

The second step:

N-methylpiperazinylpiperazine urea (2.3 g, 10.85 mmol) and 4-formylbenzeneboronic acid (1.9 g, 11.93 mmol) were dissolved in 20 ml of tetrahydrofuran and 10 ml of methanol, and a solution of acetic acid (1.2 ml, 21.72 mmol) was added. The reaction was stirred at room temperature for 1.5 hours, sodium triacetoxyborohydride (5.8 g, 27.12 mmol) was added, and the mixture was warmed to 60 ° C. The reaction was stirred until the reaction was completed by TLC, concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained: (4-benzyl-piperazin-1-yl)-N-methylpiperazin-1-yl-methanone-boronic acid (1. lg, white solid), yield: 50%, MS m/z (ESI): 347 [M + 1]. Compound 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (195 mg, 0.75 mmol) and (4-benzyl-piperazine small) at room temperature -N-methylpiperazine-based-ketone-boronic acid (174 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (20 ml, 0.65 mol), then tetratriphenylphosphine palladium (58 mg) , 0.05mmol), sodium carbonate solution (lmol / L, 3ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2) The organic phase was washed with saturated brine (50 ml*3). EtOAcjjjjjjjjjj 2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazine small group)-N-methyl-piperazine small group)-A Ketone (IV-14) (28 mg, white solid), Yield: 10%.

MS m/z (ESI): 572 [M+l] o

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.38 (s, lH), 8.30 (d, 1H), 7.80 (m, 3H), 7.44 (m, 4H), 7.24 (m, 3H), 5.45 (m, lH), 5.10 (m, lH), 3.78 (m, 2H), 3.60 (s, 2H), 3.52-3.18 (m, 12H), 2.42 (m, 4H), 2.38 (s, 3H).

Example 28: Preparation of Compound IV-15

The first step:

N-Boc piperazine (5 g, 26.8 mmol) and 4-formylbenzeneboronic acid (2.68 g, 17.9 mmol) were dissolved in 15 ml of tetrahydrofuran and 15 ml of methanol, and acetic acid solution (6 ml, 43.44 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. After adding sodium triacetoxyborohydride (9.49 g, 44.7 mmol), the mixture was heated to 60 ° C, and the reaction was stirred until the reaction was completed by TLC, and the residue was evaporated. Benzyl-piperazine-l-carboxylic acid tert-butyl ester-boric acid 4.98 g, white solid), Yield: 87.4%, MS m/z (ESI): 321 [M+1]

The second step:

The compound 2-(6-bromo-thiophene [3,2-d]pyrimidin-4-ylamine)-2-phenyl 1-ethanol (lg, 2.856 mmol) and

4-Benzyl-piperazine-1-carboxylic acid tert-butyl ester-boric acid (1.83 g, 5.714 mmol) was dissolved in N,N-dimethylformamide (30 ml, 0.975mol), sequentially added tetrakistriphenylphosphine palladium (323mg, 0.28mmol), sodium carbonate solution (lmol / L, 5ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature The organic layer was washed with saturated brine (50 ml*3). The residue obtained was purified to give 4-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino-thieno[3,2-d]-benzyl}-piperazine- 1-carbonyl-piperazine-l-carboxylic acid tert-butyl hydrazine (1. lg, white solid), Yield: 70.6%, MS m/z (ESI): 546 [M+l

third step:

4-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino-thieno[3,2-d]-benzyl}-piperazine-1-carbonyl-piperazine- 1-tert-Butyl carboxylic acid tert-butyl ester (1.09 g, 2 mmol) was dissolved in tetrahydrofuran, added trifluoroacetic acid (3 ml, 40 mmol), EtOAc. 2), the obtained organic phase is dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. Piperazine-1- 1 -methyl-phenyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethanol (IV _15) (700 mg, pale yellow solid), Yield: 78.6%.

MS m/z (ESI): 446 [M+l

1H NMR (400 Hz, DMSO-d ₆ ): 8.39 (s, lH), 8.18 (d, lH), 7.80 (m, 3H), 7.43 (m, 4H),

7.27(m,2H), 7.22(m, lH), 5.45(m,lH), 5.00(m,lH), 3.83(m,2H), 3.51(s,2H), 2.71(m,4H), 2.27 (m, 4H

Example 29: Preparation of Compound IV-16

IV-16

The first step:

1-Cyclopropionylpiperazine (2.37 g, 15.37 mmol) and p-formylbenzeneboronic acid (1.92 g, 12.81 mmol) were dissolved in dichloromethane (40 ml), stirred at room temperature for 1 hour, then added Sodium cyanoborohydride (1,77 g, 28.18 mmol), EtOAc (EtOAc m. m. Concentration gave: (4-benzylboronic acid-piperazin-1-yl)-cyclopropyl-methanone (1.6 g, white solid), yield: 43.4%.

The second step: Among them, 6-bromo-4-chloro-2-methyl-thiophene [3,2-d]pyrimidine can be produced by the methods described in WO 2009/007421 and WO2008/058285.

6-Bromo-4-chloro-2-methyl-thiophene [3,2-d]pyrimidine (830 mg, 3.15 mmol) and L-phenylglycinol (648 mg, 4.725 mmol) were dissolved in N, N at room temperature - dimethylformamide (10 ml), triethylamine (1.1 ml, 7.875 mol) was added dropwise, heated to 55 ° C, reacted for 24 hours, allowed to cool, added 40 ml of ice water, filtered under reduced pressure, filter cake The mixture was slurried with 10 ml of water, filtered under reduced pressure, and then filtered with 10 ml of n-hexane and filtered under reduced pressure to give: 2-(6-bromo-2-methyl-thiophene[3,2-d]pyrimidine-4-amino 2 -Phenyl-ethanol (780 mg, pale yellow solid), Yield: 71%.

MS m/z (ESI): 365 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.12 (d, 1H), 7.46 (m, 3H), 7.29-7.19 (m, 3H), 5.45 (m, 1H) 4.98 (t,lH), 3,75 (m, 2H), 2.38 (s, 3H).

third step:

The compound 2-(6-bromo-2-methyl-thiophene[3,2-d]pyrimidin-4-amino)-2-phenyl-ethanol (364 mg, 1.0 mmol) and (4-benzyl) Boric acid-piperazin-1-yl)-cyclopropyl-methanone (576 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (10 ml, 0.325 mol), then tetratriphenylphosphine palladium (70 mg) , 0.0604mmol), sodium carbonate solution (lmol / L, 2ml), nitrogen protection, heated to 85 ° C until TLC monitoring of the reaction of the starting materials, naturally cooled to room temperature, added with 100ml of water, extracted with ethyl acetate (100ml * 2) The organic phase was washed with brine (50 ml*3). 4-{4-[4-(2-Hydroxy-1-phenyl-ethylamine)-2-methyl-thiophene[3,2-d]pyrimidin-6-yl]-phenylpiperazine-1-yl - ketone (IV-16) (HOmg, white solid), Yield: 21%.

MS m/z (ESI): 528 [M+l].

¹ H NMR (400 Hz, DMSO-d ₆ ): 8.05 (d, lH), 7.81 (d, 2H), 7.70 (s, lH), 7.46 (m, 5H), 7.31-7.21 (m, 3H), 5.52 ( m, 1H), 4.99 (m, 1H), 3.80 (m, 2H), 3.68 (s, 2H), 3.56 (m, 4H), 2.52 (s, 3H), 2.4 l (m, 4H), 1.96 ( m, lH), 0.73 (m, 4H).

Biological evaluation

1. Receptor tyrosine kinase EGFR, VEGFR molecular level inhibition of enzyme activity

(1) Enzyme reaction substrate PolyCGlu, Tyr) 4: l diluted with potassium-free PBSClOmM sodium phosphate buffer, 150mmol/L NaCl, pH=7.2~7.4) into 2 (^g/ml, 125μ1/well coating) The plate was placed at 37 ° C for 12 to 16 hours. The liquid in the well was discarded, and the plate was washed. The plate was washed three times with 200 μl/well of T-PBS (PBS containing 0.1% Tween-20 in potassium free). 5 minutes each time; the enzyme plate was dried in an oven at 37 ° C for 1 to 2 hours.

(2) Each well was diluted with reaction buffer (50 mmol/L HEPES H 7.4, 50 mmol/L MgCl ₂ , 0.5 mmol/L MnCl ₂ , 0.2 mmol/L Na ₃ V0 ₄ , 1 mmol/L DTT). The ATP solution was 50 μM, and the final concentration was 5 mol/L. Add 1 μΐ of compound solution to each well (1% DMSO dissolved, final concentration 1 (^mol/L), then add 50 μl of c-Met tyrosine kinase protein diluted in reaction buffer; shake at 37 ° C Bed (100 rpm) reaction for 1 hour; each In the second experiment, two wells of ATP control well and corresponding DMSO solvent control wells (negative control wells) were set; the liquid in the well was discarded, and T-PBS was washed three times.

(3) Add the antibody PY99 ΙΟΟμΙ/well (antibody diluted with BSA 5 mg/ml T-PBS at a concentration of 0.4 μ _§ / ηι1), shake at 37 ° C for 0.5 hour; discard the liquid in the well, T-PBS Wash the plate three times.

(4) Horseradish peroxidase-labeled goat anti-mouse secondary antibody ΙΟΟμΙ/well (antibody diluted with BSA 5 mg/ml T-PBS at a concentration of 0.5 g/ml) and shaken at 37 ° C for 0.5 hour Discard the liquid in the well and wash the plate three times with T-PBS.

(5) Add 2 mg/ml OPD chromogenic solution ΙΟΟμΙ/well (diluted with 0.1 M citrate-sodium citrate buffer (ρΗ=5.4) containing 0.03% Η ₂ Ο ₂ ), 25 °C protected from light 1 ~10 minutes; (Ultrasound is required for OPD dissolution, and the coloring solution needs to be used now).

(6) Add 2mol/L H ₂ S0 ₄ 5 (^l/well to stop the reaction, read with VERSAmax of the tunable wavelength microplate reader, the wavelength is 490nm.

(7) The inhibition rate of the sample is obtained by the following formula:

Compound OD value - no enzyme control well OD value

Inhibition rate (%) 0 x 100

Negative control well OD value - no enzyme control well OD value

The test results are shown in Table 2.

2. Receptor tyrosine kinase EGFR, VEGFR activity inhibition IC ₅₀ evaluation experiment

The above screening compound obtained was confirmed to have inhibitory activity EGFR or VEGFR (compound 10 ^"5 M for inhibition of EGFR receptor tyrosine kinase or VEGFR 50%>) formulated as a concentration gradient, for IC _5. Evaluation The ic ₅ value of the inhibitory protein tyrosine kinase at the molecular level of each compound was calculated by a four-parameter method, and the results are shown in Table 1.

Table 2 Experimental results of enzyme activity inhibition of tyrosine kinases EGFR and VEGFR

10μΜ inhibition rate (%) IC ₅₀ value (μΜ)

Compound

EGFR VEGFR EGFR VEGFR

1 -1 86 50 0.9 〉5

1 -2 73 20 > 1

1 -3 79 22 > 1

1 -4 56 18 〉5 one

1 -5 77 21 > 1

II -1 90 43 0.7 one

II -2 83 14 > 1

II -3 81 30 > 1

II -4 86 53 0.6 one

II -5 90 46 0.6 one II -6 76 29 > 1 one

II -7 77 35 > 1

II -8 83 42 > 1

II -9 68 36 〉5 one

II -10 76 23 > 1

II -11 87 18 > 1

ΙΠ- 1 91 61 0.3 0.6

ΙΠ- 2 91 79 0.6 0.7

ΙΠ- 3 91 84 0.4 0.5

ΙΠ- 4 97 82 0.6 > 1

ΙΠ- 5 98 87 0.4 0.4

ΙΠ- 6 90 86 0.4 0.5

ΙΠ- 7 92 85 0.3 0.4

ΙΠ- 8 97 76 0.5 0.4

ΙΠ- 9 92 83 0.1 > 1

IV- 1 92 69 0.3 0.7

IV- 2 93 87 0.3 0.8

IV- 3 98 84 0.2 0.6

IV- 4 91 87 0.3 > 1

IV- 5 95 67 0.5 0.4

IV- 6 87 54 0.4 > 1

IV- 7 89 65 0.5 > 1

IV- 8 89 64 0.5 > 1

IV- 9 45 23 〉10 〉10

IV- 10 34 47 〉10 〉10

IV- 11 89 87 0.7 0.6

IV- 12 21 46 one > 10

IV- 13 18 34 a >10

IV- 14 49 27 〉10 〉10

IV- 15 53 29 〉10 〉10

IV- 16 55 35 〉10 〉10

Gefetinib 67.4 Gefetinib AEE788 (Ο.ΙμΜ) 0.38 0.003 It can be seen from Table 2 that most of the compounds of the thienopyrimidine and furand pyrimidine derivatives of the present invention have significant inhibitory activity against epidermal growth factor receptor EGFR, and some compounds have angiogenic factors. The receptor VEGFR has a good inhibitory effect, and some compounds have a good inhibitory effect on the epidermal growth factor receptor EGFR and the angiogenesis factor receptor VEGFR; and the compound activity of the [3,2-d]pyrimidine skeleton It is obviously superior to the activity of the compound having a [2,3-d]pyrimidine skeleton; the order of the substituent activity on the piperazine ring can be roughly arranged as follows: cyclopropyl>methyl>2-hydroxyethyl>ethyl>Urea; EGFR inhibitory activity of most compounds with a [3,2-d]pyrimidine skeleton is comparable to or better than the control drug Gefitinib Gefitinib, especially compounds III-9 and IV-3, the half-inhibitory concentration IC ₅ . Values were 193 nM and 118 nM, respectively, better than the positive control drug gefitinib, worth further development; compounds III-2, ΙΠ-3, 111-8, IV-1, IV-2, IV-3, IV-11 It has significant VEGFR inhibitory activity and its half inhibitory concentration, IC ₅ . Less than 1 micromolar, with medicinal prospects.

Claims

Rights request

A compound of formula V, or a tautomer, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof,

Wherein, R is selected from: hydrogen, d- alkyl or substituted alkyl of _6, d- ₆ alkyl group, C ₃ - ₆ cycloalkyl group, an olefin group or a substituted C ₂ -6 olefin acyl, aryl group or substituted aryl group, a sulfonyl group, an amide group, or a substituted amide group, a inverse amide group or an amide group substituted reverse, c ₂ - ₈ alkoxy group;

R ³ is hydrogen, d- ₆ alkyl or substituted ^- ₆ alkyl;

Z is nitrogen or CH;

R ¹ is -CH ₂ - or -C(=0)- _;

Ar is selected from the group consisting of: C ₆ _ ₂ . Aryl or substituted C ₆ _ ₂ . Aryl, or C ₄ _ ₂ . Heteroaryl or substituted C ₄ _ ₂ . Heteroaryl

Q is ― 'N ^R2

X is oxygen or sulfur, R ² is hydrogen or d- ₆ alkyl or substituted

Cl-6 yard base;

Ar _{2 is} selected from the group consisting of: C ₆ _ ₂ . Aryl or substituted C ₆ _ ₂ . Aryl, or C ₄ _ ₂ . Heteroaryl or substituted C ₄ _ ₂ . Heteroaryl.

In the following:

In the above formula:

X is oxygen or sulfur; Z is nitrogen or carbon;

R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl acyl group of 3 to 6 carbon atoms, an olefin acyl group having 2 to 6 carbon atoms or a substituted olefin acyl group, an aryl acyl group or a substituted aryl acyl group, a sulfonyl group, an amide group or a substituted amide group, reversed Any one of an amide group or a substituted reverse amide group;

Ar ¹ is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl,

Any of 2- or 3-C ₃ alkyl substituted phenyl, thienyl, 3-C ₃ alkyl substituted thienyl, furyl, 3-C ₃ alkyl substituted furanyl, 2 or 3-pyridyl One type;

Ar ₂ is phenyl, halogen-substituted phenyl, d- ₆ alkyl-substituted phenyl, biphenyl, halogen-substituted biphenyl, naphthyl, pyridyl, thienyl, halogen-substituted thienyl, d- Any one of a _3- alkyl-substituted thienyl group, a furyl group, a halogen-substituted furyl group, and a d- ₃ alkyl-substituted furyl group.

3. The compound of the formula V according to claim 1, wherein R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl acyl group of 3 to 6 carbon atoms, an olefin acyl group having 2 to 6 carbon atoms or a substituted olefin acyl group, an amide group or a substituted amide group;

Ar ¹ is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl, 2- or 3 Any one of -d- ₃ alkyl substituted phenyl;

The octa is any one of a phenyl group, a halogen-substituted phenyl group, a d- ₆ alkyl-substituted phenyl group, a biphenyl group, a halogen-substituted biphenyl group, and a naphthyl group.

4. The compound of formula V according to claim 1, wherein the compound of formula V is:

0(4-ethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl] -Phenyl ketone,

0-{4-[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenyl(4-methyl-piperazine-1 -base) - ketone,

(S)-(A-cyclopropylmethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thieno[2,3-d] Pyrimidine-6-yl]-phenyl}-methanone,

F3⁄4H4-(2-hydroxy-ethyl)-piperazin-1-yl]-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidine- 6-yl]-phenyl}-methanone,

- {4-[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[2,3-d]pyrimidin-6-yl]-phenylpiperazin-1-yl-methanone, 0 -2- {6-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino}-2-phenyl -ethanol,

(S -2- {6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino}-2- Phenyl-ethanol,

(S -2- {6-[4-(4-cyclopropylmethyl-piperazine-1-ylmethyl)-phenyl]-thieno[2,3-d]pyrimidin-4-ylamino 2 - phenyl-ethanol, (S)-2-(6- {4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-phenylthieno[2,3-d]pyrimidin-4-yl Amino}-2-phenyl-ethanol,

Phenyl-2-[6-(4-piperazin-1-ylmethyl-phenyl)-thieno[2,3-d]pyrimidin-4-ylamino]-ethanol, -(4- {4- [4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)-morpholin-4-yl )--ketone,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl) - pyrrol-1-yl-methanone,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzyl}-piperazin-1- -(4-methoxy-piperidin-1-yl)-methanone,

Dimethylamino-1 -(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylper Pyridaz-i-yl)-butyl-2-ene-i-one,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzylpiperazin-1-yl) - piperidin-1-yl)-methanone,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzyl}-piperazin-1- -N-ethyl-piperazin-1-yl)-methanone,

(S)-(4-ethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thiophene [3,2-d]pyrimidine-6- Phenyl ketone,

- {4-[4-(2-Hydroxy-1-phenyl-ethylamine)-thieno[3,2-d]pyrimidin-6-yl]-phenyl}-(4-methyl-piperazine- 1-yl)-methanone,

-(4-cyclopropylcarbonyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thieno[3,2-d]pyrimidin-6-yl ] - Phenyl ketone,

F3⁄4H4-(2-hydroxy-ethyl)-piperazin-1-yl]-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-thieno[3,2-d]pyrimidine- 6-yl]-phenyl}-methanone,

0(4-ethyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-furan[3,2-d]pyrimidin-6-yl] - Phenyl ketone,

- {4-[4-(2-Hydroxy-1-phenyl-ethylamine)-furo[3,2-d]pyrimidin-6-yl]-phenyl}-(4-methyl-piperazine- 1-yl)-methanone,

-(4-cyclopropylcarbonyl-piperazin-1-yl)-{4-[4-(2-hydroxy-1-phenyl-ethylamine)-furo[3,2-d]pyrimidin-6-yl ]- phenyl ketone,

0-4-(4-(4-(2-hydroxy-1-phenylethylamine)-thiophene[3,2-d]pyrimidin-6-yl)benzoyl)-3-methylpiperazine-1 - tert-butyl carboxylate,

0(4-(4-(2-hydroxy-1-phenylethylamine)-thiophene[3,2-d]pyrimidin-6-yl)phenyl)(2-methylpiperazin-1-yl)- ketone, 0-2-{6-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-thieno[3,2-d]pyrimidin-4-ylamino}-2-benzene Base-ethanol,

-2-{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-thieno[3,2-d]pyrimidin-4-ylamino}-2-phenyl -ethanol,

-2-{6-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-phenyl]-thieno[3,2-d]pyrimidin-4-ylamino}-2 - phenyl-ethanol,

(S)-2-(6- {4-[4-(2-hydroxy-ethyl)-piperazine-1-ylmethyl]-phenylthieno[3,2-d]pyrimidin-4-yl Amino}-2-phenyl-ethanol,

-2-{6-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-furo[3,2-d]pyrimidin-4-ylamino}-2-phenyl -ethanol,

-2-{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-furo[3,2-d]pyrimidin-4-ylamino}-2-phenyl -ethanol,

-2-{6-[4-(4-Cyclopropylmethyl-piperazin-1-methyl)-phenyl]-furo[3,2-d]pyrimidin-4-amino 2-phenyl-ethanol ,

0-2-{6-[4-(2-Methyl-piperazin-1-methyl)-phenyl]-thiophene [3,2-d]pyrimidine-4-amino-2-phenyl-ethanol, - (4-{4-[4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)- Pyrrol-1-yl-methanone,

(S)-(A- {4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazine- 1 -yl)-(4-methoxy-piperidin-1-yl)-methanone,

F3⁄4H4-{4-[4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl)- Porphyrin-4-yl)-methanone,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazin-1-yl) - piperidin-1-yl)-methanone,

(S)-(A- {4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylpiperazine- 1 -yl)-N-ethyl-piperazin-1-yl)-methanone,

-(4-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-thieno[2,3-d]pyrimidin-6-yl]-benzyl}-piperazin-1- Methyl-piperazine small base)-methanone,

Phenyl-2-[6-(4-piperazin-1-ylmethyl-phenyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethanol, or O-cyclopropyl-( 4-{4-[4-(2-Hydroxy-1-phenyl-ethylamine)-2-methyl-thiophene[3,2-d]pyrimidin-6-yl]-phenylpiperazin-1-yl ) - ketone.

The compound of the formula V, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or a combination thereof. The inorganic acid salt is any one or more of a hydrochloride, a hydrobromide, a nitrate, a sulfate, or a phosphate; the organic salt is an alkyl sulfonate, a aryl Any one or more of a sulfonate, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, or citrate Kind.

The compound of the formula V according to any one of claims 1 to 4, or a pharmaceutically acceptable solvate thereof, wherein the pharmaceutically acceptable solvate is a compound of the formula V and water And a solvate formed by any one or several solvents of ethanol, isopropanol, diethyl ether and acetone.

7. A process for the preparation of a compound of the formula V, which comprises the step of reacting a compound of the formula VI with a compound of the formula VII to obtain a compound of the formula V,

VI VI] V 4 is a hydroxyl group or a C1-C6 alkoxy group;

, R ⁵ is F, Cl, Br, I;

R, Z, R ³ , RX, R ² , Ar and Ar ₂ are as defined in claim 1.

8. The method according to claim 7, wherein the method comprises the following step 3 or step 1 and

\:/: a 3 or steps 2 and 3 or steps 1 to 3:

Or the method comprises the following step 5 or steps 2 and 5 or steps 4 and 5 or steps 2 and 4 and 5:

Or the method comprises the following step 7 or steps 1 and 7 or steps 6 and 7 or steps 1 and 6 and 7:

:

In the formulas, R, Z, Ar ¹ and Ar ₂ are as defined in claim 2.

9. A compound of formula V according to any one of claims 1 to 4, or a tautomer, racemate, enantiomer, diastereomer thereof, pharmaceutically acceptable Use of a salt or a pharmaceutically acceptable solvate, characterized in that it is used to prepare a tyrosine kinase inhibitor, preferably for the preparation of an EGFR and/or VEGFR inhibitor.

10. The use according to claim 9, wherein the preparation of the tyrosine kinase inhibitor is for preparation:

(ii) a drug that prevents or treats abnormal cell proliferation, morphological changes, hyperkinesia, angiogenesis, and metastatic disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR; or (iii) A medicament for preventing or treating tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.

A tyrosine kinase inhibitor characterized by comprising a compound of the formula V according to any one of claims 1 to 4, or a tautomer, a racemate thereof, an enantiomer thereof, A mixture of any one or more of a diastereomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate is prepared.

The tyrosine kinase inhibitor according to claim 11, wherein the tyrosine kinase inhibitor is an EGFR and/or a VEGFR inhibitor.

13. Use of a tyrosine kinase inhibitor according to claim 11 or 12, for use in the preparation of:

(iii) Drugs for preventing or treating tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound of the formula V according to any one of claims 1 to 4, or a tautomer thereof, a foreign substance A rot, an enantiomer, a diastereomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate.