CN101730703B - Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof - Google Patents

Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof Download PDF

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CN101730703B
CN101730703B CN2008800159294A CN200880015929A CN101730703B CN 101730703 B CN101730703 B CN 101730703B CN 2008800159294 A CN2008800159294 A CN 2008800159294A CN 200880015929 A CN200880015929 A CN 200880015929A CN 101730703 B CN101730703 B CN 101730703B
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amino
methyl
dmso
benzamide
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CN101730703A (en
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李庶心
刘永学
赵砚瑾
韩春光
匡先照
黄琳仪
肖文松
孙小梅
邓晓东
薛阳
叶清泉
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Institute of Radiation Medicine of CAMMS
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Abstract

Novel benzamide derivatives of formula I, wherein the definition of substituents Het, G1, G2, G3, Y, X1, X2, X3 and X4 see also in the description. Preparation processes for these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds as active ingredients in medicament for the treatment of diseases associated with proliferation, such as leukaemia and solid tumor.

Description

Benzamide derivatives with antiproliferative activity and pharmaceutical preparations thereof
Technical Field
The present invention relates to a compound for treating diseases related to proliferation, and more particularly, to a novel benzamide derivative, a preparation method thereof, a salt of the derivative, and a medicament containing the compound or the salt thereof as an active ingredient.
Background
Malignant tumor seriously threatens human life and health. According to the statistics of the world health organization, about 630 million people die from malignant tumors every year in the world, about 150 million people die from cancers every year in China, and the number of newly-increased tumor patients in China is up to more than 180 million every year at present. Due to factors such as environmental pollution and life style change, the number of deaths caused by malignant tumors in China is on the rise year by year, and the cancer prevention and treatment tasks are very difficult. The drug therapy plays an important role in three main treatment methods of malignant tumors, and the development speed is high. In recent years, considerable progress is made in tumor chemotherapy, and the survival time of tumor patients is obviously prolonged, but the treatment of most malignant tumors which have the most serious harm to the human life health still cannot achieve satisfactory effect.
Chemotherapy drugs in the traditional sense often produce more serious toxic and side effects due to lack of selectivity of action targets, and the exertion of clinical effects is greatly restricted. In recent years, the research progress of pharmacogenomics, proteomics and molecular pharmacology gradually clarifies the pathogenesis of tumors; the application of large-scale virtual screening, combinatorial chemistry and genetic engineering accelerates the research and development process of the drugs, and the research and development of the anti-tumor drugs enter a brand-new era. Pharmacologists and oncologists are more and more deeply aware that to improve the curative effect of tumor treatment, breakthrough progress must be made by starting from the mechanism of tumorigenesis and development so as to fundamentally prevent and treat cancer. Therefore, the anti-tumor drugs are developing from traditional cytotoxic drugs to novel anti-tumor drugs aiming at multi-link action molecular targets of mechanisms. For example, Gefitinib (Gefitinib), a recently marketed anti-non-small cell lung cancer drug, is a specific protein kinase aiming at a tumor cell signal transduction system, shows good curative effect and lower toxic and side effect, and the discovery and clinical application of the molecular targeted drug enable the medical treatment of tumors to be transited from palliative treatment to radical treatment.
The proteins related to the generation and metastasis of tumors are various, and the proteins having general biological significance for regulating and controlling tumor cell growth factors are most likely to be the action targets of broad-spectrum low-toxicity antitumor drugs. Histone Deacetylase (HDAC) is just one such protein, and is one of the new targets for anti-tumor effect. The gene level-based gene expression vector has attracted great attention of researchers at home and abroad due to a unique action mechanism based on the gene level.
Chromatin is composed of DNA, histones and non-histones. Nucleosomes are basic repeating units of chromatin, and are composed of octamers consisting of histones H3, H4, H2A and H2B, histones H1 located outside the nucleosomes, and DNA (deoxyribonucleic acid) wound outside the nucleosomes and containing 146 base pairs. The acetylation state of histone has important regulation and control effect on gene transcription, and research shows that epsilon-lysine of histone in nucleosome of the position with high transcription activity is in high acetylation state, while histone transcribed in a relative static position is in low acetylation state. The acetylation state of histones is regulated by two classes of enzymes, namely Histone Acetyltransferases (HAT) and Histone Deacetylases (HDAC), HAT can specifically catalyze acetylation of amino terminal lysine residues of several histone components H1, H2A, H2B, H3 and H4, HDAC can catalyze deacetylation of histones to cause reduced expression of corresponding genes, and under normal physiological conditions, the regulation of histone acetylation by the two classes of enzymes is in equilibrium. In the transformed state of the cell, the activity of HDAC is obviously enhanced. The original gene expression balance state is broken, so that the molecular expression unbalance influencing cell proliferation and regulating cell cycle is caused, and further the cell degeneration is caused.
Current studies confirm that most histones are in a hypoacetylated state in tumor cells, and that an imbalance in histone acetylation state is closely related to tumorigenesis. The relationship between histone hypoacetylation and tumorigenesis is best exemplified in the study of acute promyelocytic leukemia. Retinoic Acid Receptors (RARs) are important transcriptional regulators of myeloid differentiation, and RAR α forms heterodimers with RARs, binding retinoic acid response elements on DNA. In the case of retinoic acid deficiency, SIN3/HDAC3 may be recruited by nuclear co-repressors and retinoic acid thyroid receptor silencing regulators, thereby inhibiting transcription.
HAT is widely present in cells from yeast to mammalian organisms, and a variety of protein molecules with HAT activity have been found, and there are various classification methods depending on structure and function. Mammalian HDACs, on a molecular level, can be classified as type 3: HDAC type I/II is Zn2+Dependent, HDAC type III is Nicotinamide Adenine Dinucleotide (NAD) dependent. The I type comprises HDAC1, 2, 3, 8 and 11, all of which are positioned in a nucleus, and the relative molecular weight of the I type is 42000-55000. The class II comprises HDAC4, 5, 6, 7 and 9, is relatively large molecular weight protein and has a relative molecular weight of 120000-130000. Mainly located in the cytoplasm, but can shuttle between the nucleus and the cytoplasm. HDAC type III has homology with the Sir2 family of yeast and has not been extensively studied in mammalian systems (Liu Liao Juno Chen, et al, "three-dimensional quantitative structure-activity relationship of sulfonamide hydroxamic acid HDAC inhibitors". Physics and Chemicals, 2005, 21 (3): 333-337).
Research shows that Histone Deacetylase (HDAC) inhibitor can inhibit tumor cell growth, promote differentiation and induce apoptosis. Compared with traditional antitumor drugs, the therapeutic advantages of HDAC inhibitors will be mainly reflected in two aspects: (1) can directly act on the key link of abnormal expression of genes, thereby inhibiting and correcting hyperproliferation, escape apoptosis and differentiation capacity reduction of tumor cells, which is different from the defects that the traditional antitumor drug only aims at the single phenotype of the hyperproliferation of cells and has weaker effect on other phenotypes caused by abnormal expression of the genes; in vitro experiments prove that the HDAC inhibitor has wide antitumor effect, shows good killing effect on tumor cells of multiple tumor sources, including bladder, bone, breast, uterus, central nervous system, esophagus, lung, ovary, pancreas, prostate and the like, and after being treated by the HDAC inhibitor, the cells have obvious apoptosis, proliferation inhibition and cell cycle block. Animal experiment results show that the HDAC inhibitor can effectively inhibit and kill tumor cells of tumor-bearing animals without obvious adverse reaction. The medicine changes the mode that the traditional chemotherapy medicine completely hits all cells with rapid division, treats the gene mutation or gene expression abnormality of tumor cells, and has small influence on normal cells. (2) Aiming at the common drug resistance problem in chemotherapy of patients, the HDAC inhibitor not only can increase the selectivity of antitumor drug species, but also can be combined with drugs with different action mechanisms to resist the tumor drug resistance and finally has great significance in improving the survival rate of tumor patients. The HDAC inhibitor and a plurality of chemotherapeutic drugs are combined to show good synergistic treatment effect. For example, TSA or SAHA can increase the sensitivity of tumor cells to target DNA or topoisomerase II chemotherapeutic drug etoposide during the initial treatment period. The combination of SAHA and Gleevec can make the chronic myelocytic leukemia cells which are tolerant to Gleevec have sensibility again. The VEGF inhibitor used with the HDAC inhibitor LAQ824 inhibited 51% of cultured endothelial cells (twice the effect of either drug alone). In the mouse model, this combination was able to control neovascularization by 60% and by 50% when used alone. The inhibition of tumor growth in mice with prostate cancer was 35% and 75%, respectively. When the composition is used in combination, the inhibition rate is 85%. The tumor inhibition rates of the two inhibitors on breast cancer mice are respectively 54% and 60%, and the tumor growth is reduced by 80% when the two inhibitors are used in combination.
Known HDAC inhibitors are: (1) short chain fatty acids, such as butyric acid, phenylbutyric acid; (2) hydroxamic acids, such as SAHA, Scriptaid; (3) a cyclotetraphthalide structure containing an epoxy ketone group such as trapoxin b, HC-Toxin, etc.; (4) cyclic tetrapeptide structures without epoxy keto groups, such as FK 228; (5) benzamides, e.g. MS-275(EP0847992A1, US2002/0103192A1, WO02/26696A1, WO01/18171A 2). These compounds all show potential antitumor activity; valproic acid (7 months 2005) and SAHA (10 months 2006) are now approved by the FDA in the united states for marketing.
However, these drugs have the following disadvantages: (1) low curative effect, and poor antitumor effect of short-chain fatty acids such as butyric acid; (2) great side effect, hydroximic acid compounds are Zn2+For binding targets, many Zn-containing organisms are known2+Protein, and therefore, the side effects of the hydroxamic acid compounds are greater; (3) the cost is high, the cyclotetrapeptide structure containing epoxy ketone groups and the cyclotetrapeptide structure without epoxy ketone groups are prepared by a biological method, are separated and purified by high performance liquid chromatography, are not suitable for large-scale preparation, and have high production cost; if the preparation is carried out by a chemical method, the cost is higher. (4) The stability is poor, and the physicochemical property of the benzamides is unstable because of containing a phenylenediamine structure. MS-275 is the first histone deacetylase inhibitor demonstrated to have oral anti-cancer activity in animals, and MS-275 is currently undergoing clinical studies in the united states for leukemia and solid tumors. However, some new compounds with better performance are still to be developed in order to obtain HDAC inhibitors with high anti-cancer activity, less side effects and more stability.
Disclosure of Invention
It is an object of the present invention to provide novel benzamide derivatives having the following structure:
or a salt of a pharmaceutically acceptable acid, wherein the definition of each substituent in the formula is described in detail below.
It is another object of the present invention to provide a pharmaceutical composition containing the above compound or a pharmaceutically acceptable acid salt.
Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable acid salt thereof.
It is another object of the present invention to provide the use of the above compound or a pharmaceutically acceptable acid salt thereof.
The invention provides a novel benzamide derivative, which has a structure shown in a formula (I):
Figure GPA00000632129500032
or a salt of a pharmaceutically acceptable acid thereof,
wherein:
het is aryl, heteroaryl, cycloalkyl or heterocyclyl, which groups may be optionally substituted, each of which may be optionally fused to one or more aryl or heteroaryl groups, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclyl rings, each of which may be optionally substituted;
G1selected from a bond, T, L-T, T-L or T-L-T;
wherein in the presence of L, L is S, O, C ═ O or N (R)1) Where R is1Selected from hydrogen, alkyl, hydroxyalkyl and tert-butoxycarbonyl;
t is C when present1-C4An alkylene group;
G2is arylene or heterocycloarylene, each of which may be optionally substituted;
G3is vinylidene, or is absent (i.e. G)2The group is directly attached to-C ═ O in formula I);
y is NH2Or OH;
X1、X2、X3、X4each independently selected from hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), C1-C4Alkyl or C1-C4Alkoxy, and specifies X1、X2、X3、X4At least one of which is notAnd (3) hydrogen.
Preferred compounds of the formula I according to the invention are those in which X2Selected from fluorine, C1-C4Alkoxy radical, X1、X3、X4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C4Alkyl or C1-C4An alkoxy group.
Preferred compounds of the formula I according to the invention are those in which X2Is fluorine, C1-C4Alkoxy radical, X1、X3、X4Are all hydrogen.
Preferred compounds of the invention are of the formula I, in which G3Is absent.
Preferred compounds of the invention are of the formula I, in which G2Is phenylene, and
Het-G1is that
Figure GPA00000632129500041
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IA):
Figure GPA00000632129500042
wherein:
l is S, O or N (R)1) Wherein R is1Is hydrogen or C1-C4An alkyl group;
R2is hydrogen or C1-C4An alkyl group;
y is-NH2or-OH;
X2selected from fluorine or C1-C4An alkoxy group;
het is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzimidazolyl or benzotriazolyl, each of which may be optionally substituted.
Preferred compounds of formula (IA) of the present invention have the structure of formula (IA-1):
Figure GPA00000632129500051
wherein: l is NH or S;
p, Q, M, G and U are each independently CH or N and M, Q, U cannot be both N, so long as no more than 2 of P, Q, M, G and U are N, the S or O of one ring is not adjacent to the S or O on the other ring in rings containing P, Q, M, G and U;
R2is hydrogen or C1-C4An alkyl group;
X2selected from fluorine or C1-C4An alkoxy group;
the groups A and B may be the same or different and are independently selected from hydrogen, halogen, C1-C4Alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy, heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, amido, carbamoyl or
Figure GPA00000632129500052
Figure GPA00000632129500061
Figure GPA00000632129500071
Preferred compounds of formula (IA) of the present invention have the structure of formula (IA-2):
wherein:
l is S or NH;
R2is hydrogen or C1-C4An alkyl group;
X2selected from fluorine or C1-C4An alkoxy group;
a and B are as defined for the compound of formula (IA-1).
Preferred compounds of formula (IA) of the present invention have the structure shown in formula (IA-3):
Figure GPA00000632129500073
wherein:
l is S or NH;
X2selected from fluorine or C1-C4An alkoxy group;
A. b is as defined for the compound of formula (IA-1).
Preferred compounds of formula (IA) of the present invention have the structure shown in formula (IA-4):
Figure GPA00000632129500074
wherein:
l is S or NH;
d is N-R3 or S;
e is N or C-A;
R2and R3Each independently is hydrogen or C1-C4An alkyl group;
X2selected from fluorine or C1-C4An alkoxy group;
a and B are as defined for the compound of formula (IA-1).
Preferred compounds of formula (IA) of the present invention have the structure shown in formula (IA-5):
Figure GPA00000632129500081
wherein:
l is NH;
X2selected from fluorine or C1-C4An alkoxy group;
a and B are as defined for the compound of formula (IA-1).
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IA-6):
wherein:
a is hydrogen or C1-C4An alkyl group;
b is as defined for compounds of formula (IA-1);
X2selected from fluorine or C1-C4An alkoxy group;
preferred compounds of formula (I) of the present invention have the structure shown in formula (IA-7):
wherein:
p is CH, N;
b is as defined for compounds of formula (IA-1);
X2selected from fluorine or C1-C4An alkoxy group;
preferred compounds of formula (I) of the present invention have the structure shown in formula (IB):
Figure GPA00000632129500084
wherein:
G1is T, L-T or T-L, where L is S, O or NH; t is-CH2-；
Z1Is O, S, NH or CH2；
Z2Is N or CH;
X2selected from fluorine or C1-C4An alkoxy group;
het is selected from phenyl, pyridyl, pyrimidinyl or benzothiazolyl, and may be substituted by A and 1 or B; A. b is as defined for compounds of formula (IA-1); het may also be optionally substituted with 1, 2 or 3 groups independently selected from alkoxy, haloalkoxy, acyl, morpholino or alkoxy optionally substituted phenyl.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IC):
Figure GPA00000632129500091
wherein:
G1is T, L-T or T-L;
l is S, O or NH;
t is-CH2-；
Z2Is N or CH;
Z1is O, S, NH or CH2；
X2Selected from fluorine or C1-C4An alkoxy group;
het is selected from phenyl, pyridyl, pyrimidinyl or benzothiazolyl, and may be substituted by A and/or B, A, B are as defined for compounds of formula (IA-1); het may also be optionally substituted with 1, 2 or 3 groups independently selected from alkoxy, haloalkoxy, acyl, morpholino or alkoxy optionally substituted phenyl.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (ID):
Figure GPA00000632129500092
wherein:
het is:
Figure GPA00000632129500093
X2selected from fluorine or C1-C4An alkoxy group.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IE):
Figure GPA00000632129500101
wherein:
y is-OH or-NH2；
X2Selected from fluorine or C1-C4An alkoxy group;
het is a heterocycle or heteroaryl, each ring containing at least one nitrogen atom as part of the ring and being optionally substituted.
In preferred compounds of formula (IE) according to the invention, Y is-NH2；X2Is fluorine or C1-C4An alkoxy group;
het is a heterocycle or heteroaryl group, each ring containing at least one nitrogen atom as part of the ring and optionally substituted with 1 or 2 substituents selected from A or B, A, B as defined for compounds of formula (IA-1).
In more preferred compounds of formula (IE) of the present invention Het may be optionally substituted by 1 or 2 substituents independently selected from:
Figure GPA00000632129500102
in the preferred compounds of the formula (I) according to the invention, G3Is absent; g2Is phenylene, indolyl or indolinyl, each of which may be optionally substituted, G1Is a chemical bond, -CH2-、-O-CH2-、-S-CH2-、-S-CH(CH3) -or-N (R)1)-CH2-。
More preferred compounds of formula (I) are those in which G2Is indolyl or indolinyl; g1is-CH2-or-N (R)1)-CH2-；
Het is:
Figure GPA00000632129500103
in preferred compounds of the formula (I), G3Is absent;
G2is phenylene;
G1is-S-CH2-or-S-C (CH)3)(H)-；
Het is:
Figure GPA00000632129500104
wherein:
j is selected from the following groups:
Figure GPA00000632129500111
preferred compounds of formula (I) of the present invention have the structure shown In Formula (IF):
Figure GPA00000632129500112
wherein:
y is-OH or-NH2；
X2Selected from fluorine or C1-C4An alkoxy group;
het is a heterocycle or heteroaryl group, wherein each group may be optionally substituted and each ring contains at least one nitrogen atom.
In preferred compounds of formula (IF) according to the invention Het is:
Figure GPA00000632129500113
preferred compounds of formula (IF) of the present invention have the structure shown in formula (IF-1):
wherein:
y is-NH2；
X2Selected from fluorine or C1-C4An alkoxy group;
a is as defined for formula (IA-1).
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IG):
Figure GPA00000632129500115
wherein:
Het、G1y is as defined in formula (I) structure, X2Selected from fluorine or C1-C4An alkoxy group.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IH):
Figure GPA00000632129500121
wherein:
l is S, O or-NH-;
X2selected from fluorine or C1-C4An alkoxy group;
A. b is as defined in the structure of formula (IA-1).
Preferred compounds of formula (IH) are those wherein a is optionally substituted pyridine or optionally substituted phenyl; b is hydrogen or halogen.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (I-I):
wherein:
l is S, O or-NH;
X2selected from fluorine or C1-C4An alkoxy group;
R4is hydrogen or C1-C6An alkyl group.
The invention also provides novel benzamide derivatives having the structure of formula II:
Figure GPA00000632129500123
or a salt of a pharmaceutically acceptable acid.
Het1 is aryl or heteroaryl, optionally substituted, each optionally fused to one or more aryl or heterocyclyl groups, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclyl groups, each optionally substituted;
X1、X2、X3、X4y is as defined for formula (I);
G1is a covalent bond C0-C4Hydrocarbyl radical, C0-C4-hydrocarbyl- (CO) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (NR5) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (S) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (O) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (SO) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (SO) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (NH) - (CO) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (CO) - (NH) -C0-C4-hydrocarbyl, -NH-CO-NH-, -NH-CS-NH-, -O-CO-O-, -O-CS-O-, -NH-C (NH) -NH-, -S (O)2-N(R5)-，-N(R5)-S(O)2-, -NH-C (O) -O-, or-O-C (O) -NH-, where R5 may be hydrogen, C1-C5Alkyl, aryl, aralkyl, heterocyclyl, heterocyclylaryl, SO2-alkyl, SO2-aryl, CO-alkyl, CO-aryl, CO-NH-alkyl, CO-NH-aryl, CO-O-alkyl or CO-O-aryl;
n may be 0, 1, 2, 3 or 4;
z is N or CH;
y is NH2Or OH.
The compound contains basic groups which can form salts with acid, and the salts of the derivatives can be formed by adopting common means.
Common salts include organic acid salts, inorganic acid salts, and the like. Organic acid salts which are commonly used are citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate, etc.; examples of the inorganic acid salts include halogen acid salts, sulfates, phosphates, nitrates and the like.
For example, with lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, and the like, methanesulfonate, trifluoromethanesulfonate, etc. may be formed; with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid, etc. to form p-toluenesulfonic acid salts, benzenesulfonic acid salts; can form corresponding salt with organic carboxylic acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; with amino acids, such as glutamic acid or aspartic acid, glutamate or aspartate can be formed. Corresponding salts can also be formed with inorganic acids, such as hydrohalic acids (e.g., hydrofluoric, hydrobromic, hydroiodic, hydrochloric), nitric, carbonic, sulfuric, or phosphoric acids, and the like.
The invention also provides a solvate of the benzamide derivative, wherein the solvent is preferably water, ethanol or methanol.
The invention also provides a preparation method of the benzamide derivative.
The preparation method of the compound of the formula I comprises the following steps of reacting a compound of a formula III with a compound of a formula IV in a solvent to obtain a product, wherein the reaction formula is as follows:
Figure GPA00000632129500131
wherein Het and G in the compound of formula III1、G2、G3Is as defined for compounds of formula I, and compounds of formula IV wherein Y is-NH 2, or OH, X1、X2、X3、X4Each independently selected from hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), C1-C4Alkyl or C1-C4Alkoxy, and specifies X1、X2、X3、X4At least one of which is not hydrogen.
The starting compound of formula III is prepared according to or with reference to the methods disclosed in WO 2005092899.
Compound IV is commercially available or can be synthesized by conventional methods.
The solvent used in the preparation method can be selected from various solvents, such as chloroform, dichloromethane, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, xylene, toluene, dimethyl sulfoxide, triethylamine and the like; the reaction temperature is-30- +80 ℃; if necessary, a base such as sodium hydroxide, triethylamine, pyridine, etc. may be added, and an acid such as hydrochloric acid, acetic acid, trifluoroacetic acid, etc. may be added.
Het, G of the compound of the formula III1、G2、G3Or the amino group (if any) and the hydroxyl group (if any) of the compound of formula IV can be protected by corresponding protecting groups to obtain a protecting group-containing compound of formula I, and then deprotection is carried out to obtain the compound of formula I. These protecting groups and methods for their introduction or removal are well known to those skilled in the art.
The compound shown in the general formula I can be purified by adopting a common separation method, such as column chromatography, recrystallization and the like.
Similarly, compounds of formula (II) may be prepared according to the method of synthesizing amides:
wherein, Het1, G1、Z、n、X1、X2、X3、X4Or Y is as defined for the compound of formula (II).
The invention also provides a pharmaceutical composition containing the benzamide compound or the salt or the solvate thereof.
The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, which include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. which are conventional in the pharmaceutical field, and if necessary, flavoring agents, sweeteners, etc. The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field. Among them, oral administration is the most preferable in clinical practice. The dosage is 0.0001-200mg/kg body weight per day.
The invention also provides the application of the benzamide compound or the salt or the solvate thereof in treating diseases related to proliferation, such as leukemia and solid tumors.
The inventor of the invention proves through experiments that the compound disclosed by the invention has a positive inhibition effect on tumor cell proliferation, the tumor inhibition activity is obviously superior to that of a positive control medicament MS-275, and the compound has lower toxicity on normal cells than MS-275.
In addition, the compound disclosed by the invention has more stable physicochemical properties than the positive control drugs MS-275 and the compound disclosed by WO 2005092899.
Best mode for carrying out the invention
The following examples are provided to illustrate the applicability of the present invention, and it will be understood by those skilled in the art that various modifications and substitutions can be made to the corresponding features according to the teachings of the prior art, and still fall within the scope of the invention as claimed.
Figure GPA00000632129500151
Reaction scheme 1
EXAMPLE 1 Synthesis of N- (2-amino-5-fluorophenyl) -4((4- (pyridin-3-yl) pyrimidin-2-amino) methyl) benzamide (Compound 1)
Step 1. Synthesis of 3, 3-dimethylamino-1-pyridin-3-yl-propenone
Dissolving 2g of 3-acetylpyridine in 5ml of anhydrous N, N-dimethylformamide, adding 5ml of N, N-dimethylformamide diacetal into the solution, heating to 110 ℃ after the addition is finished, reacting for 3 hours, performing thin layer chromatography to show that the reaction is finished, recovering N, N-dimethylformamide under reduced pressure, placing the residual solution in a refrigerator overnight, separating out a yellow solid, performing suction filtration, and washing with ethyl acetate/petroleum ether at a ratio of 1: 1 to obtain 2.05g of the yellow solid.
The melting point of the product is m.p.82-83 ℃;
step 2. Synthesis of 4-guanidinomethyl-benzoic acid
2g of methylisothiouronium sulfate is dissolved in 10ml of 1mol/L aqueous solution of sodium hydroxide, 2.15g of 4-aminomethyl benzoic acid is slowly dropped under ice bath, after the addition is finished, the mixture is stirred and reacts at room temperature overnight, white solid is separated out, and the white solid is filtered and dried to obtain 2.56g of the white solid.
Step 3. Synthesis of 4- [ (4-pyridin-3-yl-pyrimidin-2-yl-amino) -methyl ] benzoic acid
1.57g of the product in the step 1 and 1.88g of the product in the step 2 are dissolved in 10ml of isopropanol, 1.26g of potassium carbonate is added at the same time, after the addition is finished, the temperature is increased and the reflux is carried out for 12 hours, the thin layer chromatography shows that the reaction is finished, and the white solid is obtained by cooling, filtering and drying, wherein 1.87g of the white solid is obtained.
The melting point of the product is m.p.219.5-221 ℃;
step 4 Synthesis of N- (2-amino-5-fluorophenyl) -4((4- (pyridin-3 yl) pyrimidin-2-amino) methyl) benzamide (Compound 1)
1g of the product of step 3, 0.54g N, N-carbonyldiimidazole, was dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5h, and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 0.52g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.38g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, washing residues with silica gel column and ethyl acetate/petroleum ether/ethanol at a ratio of 2: 1: 2, concentrating eluent, and crystallizing to obtain 0.28g of white solid.
The melting point of the product is m.p.180-181.5 ℃;
1HNMR(DMSO-d6)(δppm)：4.640-4.654(d，2H)，5.212(s，2H)，6.338-6.354(m，1H)，6.506-6.541(dd，1H)，7.069-7.107(t，1H)，7.262-7.274(d，1H)，7.492-7.531(m，3H)，7.910-8.044(m，3H)，8.407-8.420(d，2H)，8.680-8.690(d，1H)，9.246(s，1H)，9.515-9.532(d，1H)。
synthesis procedures for the following Compounds 2 to 4, 9 to 17, 51 to 55, 125 to 126 were as in example 1 (Compound 1) N- (2-amino-5-fluorophenyl) -4((4- (pyridin-2-yl) pyrimidin-2-amino) methyl) benzamide (Compound 2)
The melting point of the product is m.p.206-207 ℃;
1HNMR(DMSO-d6)(δppm)：4.653-4.667(d，2H)，5.208(s，2H)，6.337-6.344(m，1H)，6.503-6.539(dd，1H)，7.066-7.104(t，1H)，7.494-7.520(m，4H)，7.908-7.997(m，4H)，8.317-8.337(d，1H)，8.442-8.455(d，1H)，8.692-8.703(d，1H)，9.525(s，1H)。
n- (2-amino-5-fluorophenyl) -4((4- (pyridin-4-yl) pyrimidin-2-amino) methyl) benzamide (compound 3)
The melting point of the product is m.p.206-207 ℃;
1HNMR(DMSO-d6)(δppm)：4.647-4.662(d，2H)，5.192(s，2H)，6.324-6.367(m，1H)，6.508-6.543(dd，1H)，7.073-7.111(m，1H)，7.284-7.297(d，1H)，7.486-7.494(d，2H)，0.89(t，3H)，7.909-8.074(m，5H)，8.460-8.472(d，1H)，8.720-8.734(d，2H)9.510(s，1H)。
n- (2-amino-5-fluorophenyl) -4- (4- (4-methoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 4)
The melting point of the product is m.p.209-209.5 ℃;
1HNMR(DMSO-d6)(δppm)：3.831(s，3H)，4.676(s，2H)，6.349-6.392(m，1H)，6.528-6.563(dd，1H)，7.049-7.220(m，4H)，7.484-7.503(d，2H)，7.916-7.936(d，2H)，8.081-8.110(dd，2H)，8.318-8.331(d，1H)，9.539(s，1H)。
n- (2-amino-5-fluorophenyl) -4((4- (4-bromophenyl) pyrimidin-2-amino) methyl) benzamide (compound 9)
1HNMR(DMSO-d6)(δppm)：4.632-4.645(d，2H)，5.223(s，2H)，6.330-6.367(m，1H)，6.514-6.549(dd，1H)，7.075-7.112(t，1H)，7.186-7.200(d，1H)，7.481(s，2H)，7.698-7.717(d，2H)，7.912-8.050(m，5H)，8.372-8.384(d，1H)，9.540(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (3, 4-difluorophenyl) pyrimidin-2-amino) methyl) benzamide (compound 10)
1HNMR(DMSO-d6)(δppm)：4.631-4.654(d，2H)，5.189(s，2H)，6.337-6.344(m，1H)，6.507-6.542(dd，1H)，7.071-7.108(t，1H)，7.218-7.230(d，1H)，7.487-7.579(m，3H)，7.904-7.974(m，4H)，8.120-(s，1H)，8.381-8.393(d，1H)，9.509(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (2, 4-dimethylthiazol-5-yl) pyrimidin-2-amino) methyl) benzamide (compound 11)
1HNMR(DMSO-d6)(δppm)：2.614(s，6H)，4.558-4.574(d，2H)，5.192(s，2H)，6.326-6.361(m，1H)，6.509-6.544(dd，1H)，6.826-6.839(d，1H)，7.075-7.112(t，1H)，7.440-7.459(d，2H)，7.899-7.919(d，3H)，8.317-8.329(d，1H)，9.507(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- ((2- (piperidin-1-yl) ethoxy) phenyl) pyrimidin-2-amino) methyl) benzamide (compound 12)
1HNMR(DMSO-d6)(δppm)：1.525-1.759(m，6H)，3.155-3.601(m，6H)，4.359-4.372(t，2H)，4.626-4.614(d，2H)，5.188(s，2H)，6.340-6.368(m，1H)，6.511-6.540(dd，1H)，7.072-7.129(m，4H)，7.464-7.483(d，2H)，7.802(t，1H)，7.903-7.923(d，2H)，8.068-8.090(d，2H)，8.300-8.321(d，1H)，9.512(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (3-fluoro-4- (methylthio) phenyl) pyrimidin-2-amino) methyl) benzamide (compound 13)
1HNMR(DMSO-d6)(δppm)：2.505(s，3H)，4.625-4.640(d，2H)，5.188(s，2H)，6.337-6.366(m，1H)，6.507-6.542(dd，1H)，7.072-7.110(q，1H)，7.199-7.212(d，1H)，7.423-7.485(m，3H)，7.904-7.966(m，5H)，8.354-8.366(d，1H)，9.508(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (3-fluoro-4- (methoxy) phenyl) pyrimidin-2-amino) methyl) benzamide (compound 14)
1HNMR(DMSO-d6)(δppm)：3.904(s，3H)，4.621-4.635(d，2H)，5.213(s，2H)，6.326-6.369(m，1H)，6.508-6.543(dd，1H)，7.070-7.107(t，1H)，7.161-7.173(d，1H)，7.254-7.296(t，1H)，7.483(s，2H)，7.908-7.928(m，5H)，8.316-8.329(d，1H)，9.534(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (pyrazin-2-yl) pyrimidin-2-amino) methyl) benzamide (compound 15)
1HNMR(DMSO-d6)(δppm)：4.673(d，2H)，5.215(s，2H)，6.338-6.35(m，1H)，6.503-6.538(dd，1H)，7.065-7.101(t，1H)，7.451-7.531(m，3H)，7.915-7.935(dd，2H)，8.159(s，1H)，8.503-8.515(d，1H)，8.785(s，2H)，9.451(s，1H)，9.539(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4- (thiophen-3-yl)) pyrimidin-2-amino) methyl) benzamide (compound 16)
1HNMR(DMSO-d6)(δppm)：4.602-4.618(d，2H)，5.190(s，2H)，6.337-6.366(m，1H)，6.514-6.542(dd，1H)，7.045-7.094(t，2H)，7.498(d，2H)，7.639-7.918(m，5H)，8.287-8.306(d，2H)，9.503(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-methylthiophenyl) pyrimidin-2-amino) methyl) benzamide (compound 17)
1HNMR(DMSO-d6)(δppm)：2.511(s，3H)，4.627-4.642(d，2H)，5.192(s，2H)，6.325-6.367(m，1H)，6.518-6.546(dd，1H)，7.090-7.149(m，2H)，7.344-7.488(q，4H)，7.832-8.040(m，5H)，8.320-8.333(d，1H)，9.508(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4- (2-morpholinoethoxy) phenyl) pyrimidin-2-amino) methyl) benzamide (compound 51)
MS(FAB)：543(M+1)
N- (2-amino-5-fluorophenyl) -4((4- (4-ethoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 52)
1HNMR(DMSO-d6)(δppm)：1.33-1.36(m，3H)，4.07-4.10(q，2H)，4.63-4.64(d，2H)，5.19(s，2H)，6.33-6.37(q，1H)，6.51-6.55(dd，1H)，7.01-7.11(q，4H)，7.47-7.49(d，2H)，7.76-7.79(m，1H)，7.90-7.92(d，2H)，8.03-8.05(d，2H)，8.28-8.29(d，1H)，9.51(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-butoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 53)
1HNMR(DMSO-d6)(δppm)：0.92-0.96(m，3H)，1.43-1.45(q，2H)，1.70-1.71(q，2H)，4.02-4.05(m，2H)，4.62-4.63(d，2H)，5.21(s，2H)，6.34-6.35(q，1H)，6.50-6.54(dd，1H)，7.02-7.11(q，4H)，7.46-7.48(q，2H)，7.80-7.83(m，1H)，7.90-7.92(d，2H)，8.03-8.05(d，2H)，8.28-8.29(d，1H)，9.53(s，1H)。
N- (2-amino-5-fluorophenyl) -4 ((4-phenyl) pyrimidin-2-amino) methyl) benzamide (compound 54)
1HNMR(DMSO-d6)(δppm)：4.64-4.65(d，2H)，5.21(s，2H)，6.33-6.36(q，1H)，6.51-6.54(dd，1H)，7.07-7.11(m，1H)，7.17-7.19(d，1H)，7.50(s，5H)，7.91-7.93(m，3H)，8.08-8.09(d，2H)，8.35-8.37(d，1H)，9.53(s，1H)。
N- (2-amino-5-fluorophenyl) -4 ((4-cyclopentyloxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 55)
1HNMR(DMSO-d6)(δppm)：1.59-1.71(q，6H)，1.94-1.99(q，2H)，4.62-4.63(d，2H)，4.88-4.91(m，1H)，5.21(s，2H)，6.34-6.37(q，1H)，6.51-6.53(dd，1H)，6.98-7.10(q，4H)，7.46-7.48(d，2H)，7.79-7.82(q，1H)，7.90-7.92(d，2H)，8.02-8.04(d，2H)，8.28-8.29(d，1H)，9.53(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (3-methoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 125)
1HNMR(DMSO-d6)(δppm)：3.814(s，3H)，4.623-4.638(d，2H)，5.187(s，2H)，6.322-6.343(m，1H)，6.512-6.541(dd，1H)，7.059-7.179(m，3H)，7.382-7.647(m，5H)，7.877-7.921(t，3H)，8.345-8.358(d，1H)，9.504(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (3, 4-methylenedioxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 126)
1HNMR(DMSO-d6)(δppm)：4.615-4.630(d，2H)，5.190(s，2H)，6.096(s，2H)，6.336-6.344(m，1H)，6.506-6.541(dd，1H)，7.077-7.111(m，3H)，7.457-7.477(d，2H)，7.625-7.620(m，5H)，8.282-8.295(d，1H)，9.507(s，1H)。
Figure GPA00000632129500191
R1＝H R2＝OCH3 R3＝H R4＝H R5Compound 5 ═ H
R1＝H R2＝OCH3 R3＝OCH3 R4＝H R5Compound 6 ═ H
R1＝OCH3 R2＝OCH3 R3＝OCH3 R4＝H R5Compound 7 ═ H
R1＝H R2＝OCF3 R3＝H R4＝H R5Compound 18 ═ H
R1，R2＝
Figure GPA00000632129500192
R3＝H R4＝H R5Compound 19 ═ H
R1＝CH3 R2＝H R3＝H R4＝H R5Compound 82 ═ H
R1＝H R2＝H R3＝H R4＝H R5Compound 83 ═ H
R1＝H R2＝CH3 R3＝H R4＝H R5Compound 84 ═ H
R1＝H R2＝OC2H5 R3＝H R4＝H R5Compound 85 ═ H
R1＝H R2＝Cl R3＝H R4＝H R5H compound 86
R1＝H R2＝Br R3＝H R4＝H R5Compound 87 ═ H
R1＝H R2＝H R3＝CF3 R4＝H R5H compound 88
R1＝H R2＝H R3＝H R4＝CH3 R5Compound 89 ═ H
R1＝H R2＝H R3＝H R4＝Cl R5＝CH3Compound 90
Reaction formula 2
EXAMPLE 2 Synthesis of N- (2-amino-5-fluorophenyl) -4- ((4-methoxyphenylamino) methyl) benzamide (Compound 5)
Step 1. Synthesis of Paraldehyde methyl benzoate
Dissolving 2.0g of p-formyl benzoic acid in 20ml of methanol, slowly and dropwise adding 1.81ml of thionyl chloride in ice bath, heating and refluxing for 3 hours after the addition is finished, performing thin-layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, cooling and filtering to obtain 2.13g of light yellow solid.
The melting point of the product is m.p.59-61 ℃;
step 2. Synthesis of methyl 4- ((4-methoxyphenylamino) methyl) benzoate hydrochloride
1.59g of p-aminoanisole and 2.13g of the product of step 1 were dissolved in 15ml of methanol and 3.07g of NaBH were added in portions in ice bath4And dropwise adding glacial acetic acid to keep the pH of the reaction solution at 5-6, carrying out thin-layer chromatography to show that the reaction is finished, decompressing and removing the solvent, distributing the residue in ethyl acetate/water, adjusting the acidity with 2N hydrochloric acid, separating out a large amount of white solid, filtering, and drying to obtain 2.89g of the white solid.
Step 3. Synthesis of 4- ((4-methoxyphenyl amino) methyl) benzoic acid
Suspending 2.67g of the product in the step 2 in 8ml of tetrahydrofuran/8 ml of water, adding 0.53g of lithium hydroxide, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, adding 20ml of water to dissolve the residue, adjusting the pH value of the solution to be about 5 by using 1N hydrochloric acid, standing, and filtering to obtain 2.17g of a white solid.
The melting point of the product is m.p.178-180.5 ℃;
step 4. Synthesis of N- (2-amino-5-fluorophenyl) -4- ((4-methoxyphenylamino) methyl) benzamide (Compound 5)
2.17g of the product in the step 3 and 1.39g of N, N-carbonyldiimidazole are dissolved in 10ml of anhydrous tetrahydrofuran, reacted for 1.5h at 45 ℃, and cooled for later use. Taking another three-necked bottle, dissolving 1.34g of 4-fluoro-1, 2-phenylenediamine in anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.98g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature for reacting overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, washing with ethyl acetate/petroleum ether at a ratio of 1: 2, concentrating the eluent, and crystallizing to obtain 1.05g of a white solid.
The melting point of the product is m.p.205.5-206 ℃;
1HNMR(DMSO-d6)(δppm)：3.603(s，3H)，4.284-4.299(d，2H)，5.214(s，2H)，5.939-5.969(t，1H)，6.329-6.372(m，1H)，6.496-6.539(m，3H)，6.660-6.683(d，2H)，7.073-7.111(q，1H)，7.448-7.469(d，2H)，7.900-7.920(d，2H)，9.529(s，1H)。
the following compounds 6 to 7, 18 to 19, 82 to 90 were synthesized in the same manner as in example 2 (compound 5).
N- (2-amino-5-fluorophenyl) -4- ((3, 4-dimethoxyphenylaminomethyl) benzamide (Compound 6)
The melting point of the product is m.p.135.5-136.5 ℃;
1HNMR(DMSO-d6)(δppm)：3.589(s，3H)，3.659(s，3H)，4.292-4.306(d，2H)，5.192(s，2H)，5.968-6.009(m，2H)，6.324-6.352(m，2H)，6.517-6.665(m，2H)，7.081-7.118(t，1H)，7.460-7.480(d，2H)，7.097-7.790(d，2H)，9.521(s，1H)。
n- (2-amino-5-fluorophenyl) -4- ((3, 4, 5-trimethoxyphenylamino) methyl) benzamide (compound 7)
The melting point of the product is m.p.166-167 ℃;
1HNMR(DMSO-d6)(δppm)：3.495(s，3H)，3.624(s，3H)，3.643(s，3H)，4.313-4.328(d，2H)，5.229(s，2H)，5.882(s，2H)，6.332-6.375(m，2H)，6.512-6.548(dd，1H)，7.075-7.097(q，1H)，7.479-7.499(d，2H)，7.919-7.939(d，2H)，9.551(s，1H)。
n- (2-amino-5-fluorophenyl) -4- ((4-trifluoromethoxyphenylamino) methyl) benzamide (compound 18)
1HNMR(DMSO-d6)(δppm)：4.408-4.423(d，2H)，5.234(s，2H)，6.333-6.375(m，1H)，6.514-6.542(dd，1H)，6.797-6.894(m，4H)，7.076-7.266(m，2H)，7.465-7.486(d，2H)，7.931-7.951(d，2H)，9.562(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((3, 4-methylenedioxyphenylamino) methyl) benzamide (compound 19)
1HNMR(DMSO-d6)(δppm)：4.277-4.292(d，2H)，5.230(s，2H)，5.804(s，2H)，5.956-5.979(dd，1H)，6.016-6.137(t，1H)，6.257-6.262(d，1H)，6.336-6.374(m，1H)，6.512-6.627(m，2H)，7.090-7.112(q，1H)，7.445-7.465(d，2H)，7.907-7.928(d，2H)，9.543(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((3-methylphenylamino) methyl) benzamide (compound 82)
1HNMR(DMSO-d6)(δppm)：3.047(s，3H)，4.641(s，2H)，5.229(s，2H)，6.327-6.370(q，1H)，6.507-6.542(dd，1H)，6.598-6.634(q，1H)，6.698-6.719(d，2H)，7.069-7.165(q，3H)，7.305-7.325(d，2H)，7.902-7.923(d，2H)，9.541(s，1H)。
N- (2-amino-5-fluorophenyl) -4- (phenylaminomethyl) benzamide (compound 83)
1HNMR(DMSO-d6)(δppm)：4.336-4.351(d，2H)，5.220(s，2H)，6.343-6.381(q，2H)，6.506-6.560(q，4H)，7.009-7.110(q，3H)，7.454-7.475(d，2H)，7.908-7.928(d，2H)，9.535(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((4-methylphenylamino) methyl) benzamide (compound 84)
1HNMR(DMSO-d6)(δppm)：2.111(s，3H)，4.305-4.320(d，2H)，5.222(s，2H)，6.142-6.174(m，1H)，6.330-6.372(q，1H)，6.451-6.472(d，2H)，6.509-6.554(dd，1H)，6.831-6.852(d，2H)，7.070-7.107(t，1H)，7.898-7.918(d，2H)，9.535(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((4-ethoxyphenylamino) methyl) benzamide ((Compound 85)
1HNMR(DMSO-d6)(δppm)：1.223-1.258(q，3H)，3.817-3.851(q，2H)，4.279-4.295(d，2H)，5.226(s，2H)，5.946-5.997(m，1H)，6.331-6.373(q，1H)，6.479-6.539(q，3H)，6.649-6.671(d，2H)，7.071-7.109(t，1H)，7.449-7.484(m，2H)，7.903-7.923(d，2H)，9.541(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((4-chlorophenylamino) methyl) benzamide (Compound 86)
1HNMR(DMSO-d6)(δppm)：4.335-4.350(d，2H)，5.225(s，2H)，6.331-6.374(q，2H)，6.512-6.585(q，4H)，7.046-7.089(q，3H)，7.437-7.457(d，2H)，7.913-7.933(d，2H)，9.543(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((4-bromophenylamino) methyl) benzamide (compound 87)
1HNMR(DMSO-d6)(δppm)：4.332-4.348(d，2H)，5.229(s，2H)，6.345-6.353(q，1H)，6.501-6.546(q，3H)，6.609-6.625(m，1H)，7.072-7.109(t，1H)，7.158-7.180(q，2H)，7.432-7.453(d，2H)，7.912-7.932(d，2H)，9.547(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((3-trifluoromethylphenylamino) methyl) benzamide (Compound 88)
1HNMR(DMSO-d6)(δppm)：4.363-4.379(d，2H)，5.189(s，2H)，6.302-6.330(q，1H)，6.467-6.495(dd，1H)，6.752-6.850(q，4H)，7.029-7.067(t，1H)，7.182-7.222(m，1H)，7.420-7.441(d，2H)，7.884-7.905(d，2H)，9.515(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((2-methylphenylamino) methyl) benzamide (Compound 89)
1HNMR(DMSO-d6)(δppm)：2.175(s，3H)，4.419-4.435(d，2H)，5.220(s，2H)，5.749-5.779(m，1H)，6.292-6.349(q，2H)，6.441-6.475(q，1H)，6.507-6.543(dd，H)，6.845-6.884(m，1H)，6.956-6.973(d，1H)，7.070-7.107(t，1H)，7.451-7.472(d，2H)，7.894-7.915(d，2H)，9.524(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((2-chloro-4-methylphenylamino) methyl) benzamide (compound 90)
1HNMR(DMSO-d6)(δppm)：2.250(s，3H)，4.363-4.403(m，2H)，5.200(s，2H)，6.324-6.367(q，1H)，6.518-6.546(dd，1H)，6.731-6.769(q，1H)，7.003-7.156(q，3H)，7.422-7.457(m，2H)，7.811-7.894(m，2H)，9.517(s，1H)。
Figure GPA00000632129500221
Reaction formula 3
EXAMPLE 3 Synthesis of 4- (((phenethyl) (2-hydroxyethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 8)
Step 1 Synthesis of methyl 4- ((ethylamino) methyl) benzoate hydrochloride
Dissolving 1.43ml of phenethylamine and 1.46g of methyl p-aldehyde benzoate in 10ml of methanol, adding 2.5g of sodium borohydride in batches under ice bath, dropwise adding glacial acetic acid to keep the pH of the reaction solution at 5-6, carrying out thin-layer chromatography to show that the reaction is finished, decompressing and removing the solvent, distributing the residue in ethyl acetate/water, adjusting the residue to be acidic by using 2N hydrochloric acid, separating out a large amount of white solid, filtering, and drying to obtain 2.06g of the white solid.
Step 2 Synthesis of methyl 4- (((2- (tert-Butyldimethylsilanyloxy) ethyl) (phenethyl) amino) methyl) benzoate
Taking a 100ml dry three-necked bottle, dissolving 2.06g of 4- ((phenethylamino) methyl benzoate hydrochloride in 20ml of anhydrous dimethyl sulfoxide under the protection of dry nitrogen, stirring at room temperature, adding 2.87ml of anhydrous triethylamine free hydrochloride, adding 3.91g of (2-bromoethoxy) (tert-butyl) dimethyl silane after the solid is dissolved, heating to 60 ℃, reacting for 24 hours at constant temperature, performing thin layer chromatography to show that the reaction is finished, distributing the reaction liquid in ethyl acetate/water, collecting an ethyl ester layer, recovering the solvent under reduced pressure, passing the concentrated solution through a silica gel column, eluting by ethyl acetate/petroleum ether 1: 6, and concentrating the eluent under reduced pressure to obtain 1.53g of light yellow oily matter.
Step 3 Synthesis of 4- (((2- (tert-Butyldimethylsilanyloxy) ethyl) (phenethyl) amino) methyl) benzoic acid (IV)
1.53g of the product of step 2 was dissolved in 6ml of THF/6ml of water, 0.32g of lithium hydroxide was added, stirring was carried out overnight, thin layer chromatography showed the reaction to be complete, the solvent was recovered under reduced pressure, the residue was dissolved in water, the pH of the residue was carefully adjusted to 6.5 with 1N hydrochloric acid, and filtration and drying were carried out to give 1.02g of a white solid.
The melting point of the product is m.p.246-248.5 ℃;
step 4 Synthesis of 4- (((2- (tert-Butyldimethylsilanyloxy) ethyl) (phenethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 8)
1.02g of the product of step 3, 0.44g N, N-carbonyldiimidazole, was dissolved in 7ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5 hours, and cooled for use. Taking another 100ml dry three-necked bottle, dissolving 0.35g 4-fluorine-1, 2-phenylenediamine in 5ml anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.26g trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, washing ethyl acetate and petroleum ether at a ratio of 1: 2, concentrating the eluent, and crystallizing to obtain 0.34g white solid
Step 5 Synthesis of 4- (((phenethyl) (2-hydroxyethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 8)
Taking a 100ml dry three-necked bottle, introducing dry nitrogen, adding 0.34g of the product of the step 4 at-20 ℃, dissolving 5ml of anhydrous tetrahydrofuran, slowly dropwise adding 0.17g of tetrabutyl ammonium fluoride, slowly heating to room temperature after adding, stirring for reacting overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, eluting with ethyl acetate/petroleum ether at a ratio of 1: 4, concentrating the eluent, and crystallizing to obtain 0.102g of white solid
The melting point of the product is m.p.100.0-101.5 ℃;
1HNMR(DMSO-d6)(δppm)：2.593-2.746(m，6H)，3.611-3.750(q，4H)，5.182(s，2H)，6.317-6.359(m，1H)，6.502-6.537(dd，1H)，7.063-7.391(m，8H)，7.873-7.893(d，2H)，9.521(s，1H)。
the following Synthesis procedures for Compounds 20 to 21 were the same as in example 3 (Compound 8).
4- (((4-Methoxybenzyl) (2-hydroxyethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 20)
11HNMR(DMSO-d6)(δppm)：2.498-2.508(t，2H)，3.487-3.523(d，4H)，3.601-3.634(t，2H)，3.730(s，3H)，5.234(s，2H)，6.333-6.376(m，1H)，6.513-6.548(dd，1H)，6.879-6.901(d，2H)，7.077-7.115(q，1H)，7.263-7.285(d，2H)，7.469-7.490(m，2H)，7.922-7.943(d，2H)，9.563(s，1H)。
4- (((3, 4-difluorobenzyl) (2-hydroxyethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 21)
11HNMR(DMSO-d6)(δppm)：2.500-2.509(t，2H)，3.387-3.423(d，4H)，3.594-3.603(t，2H)，5.235(s，2H)，6.333-6.379(m，1H)，6.520-6.552(dd，1H)，7.095-7.108(q，1H)，7.231-7.233(d，1H)，7.368-7.395(d，1H)，7.487-7.539(m，3H)，7.930-7.951(d，2H)，9.569(s，1H)。
Figure GPA00000632129500241
Reaction formula 4
EXAMPLE 4 Synthesis of 4- (2-Fluorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 22)
Step 1. Synthesis of 4- (2-fluorobenzylamino) benzoic acid
1.59g 2-fluorobenzaldehyde and 2.13g 4-aminobenzoic acid were dissolved in 15ml methanol and 3.07g NaBH were added in portions under ice-bath4And dropwise adding glacial acetic acid to keep the pH of the reaction solution at 5-6, carrying out thin-layer chromatography to show that the reaction is finished, removing the solvent under reduced pressure, adding a proper amount of water into the residue, adjusting the pH value to be acidic by using 2N hydrochloric acid, separating out a large amount of white solid, filtering, and drying to obtain 2.89g of the white solid.
The melting point of the product is m.p.178-180.5 ℃;
step 2. Synthesis of N- (2-amino-5-fluorophenyl) -4- ((4-methoxyphenylamino) methyl) benzamide (Compound 22)
2.17g of the product in the step 1 and 1.39g of N, N-carbonyldiimidazole are dissolved in 10ml of anhydrous tetrahydrofuran, reacted for 1.5h at 45 ℃, and cooled for later use. Taking another three-necked flask, dissolving 1.34g of 4-fluoro-1, 2-phenylenediamine in anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.98g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature for reaction overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, washing with ethyl acetate/petroleum ether at a ratio of 1: 2, concentrating the eluent, and crystallizing to obtain 1.05g of a white solid
1HNMR(DMSO-d6)(δppm)：4.385-4.400(d，2H)，5.113(s，2H)，6.317-6.360(m，1H)，6.504-6.644(m，3H)，6.807-6.837(t，1H)，7.044-7.081(q，1H)，7.155-7.227(m，2H)，7.301-7.395(m，2H)，7.727-7.749(d，2H)，9.190(s，1H)。
The following compounds 23 to 31, 56 to 62 were synthesized in the same manner as in example 4 (compound 22).
4- (4-Fluorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 23)
1HNMR(DMSO-d6)(δppm)：4.329-4.344(d，2H)，5.136(s，2H)，6.318-6.339(m，1H)，6.507-6.615(m，3H)，6.908-7.184(m，4H)，7.371-7.405(t，2H)，7.710-7.731(d，2H)，9.207(s，1H)。
4- (4-chlorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 24)
1HNMR(DMSO-d6)(δppm)：4.343-4.358(d，2H)，5.110(s，2H)，6.316-6.358(m，1H)，6.504-6.607(m，3H)，6.897-6.927(t，1H)，7.041-7.079(q，1H)，7.354-7.404(m，4H)，7.709-7.731(d，2H)，9.178(s，1H)。
N- (2-amino-5-fluorophenyl) -4- (pyridin-3-yl-methylamino) benzamide (compound 25)
1HNMR(DMSO-d6)(δppm)：4.388-4.401(d，2H)，5.115(s，2H)，6.313-6.353(m，1H)，6.507-6.648(m，3H)，6.906-7.130(m，2H)，7.338-7.368(t，1H)，7.726-7.743(d，3H)，8.446-8.456(d，1H)，8.590(s，1H)，9.194(s，1H)。
4- (4-Methoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 26)
1HNMR(DMSO-d6)(δppm)：3.722(s，3H)，4.259-4.274(d，2H)，5.121(s，2H)，6.318-6.360(m，1H)，6.501-6.614(m，3H)，6.804-6.903(m，3H)，7.037-7.058(q，1H)，7.263-7.285(d，2H)，7.702-7.723(d，2H)，9.184(s，1H)。
4- (4-N, N-Dimethylaminobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 27)
1HNMR(DMSO-d6)(δppm)：3.000(s，6H)，4.727(s，2H)，5.105(s，2H)，6.111-6.140(m，1H)，6.278-6.313(m，1H)，6.409-6.430(m，1H)，6.593-6.701(m，2H)，6.821-6.842(d，2H)，7.160-7.204(m，1H)，7.698-7.720(d，1H)，7.963-7.986(m，2H)，9.161(s，1H)。
4- (3, 4-Methylenedioxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 28)
1HNMR(DMSO-d6) (δ ppm): 4.242-4.257(d, 2H), 5.111(s, 2H), 5.971(s, 2H), 6.316-6.359(m, 1H), 6.502-6.615(m, 3H), 6.792-6.906(m, 4H), 7.043-7.080(q, 1H), 7.706-7.728(d, 2H), 9.171(s, 1H). 4- (3, 4-Difluorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 29)
1HNMR(DMSO-d6)(δppm)：4.34-4.358(d，2H)，5.135(s，2H)，6.318-6.361(m，1H)，6.500-6.530(dd，1H)，6.595-6.617(d，2H)，6.940-6.962(t，1H)，7.033-7.070(q，1H)，7.209(s，1H)，7.365-7.413(m，2H)，7.718-7.739(d，2H)，9.212(s，1H)。
4- (2-chlorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 30)
1HNMR(DMSO-d6)(δppm)：4.408-4.423(d，2H)，5.137(s，2H)，6.320-6.363(m，1H)，6.501-6.530(dd，1H)，6.580-6.602(d，2H)，6.915-6.945(q，1H)，7.289-7.490(m，4H)，7.731-7.753(d，2H)，9.217(s，1H).
4- (2, 4-Dichlorobenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 31)
1HNMR(DMSO-d6)(δppm)：4.388-4.403(d，2H)，5.138(s，2H)，6.320-6.363(m，1H)，6.503-6.538(dd，1H)，6.568-6.591(d，2H)，6.936-6.967(t，1H)，7.038-7.076(q，1H)，7.342-7.363(d，1H)，7.401-7.428(dd，1H)，7.649-7.655(d，1H)，7.735-7.757(d，2H)，9.226(s，1H)。
4- (2-methoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 56)
1HNMR(DMSO-d6)(δppm)：3.846(s，3H)，4.285-4.299(d，2H)，5.109(s，2H)，6.316-6.359(q，1H)，6.503-6.695(q，4H)，6.884-7.252(q，5H)，7.710-7.732(d，2H)，9.172(s，1H)。
4- (3-methoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 57)
1HNMR(DMSO-d6)(δppm)：3.73(s，3H)，4.31-4.33(d，2H)，5.13(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.60-6.62(d，2H)，6.79-6.81(m，1H)，6.88-6.93(q，2H)，7.04-7.7.0(t，1H)，7.22-7.26(m，1H)，7.71-7.73(d，2H)，9.19(s，1H)。
4- (4-ethoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 58)
1HNMR(DMSO-d6)(δppm)：1.29-1.32(m，3H)，3.96-3.99(t，2H)，4.25-4.27(d，2H)，5.13(s，2H)，6.31-6.36(q，1H)，6.50-6.54(dd，1H)，6.59-6.61(d，2H)，6.81-6.84(m，1H)，6.86-6.89(d，2H)，7.04-7.07(t，1H)，7.25-7.27(d，2H)，7.70-7.72(d，2H)，9.19(s，1H)。
4- (2-ethoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 59)
1HNMR(DMSO-d6)(δppm)：1.36-1.40(m，3H)，4.09-4.11(t，2H)，4.29-4.31(d，2H)，5.13(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.57-6.60(d，2H)，6.71-6.74(m，1H)，6.85-6.89(m，1H)，6.98-7.00(d，1H)，7.04-7.07(t，1H)，7.19-7.22(m，2H)，7.71-7.73(d，2H)，9.20(s，1H)。
4- (2, 4-Dimethoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (compound 60)
1HNMR(DMSO-d6)(δppm)：3.73(d，6H)，4.252-4.266(d，2H)，5.131(s，2H)，6.334-6.363(q，1H)，6.505-6.533(dd，1H)，6.607-6.629(d，2H)，6.812-6.886(q，3H)，6.977-6.980(m，1H)，7.055-7.061(t，1H)，7.713-7.734(d，2H)，9.200(s，1H)。
4- (2-methoxy-4-ethoxybenzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 61)
1HNMR(DMSO-d6)(δppm)：1.28-1.32(m，3H)，3.72-3.74(m，3H)，3.95-3.97(t，2H)，4.25-4.26(d，2H)，5.13(s，2H)，6.33-6.34(q，1H)，6.50-6.54(dd，1H)，6.61-6.63(d，2H)，6.80-7.07(q，5H)，7.71-7.73(d，2H)，9.20(s，1H)。
4- (4- (Cyclopentyloxy) benzylamino) -N- (2-amino-5-fluorophenyl) benzamide (Compound 62)
1HNMR(DMSO-d6)(δppm)：1.57-1.68(q，6H)，1.88-1.89(q，2H)，3.95-3.97(t，2H)，4.24-4.26(d，2H)，4.77(m，1H)，5.11(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.60-6.62(d，2H)，6.76-6.79(m，1H)，6.84-6.86(d，2H)，7.04-7.08(t，1H)，7.23-7.25(d，2H)，7.71-7.73(d，2H)，9.17(s，1H)。
Figure GPA00000632129500271
Reaction formula 5
EXAMPLE 5 Synthesis of N- (2-amino-5-fluorophenyl) -4((4- (3, 4-difluorophenyl) pyrimidin-2-sulfanyl) methyl) benzamide (Compound 32)
Step 1, synthesizing 3, 3-dimethylamino-1- (3, 4-difluorophenyl) -propenone
Dissolving 2g of 3, 4-difluoroacetophenone in 5ml of anhydrous DMF, adding 2.56ml of DMAPDMA into the solution, heating to 110 ℃ to react for 3 hours after the addition is finished, recovering DMF under reduced pressure after TCL shows that the reaction is finished, putting the residual solution in a refrigerator overnight, separating out yellow solid, performing suction filtration, and washing with ethyl acetate/petroleum ether at a ratio of 1: 1 to obtain 1.86g of yellow solid.
The melting point of the product is m.p.79-81 ℃;
step 2, synthesizing 4- (3, 4-difluorophenyl) pyrimidine-2-thiol
Dissolving 0.17g of sodium in 20ml of absolute ethyl alcohol, adding 0.58g of thiourea and 1.60g of the product obtained in the step 1, heating and refluxing for 4 hours after the addition is finished, recovering the solvent under reduced pressure after TCL shows that the reaction is finished, adding a proper amount of water into the residue to dissolve, adjusting the pH value to be weakly acidic by using 1N hydrochloric acid, separating out a large amount of yellow solid, filtering and drying to obtain the sodium-potassium-sodium-titanate composite material.
Step 3. Synthesis of methyl 4- ((4- (3, 4-difluorophenyl) pyrimidin-2-sulfanyl) -methyl) benzoate
Suspending 0.22g of sodium hydride in 20ml of anhydrous DMF, adding 1.40g of the product obtained in the step 1, adding 1.16g of 4-chloromethyl methyl benzoate after half an hour, reacting for 6 hours at room temperature, adding a proper amount of water into a reaction bottle to precipitate a large amount of solid after TCL shows that the reaction is finished, filtering, and drying to obtain 1.76g of a colored solid.
The melting point of the product is m.p.102.5-104 ℃;
step 4. Synthesis of 4- ((4- (3, 4-difluorophenyl) pyrimidin-2-sulfanyl) -methyl) benzoic acid
Suspending 1.5g of the product of the step 3 in 15ml of methanol 15/ml of water, adding 0.52g of lithium hydroxide, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, adding 20ml of water to dissolve the residue, adjusting the pH value of the solution to be about 5 by using 1N hydrochloric acid, standing, and filtering to obtain 1.29g of a solid.
Step 5 Synthesis of N- (2-amino-5-fluorophenyl) -4((4- (3, 4-difluorophenyl) pyrimidin-2-ylthio) methyl) benzamide (Compound 32)
1g of the product of step 4, 0.46g of N, N-carbonyldiimidazole are dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5h and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 0.42g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.32g of trifluoroacetic acid, dropwise adding a standby reaction solution, stirring at room temperature overnight, recovering the solvent under reduced pressure, washing residues with silica gel column and ethyl acetate/petroleum ether at a ratio of 2: 1, concentrating eluent, and crystallizing to obtain 0.29g of white solid.
1HNMR(DMSO-d6)(δppm)：4.573-4.587(d，2H)，5.221(s，2H)，6.324-6.367(m，1H)，6.508-6.536(dd，1H)，7.071-7.093(q，1H)，7.849-7.929(m，3H)，8.104-8.291(m，2H)，8.737-8.750(d，1H)，9.530(s，1H)。
The following compounds 33 to 38, 63 to 69 were synthesized in the same manner as in example 5 (compound 32).
N- (2-amino-5-fluorophenyl) -4((4- (3-fluoro-4-methoxyphenyl) pyrimidin-2-sulfanyl) methyl) benzamide (compound 33)
1HNMR(DMSO-d6)(δppm)：3.934(s，3H)，4.575(s，2H)，5.205(s，2H)，6.495-6.515(m，1H)，6.712-6.741(dd，1H)，7.152-7.189(q，1H)，7.317-7.361(t，1H)，7.600-7.621(d，2H)，7.774-8.076(m，5H)，8.654-8.668(d，1H)，9.528(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-methylthiophenyl) pyrimidin-2-ylthio) methyl) benzamide (compound 34)
1HNMR(DMSO-d6)(δppm)：2.550(s，3H)，4.571-4.954(s，2H)，5.202(s，2H)，6.335-6.363(m，1H)，6.504-6.532(dd，1H)，7.069-7.090(q，1H)，7.406-7.428(d，2H)，7.587-7.608(d，2H)，7.766-7.923(m，3H)，8.140-8.162(d，2H)，8.659-8.672(d，1H)，9.522(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (thiophen-3-yl) pyrimidin-2-ylthio) methyl) benzamide (compound 35)
1HNMR(DMSO-d6)(δppm)：4.557(S，2H)，5.232(s，2H)，6.321-6.364(m，1H)，6.499-6.535(dd，1H)，7.061-7.099(q，1H)，7.593-7.614(d，2H)，7.672-7.686(d，1H)，7.735-7.755(q，1H)，7.841-7.920(m，3H)，8.552-8.560(m，1H)，8.647-8.660(d，1H)，9.548(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-bromophenyl) pyrimidin-2-ylthio) methyl) benzamide (compound 36)
1HNMR(DMSO-d6)(δppm)：4.574(s，2H)，5.168(s，2H)，6.361-6.395(m，1H)，6.531-6.566(dd，1H)，7.086-7.102(d，1H)，7.602-7.621(d，2H)，7.772-7.792(d，3H)，7.898-7.914(d，2H)，8.129-8.145(d，2H)，8.710-8.723(d，1H)，9.580(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (pyridin-2-yl) pyrimidin-2-ylthio) methyl) benzamide (compound 37)
1HNMR(DMSO-d6)(δppm)：4.609(s，2H)，5.203(s，2H)，6.315-6.365(m，1H)，6.501-6.536(dd，1H)，7.066-7.103(q，1H)，7.580-7.631(m，3H)，7.905-8.096(m，4H)，8.458-8.478(d，1H)，8.763-8.811(d，2H)，9.522(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (pyridin-3-yl) pyrimidin-2-ylthio) methyl) benzamide (compound 38)
1HNMR(DMSO-d6)(δppm)：4.598(s，2H)，5.207(s，2H)，6.322-6.365(m，1H)，6.510-6.541(dd，1H)，7.071-7.093(q，1H)，7.590-7.617(m，3H)，7.902-7.914(m，3H)，8.541-8.562(m，1H)，8.764-8.776(m，2H)，9.360-9.365(t，1H)，9.529(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (pyridin-4-yl) pyrimidin-2-ylthio) methyl) benzamide (compound 63)
1HNMR(DMSO-d6)(δppm)：4.607(s，2H)，5.227-5.259(q，1H)，5.840-5.820(d，1H)，6.496-6.503(q，1H)，6.708-6.731(dd，1H)，7.145-7.166(t，1H)，7.615-7.635(d，2H)，7.912-7.957(q，3H)，8.134-8.149(d，2H)，8.801-8.833(q，3H)，9.522(s，1H)。
N- (2-amino-5-fluorophenyl) -4 ((4-phenylpyrimidin-2-thio) methyl) benzamide (Compound 64)
1HNMR(DMSO-d6)(δppm)：4.59(s，2H)，5.23(s，2H)，6.33-6.37(q，1H)，6.51-6.54(dd，1H)，7.07-7.11(q，1H)，7.57-7.62(q，5H)，7.81-7.93(q，3H)，8.20-8.22(q，2H)，8.71-8.72(d，1H)，9.55(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-fluoro-3-methylthiophenyl) pyrimidin-2-ylthio) methyl) benzamide (compound 65)
1HNMR(DMSO-d6)(δppm)：2.503-2.572(s，3H)，4.580(s，2H)，5.226(s，2H)，6.332-6.365(q，1H)，6.501-6.537(dd，1H)，7.063-7.101(t，1H)，7.484-7.525(m，1H)，7.592-7.613(d，2H)，7.839-7.852(d，1H)，7.907-7.928(d，2H)，8.013-8.047(dd，1H)，8.102-8.106(dd，1H)，9.548(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-methoxyphenyl) pyrimidin-2-sulfanyl) methyl) benzamide (compound 66)
1HNMR(DMSO-d6)(δppm)：3.832-3.849(s，3H)，4.568(s，2H)，5.231(s，2H)，6.325-6.368(q，1H)，6.506-6.541(dd，1H)，7.089-7.119(q，3H)，7.591-7.745(q，3H)，7.908-7.928(d，2H)，8.182-8.205(q，2H)，8.621-8.635(d，1H)，9.550(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4- (cyclopentyloxy) phenyl) pyrimidin-2-ylthio) methyl) benzamide (compound 67)
1HNMR(DMSO-d6)(δppm)：1.72-1.73(q，6H)，1.96-1.99(q，2H)，4.56(s，2H)，4.91-4.93(q，1H)，5.23(s，2H)，6.34-6.37(q，1H)，6.51-6.54(dd，1H)，7.05-7.10(q，3H)，7.59-7.73(q，3H)，7.91-7.97(q，2H)，8.12-8.17(q，2H)，8.61-8.62(d，1H)，9.55(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-ethoxyphenyl) pyrimidin-2-sulfanyl) methyl) benzamide (compound 68)
1HNMR(DMSO-d6)(δppm)：1.34-1.38(m，3H)，4.10-4.13(t，2H)，4.56(s，2H)，，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，7.07-7.11(q，3H)，7.58-7.60(q，3H)，7.90-7.92(d，2H)，8.16-8.18(d，2H)，8.61-8.63(d，1H)，9.52(s，1H)。
N- (2-amino-5-fluorophenyl) -4((4- (4-N-butoxyphenyl) pyrimidin-2-ylthio) methyl) benzamide (compound 69)
1HNMR(DMSO-d6)(δppm)：0.93-0.96(m，3H)，1.44-1.46(q，2H)，1.71-1.73(q，2H)，4.05-4.08(q，2H)，4.56(s，2H)，5.23(s，2H)，6.34-6.37(q，1H)，6.50-6.54(dd，1H)，7.06-7.10(q，3H)，7.59-7.74(q，3H)，7.90-7.92(q，2H)，8.16-8.18(q，2H)，8.61-8.63(d，1H)，
Figure GPA00000632129500301
R1＝H R2＝OCH3 R3Compound 39 ═ H
R1＝H R2＝OCH3 R3＝OCH3Compound 40
R1＝OCH3 R2＝OCH3 R3＝OCH3Compound 41
R1＝H R2＝H R3Compound 70 ═ H
R1＝H R2＝F R3H compound 71
R1＝H R2＝Cl R3Compound 72 ═ H
R1＝H R2＝H R3＝CH3Compound 73
R1＝H R2＝CF3 R3H compound 74
R1＝H R2＝OCF3 R3Compound 75 ═ H
Reaction formula 6
EXAMPLE 6 Synthesis of N- (2-amino-5-fluorophenyl) -3- (4- ((4-methoxyphenylamino) methyl) phenylacrylamide (Compound 39)
Step 1. Synthesis of methyl 3- (4- ((4-methoxyphenylamino) methyl) phenyl) acrylate hydrochloride
2g of p-aminoanisole and 3.09g of methyl 4-formylphenylacrylate were dissolved in 15ml of methanol, and 3.07g of NaBH was added in portions in ice bath4And dropwise adding glacial acetic acid to keep the pH of the reaction solution at 5-6, carrying out thin-layer chromatography to show that the reaction is finished, decompressing and removing the solvent, distributing the residue in ethyl acetate/water, adjusting the acidity with 2N hydrochloric acid, separating out a large amount of white solid, filtering, and drying to obtain 3.10g of the white solid.
Step 2. Synthesis of 3- (4- ((4-methoxyphenylamino) methyl) phenyl) acrylic acid
Suspending 3.10g of the product of the step 2 in 8ml of THF/8ml of water, adding 0.66g of lithium hydroxide, stirring at room temperature overnight, carrying out thin-layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, adding 20ml of water to dissolve the residue, adjusting the pH value to about 5 by using 1N hydrochloric acid, standing, and filtering to obtain 2.99g of a white solid.
The melting point of the product is m.p.176.5-178.5 ℃;
step 3 Synthesis of N- (2-amino-5-fluorophenyl) -3- (4- ((4-methoxyphenylamino) methyl) phenylacrylamide (Compound 39)
2.50g of the product in the step 3 and 1.44g of N, N-carbonyldiimidazole are dissolved in 10ml of anhydrous tetrahydrofuran, reacted for 1.5h at the temperature of 45 ℃, and cooled for later use. Taking another three-necked flask, dissolving 1.33g of 4-fluoro-1, 2-phenylenediamine in anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 1.01g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature for reacting overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, washing with ethyl acetate/petroleum ether at a ratio of 1: 2, concentrating the eluent, and crystallizing to obtain 1.57g of a white solid
1HNMR(DMSO-d6)(δppm)：3.605(s，3H)，4.238-4.276(d，2H)，5.238(s，2H)，6.325-6.367(m，1H)，6.496-6.532(m，4H)，6.675-6.691(d，2H)，6.800-6.840(d，1H)，7.257-7.294(q，1H)，7.390-7.421(d，2H)，7.497-7.607(m，3H)，7.445-7.465(d，2H)，7.907-7.928(d，2H)，9.543(s，1H)。
The following compounds 40 to 41, 70 to 75 were synthesized in the same manner as in example 6 (compound 39).
N- (2-amino-5-fluorophenyl) -3- (4- ((3, 4-dimethoxyphenylamino) methyl) phenylacrylamide (compound 40)
1HNMR(DMSO-d6)(δppm)：3.592(s，3H)，3.655(s，3H)，4.239-4.254(d，2H)，5.261(s，2H)，5.905-5.935(t，1H)，5.994-6.022(dd，1H)，6.320-6.370(m，2H)，6.502-6.538(dd，1H)，6.653-6.675(d，1H)，6.803-6.843(d，1H)，7.256-7.293(q，1H)，7.410-7.430(d，2H)，7.500-7.572(m，3H)，9.319(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- ((2, 3, 4-trimethoxyphenylamino) methyl) phenylacrylamide (compound 41)
1HNMR(DMSO-d6)(δppm)：3.504(s，3H)，3.644(s，6H)，4.263-4.274(d，2H)，5.274(s，2H)，5.887(s，2H)，6.070-6.084(t，1H，6.324-6.369(m，1H)，6.502-6.534(dd，1H)，6.807-6.846(d，1H)，7.254-7.292(q，1H)，7.425-7.446(d，2H)，7.502-7.582(q，3H)，9.328(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4-phenylaminomethyl) phenylacrylamide (Compound 70)
1HNMR(DMSO-d6)(δppm)：4.28-4.30(d，2H)，5.27(s，2H)，6.29-6.37(q，2H)，6.49-6.57(q，4H)，6.80-6.84(d，1H)，7.02-7.06(t，2H)，7.25-7.29(t，1H)，7.41-7.58(q，5H)，9.33(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- (4-fluorophenylamino) methyl) phenylacrylamide (compound 71)
1HNMR(DMSO-d6)(δppm)：4.26-4.27(d，2H)，5.25(s，2H)，6.20-6.23(m，1H)，6.33-6.37(q，1H)，6.53-6.57(q，3H)，6.80-6.96(q，3H)，7.26-7.29(t，1H)，7.40-7.42(d，2H)，7.50-7.57(q，3H)，9.31(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- (4-chlorophenylamino) methyl) phenylacrylamide (Compound 72)
1HNMR(DMSO-d6)(δppm)：4.28-4.30(d，2H)，5.27(s，2H)，6.34-6.37(q，1H)，6.53-6.57(q，4H)，6.80-6.84(d，1H)，7.05-7.07(d，2H)，7.25-7.29(t，1H)，7.39-7.41(d，2H)，7.50-7.58(q，3H)，9.34(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- (3-methylphenylamino) methyl) phenylacrylamide (compound 73)
1HNMR(DMSO-d6)(δppm)：2.12(s，3H)，4.25-4.27(d，2H)，5.25(s，2H)，6.04-6.07(m，1H)，6.32-6.53(q，4H)，6.80-6.86(q，3H)，7.26-7.56(q，6H)，9.31(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- (4-trifluoromethylphenylamino) methyl) phenylacrylamide (Compound 74)
1HNMR(DMSO-d6)(δppm)：4.35-4.37(d，2H)5.26(s，2H)，6.33-6.37(q，1H)，6.50-6.53(dd，1H)，6.80-6.85(q，5H)，7.23-7.29(t，2H)，7.41-7.43(d，2H)，7.50-7.59(q，3H)，9.33(s，1H)。
N- (2-amino-5-fluorophenyl) -3- (4- (4-trifluoromethoxy-phenylamino) -methyl) phenylacrylamide (compound 75)
1HNMR(DMSO-d6)(δppm)：4.30-4.31(d，2H)，5.27(s，2H)，6.33-6.37(q，1H)，6.50-6.63(q，4H)，6.81-6.85(d，1H)，7.03-7.05(d，2H)，7.25-7.29(q，1H)，7.41-7.43(d，2H)，7.50-7.59(q，3H)，9.34(s，1H)。
Figure GPA00000632129500321
Reaction formula 7
EXAMPLE 7 Synthesis of 6- (4-methoxybenzylamino) -N- (2-amino-5-fluorophenyl) -nicotinic amide (Compound 42)
Step 1. Synthesis of 6- (4-methoxybenzylamine) nicotinic acid
1g of 6-chloronicotinic acid, 1.26g of p-methoxybenzylamine, 1.3g K2CO3Adding 20ml of anhydrous DMF into a reaction bottle, heating to 150 ℃, reacting for 6h, adding a proper amount of water into the reaction bottle, and extracting with ethyl acetateTaking the mixture once, adjusting the pH of a water layer to 6-7 with 1N hydrochloric acid, separating out a large amount of white solid, filtering, and drying to obtain 1.67 g.
The melting point of the product is m.p.221-223 ℃;
step 2. Synthesis of 6- (4-methoxybenzylamino) -N- (2-amino-5-fluorophenyl) -nicotinic acid amide (Compound 42)
1g of the product of step 1, 0.64g of N, N-carbonyldiimidazole are dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5h and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 0.6g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.44g of trifluoroacetic acid, dropwise adding a standby reaction solution, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, washing residues with silica gel column and ethyl acetate/petroleum ether at a ratio of 3: 2, concentrating eluent, and crystallizing to obtain 0.31g of white solid.
1HNMR(DMSO-d6)(δppm)：3.715(S，3H)，4.529-4.543(d，2H)，5.266(s，2H)，6.302-6.345(m，1H)，6.487-6.522(dd，1H)，6.623-6.654(q，1H)，6.862-6.883(d，2H)，7.011-7.049(q，1H)，7.248-7.269(d，2H)，8.191-8.207(m，2H)，8.516(t，1H)，9.554(s，1H)。
The following Synthesis procedures of Compounds 43 to 44 and 76 were carried out in the same manner as in example 7 (Compound 42)
N- (2-amino-5-fluorophenyl) -6- ((3, 4-methylenedioxyphenyl) methylamino) nicotinic amide (Compound 43)
1HNMR(DMSO-d6)(δppm)：4.512-4.526(d，2H)，5.253(s，2H)，5.961(s，2H)，6.305-6.348(m，1H)，6.491-6.656(m，2H)，6.814-7.059(m，4H)，8.187-8.203(m，2H)，8.491-8.519(t，1H)，9.543(s，1H)。
N- (2-amino-5-fluorophenyl) -6- (2- (1H-indol-3-yl) ethylamino) nicotinic amide (compound 44)
1HNMR(DMSO-d6)(δppm)：2.964-2.983(t，2H)，3.690-3.704(q，2H)，5.222(s，2H)，6.316-6.359(m，1H)，6.498-6.620(m，2H)，6.964-7.172(m，4H)，7.313-7.333(d，1H)，7.573-7.593(d，1H)，8.114-8.288(m，3H)，9.486(s，1H)，10.796(s，1H)。
6- (2-benzyl) ethylamino-N- (2-amino-5-fluorophenyl) -nicotinic amide (compound 76)
1HNMR(DMSO-d6)(δppm)：2.853-2.871(m，2H)，3.633-3.648(t，2H)，5.28(s，2H)，6.331-6.334(q，1H)，6.599-6.630(q，2H)，7.253-7.285(q，6H)，8.213-8.225(q，3H)，9.499(s，1H)。
Figure GPA00000632129500331
Reaction formula 8
EXAMPLE 8 Synthesis of N- (2-amino-5-fluorophenyl) -5- ((3, 4-methylenedioxyphenyl) methylamino) -benzofuran-2-carboxamide (Compound 45)
Step 1. Synthesis of 5-nitrobenzofuran-2-carboxylic acid ethyl ester
1.0g of 2-hydroxy-5-nitrobenzaldehyde and 1.65 g of K2CO3Dissolving in 20ml of N, N-dimethylformamide, stirring at room temperature for reaction for 1h, then slowly dropwise adding 0.67 ethyl bromoacetate, heating to 80 ℃ after the addition, reacting for 3h, performing thin layer chromatography to show that the reaction is finished, cooling, adding water to dilute the reaction solution, and filtering to obtain 1.53g of yellow gray solid.
Step 2. Synthesis of 5-aminobenzofuran-2-carboxylic acid Ethyl ester
1.40g of iron powder and 0.51 g of NaCl were added to a 100ml three-necked flask, and 6.63ml of H was added2O and 0.15ml of 30% HCl, and after the addition, the temperature is raised to 100 ℃ and the mixture is refluxed for 1 h. Keeping the temperature, adding 1.51g of 5-nitrobenzofuran-2-ethyl formate (product in the first step), continuously refluxing for 3h, performing thin layer chromatography to show that the reaction is finished, cooling, filtering, washing with water and ethyl acetate,collecting ethyl acetate layer, anhydrous MgSO4Drying, filtering, and recovering ethyl acetate under reduced pressure to obtain a light yellow oil 1.16g, step 3, Synthesis of ethyl 5- ((3, 4-methylenedioxyphenyl) methylamino) benzofuran-2-carboxylate hydrochloride
1.10g3, 4-methylenedioxybenzaldehyde and 1.50g of the product of step 2 were dissolved in 15ml methanol and 3.07g NaBH were added portionwise in an ice bath4Dropwise adding glacial acetic acid to keep the pH of the reaction solution at 5-6, performing thin layer chromatography to show that the reaction is finished, removing the solvent under reduced pressure, distributing the residue in ethyl acetate/water, adjusting the pH to be acidic by using 5N hydrochloric acid, precipitating a large amount of white solid, filtering, and drying to obtain 1.96g of white solid
Step 4. Synthesis of 5- ((3, 4-methylenedioxyphenyl) methylamino) benzofuran-2-carboxylic acid
Suspending 1.56g of the product of the step 3 in 8ml of tetrahydrofuran/8 ml of water, adding 0.53g of lithium hydroxide, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, adding 20ml of water to dissolve the residue, adjusting the pH value of the solution to be about 5 by using 1N hydrochloric acid, standing, and filtering to obtain 1.30g of a white solid.
Step 5 Synthesis of N- (2-amino-5-fluorophenyl) -5- ((3, 4-methylenedioxyphenyl) methylamino) -benzofuran-2-carboxamide (Compound 45)
0.68g of the product in the step 4 and 0.358g of N, N-carbonyldiimidazole are dissolved in 10ml of anhydrous tetrahydrofuran, reacted for 1.5h at 45 ℃, and cooled for later use. Taking another three-necked flask, dissolving 0.331g of 4-fluoro-1, 2-phenylenediamine in anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.36g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature for reaction overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, passing the residue through a silica gel column, washing with ethyl acetate/petroleum ether at a ratio of 1: 2, concentrating the eluent, and crystallizing to obtain 0.38g of white solid
The melting point of the product is m.p.205.5-206 ℃;
1HNMR(DMSO-d6)(δppm)：4.195-4.210(d，2H)，5.253(s，2H)，5.971(s，2H)，6.150-6.180(t，1H)，6.338-6.381(m，1H)，6.520-6.556(dd，1H)，6.727-6.733(d，1H)，6.848-6.874(m，3H)，6.953-6.955(d，1H)，7.099-7.137(q，1H)，7.376-7.398(d，1H)，7.422(s，1H)，9.656(s，1H)。
the following Synthesis procedures for Compounds 46 to 50, 77 to 81 were carried out in the same manner as in example 8 (Compound 45)
N- (2-amino-5-fluorophenyl) -5- (4- (dimethylamino) benzylamino) -benzofuran-2-carboxamide (Compound 46)
11HNMR(DMSO-d6)(δppm)：2.854(s，6H)，4.145-4.159(d，2H)，5.250(s，2H)，6.007-6.035(t，1H)，6.338-6.373(m，1H)，6.521-6.549(dd，1H)，6.686-6.738(q，3H)，6.855-6.883(dd，1H)，7.101-7.224(m，3H)，7.362-7.384(d，1H)，7.439(s，1H)，9.649(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (4-fluorobenzylamino) -benzofuran-2-carboxamide (Compound 47)
HNMR(DMSO-d6)(δppm)：4.280-4.294(d，2H)，5.253(s，2H)，6.221-6.251(t，1H)，6.338-6.380(m，1H)，6.521-6.556(dd，1H)，6.726-6.731(d，1H)，6.856-6.885(dd，1H)，7.099-7.175(m，3H)，7.382-7.448(m，4H)，9.657(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (2-fluorobenzylamino) -benzofuran-2-carboxamide (Compound 48)
1HNMR(DMSO-d6)(δppm)：4.34-4.35(d，2H)，5.25(s，2H)，6.17-6.20(t，1H)，6.35-6.38(m，1H)，6.52-6.55(dd，1H)，6.75-6.76(d，1H)，6.88-6.90(dd，1H)，7.11-7.45(m，7H)，9.66(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (2-chlorobenzylamino) -benzofuran-2-carboxamide (Compound 49)
1HNMR(DMSO-d6)(δppm)：4.37-4.38(d，2H)，5.25(s，2H)，6.29-6.36(m，2H)，6.52-6.55(dd，1H)，6.67-6.20(d，1H)，6.87-6.89(dd，1H)，7.11-7.13(q，1H)，7.28-7.48(m，6H)，9.66(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (2, 4-dichlorobenzylamino) -benzofuran-2-carboxamide (Compound 50)
1HNMR(DMSO-d6)(δppm)：4.35-4.36(d，2H)，5.25(s，2H)，6.33-6.38(m，2H)，6.52-6.67(m，2H)，6.86-6.88(dd，1H)，7.10-7.14(q，1H)，7.41-7.45(m，4H)，7.63-7.64(d，1H)，9.67(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (3, 4-difluorophenylamino) -benzofuran-2-carboxamide (Compound 77)
1HNMR(DMSO-d6)(δppm)：4.292-4.306(d，2H)，5.271(s，2H)，6.317-6.377(q，2H)，6.513-6.548(dd，1H)，6.714-6.720(d，1H)，6.847-6.875(dd，1H)，7.086-7.123(t，1H)，7.248(s，1H)，7.378-7.450(q，4H)，9.688(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (2-methoxybenzylamino) -benzofuran-2-carboxamide (Compound 78)
1HNMR(DMSO-d6)(δppm)：3.853(s，3H)，4.246-4.261(d，2H)，5.250(s，2H)，6.024-6.054(m，1H)，6.339-6.381(q，1H)，6.522-6.557(dd，1H)，6.687-6.692(d，1H)，6.859-6.902(q，2H)，7.002-7.022(d，1H)，7.100-7.138(t，1H)，7.212-7.296(q，2H)，7.379-7.441(q，2H)，9.658(s，1H).
N- (2-amino-5-fluorophenyl) -5- (4-methoxybenzylamino) -benzofuran-2-carboxamide (Compound 79)
1HNMR(DMSO-d6)(δppm)：3.724(s，3H)，4.207-4.222(d，2H)，5.275(s，2H)，6.150-6.179(m，1H)，6.338-6.381(q，1H)，6.518-6.553(dd，1H)，6.723-6.728(d，1H)，6.855-6.909(q，3H)，7.092-7.130(t，1H)，7.307-7.443(q，4H)，9.686(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (3, 4-dimethoxybenzylamino) -benzofuran-2-carboxamide (Compound 80)
1HNMR(DMSO-d6)(δppm)：3.737(s，6H)，4.201-4.215(d，2H)，5.276(s，2H)，6.156-6.157(m，1H)，6.352-6.359(q，1H)，6.515-6.550(dd，1H)，6.740-6.745(d，1H)，6.885-6.911(q，3H)，7.015-7.016(d，1H)，7.090-7.128(t，1H)，7.379-7.451(q，2H)，9.687(s，1H)。
N- (2-amino-5-fluorophenyl) -5- (pyridin-3-yl-methylamino) -benzofuran-2-carboxamide (Compound 81)
1HNMR(DMSO-d6)(δppm)：4.332-4.347(d，2H)，5.276(s，2H)，6.309-6.358(q，2H)，6.513-6.549(dd，1H)，6.764-6.770(d，1H)，6.868-6.898(dd，1H)，7.087-7.125(t，1H)，7.356-7.451(q，3H)，7.780-7.800(q，1H)，8.443-8.455(dd，1H)，8.622-8.627(d，1H)，9.694(s，1H).
Figure GPA00000632129500351
Reaction formula 9
EXAMPLE 9 Synthesis of N- (2-amino-5-methoxyphenyl) -4((4- (pyridin-3 yl) pyrimidin-2-amino) methyl) benzamide (Compound 97)
Step 1. Synthesis of 3, 3-dimethylamino-1-pyridin-3-yl-propenone
Dissolving 2g of 3-acetylpyridine in 5ml of anhydrous DMF, adding 5ml of DMAPDMA into the solution, heating to 110 ℃ after the addition is finished, reacting for 3 hours, carrying out thin layer chromatography to show that the reaction is finished, recovering the DMF under reduced pressure, placing the residual solution in a refrigerator overnight, separating out a yellow solid, carrying out suction filtration, and washing with ethyl acetate/petroleum ether at a ratio of 1: 1 to obtain 2.05g of the yellow solid.
Melting point of the product is m.p.82-83 ℃ MS (FAB);
step 2. Synthesis of 4-guanidinomethyl-benzoic acid
Dissolving 2g of methylisothiouronium sulfate in 10ml of 1mol/LNaOH aqueous solution, slowly and dropwise adding 2.15g of 4-aminomethyl benzoic acid under ice bath, stirring at room temperature for reacting overnight after the addition is finished, separating out a white solid, filtering, and drying to obtain 2.56g of the white solid.
Step 3. Synthesis of 4- [ (4-pyridin-3-yl-pyrimidin-2-yl-amino) -methyl ] benzoic acid
1.57g of the product of the step 1 and 1.88g of the product of the step 2 are dissolved in 10ml of isopropanol, 1.26g of K2CO3 are added at the same time, after the addition is finished, the mixture is heated and refluxed for 12 hours, and thin layer chromatography shows that the reaction is finished, and the mixture is cooled, filtered and dried to obtain 1.87g of white solid.
The melting point of the product is m.p.219.5-221 ℃;
step 4 Synthesis of N- (2-amino-5-fluorophenyl) -4((4- (pyridin-3 yl) pyrimidin-2-amino) methyl) benzamide (Compound 1)
1g of the product of step 3, 0.54g of N, N-carbonyldiimidazole was dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5 hours, and cooled for further use. Taking another dry 100ml three-neck bottle, under the protection of nitrogen, dissolving 0.52g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran, dropwise adding 0.38g of trifluoroacetic acid, dropwise adding the standby reaction solution, stirring at room temperature overnight, after the reaction is shown by thin layer chromatography, recovering the solvent under reduced pressure, washing residues by silica gel column and ethyl acetate/petroleum ether/ethanol at a ratio of 2: 1: 2, concentrating eluent, and crystallizing to obtain 0.28g of white solid.
The melting point of the product is m.p.165-167 ℃;
1HNMR(DMSO-d6)(ppm)：3.641-3.670(d，3H)，4.636-4.649(d，2H)，5.212(s，2H)，6.150-6.178(dd，1H)，6.330-6.337(d，1H)，δ6.969-6.991(d，1H)，7.262-7.274(d，1H)，7.492-7.531(m，3H)，7.901-8.045(m，3H)，8.407-8.420(d，2H)，8.680-8.690(d，1H)，9.246(s，1H)，9.475(d，1H)
compounds of examples 98-102 were synthesized according to the procedure for example 9
N- (2-amino-5-methoxyphenyl) -4((4- (4-ethoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 98)
The melting point of the product is m.p.215-217 ℃;
1HNMR(DMSO-d6)(δppm)：1.328-1.363(m，3H)，3.670(s，3H)，4.066-4.101(dd，2H)，4.620-4.634(d，2H)，4.877(s，2H)，6.159-6.180(dd，1H)，6.334-6.340(d，1H)，6.997-7.104(m，4H)，7.453-7.473(d，2H)，7.751-8.048(m，5H)，8.277-8.289(d，1H)，9.443(s，1H)。
n- (2-amino-5-methoxyphenyl) -4((4- (4-methoxyphenyl) pyrimidin-2-amino) methyl) benzamide (compound 99)
The melting point of the product is m.p.183-186 ℃;
1HNMR(DMSO-d6)(δppm)：3.562-3.670(m，3H)，3.818(s，3H)，4.620-4.632(d，2H)，4.899(s，2H)，6.158-6.180(dd，1H)，6.333-6.339(d，1H)，7.028-7.117(m，4H)，7.460-7.475(d，2H)，7.815-7.917(m，3H)，8.046-8.067(d，2H)，8.283-8.296(d，2H)，9.469(s，1H)。
n- (2-amino-5-methoxyphenyl) -4((4- (4-methoxy-5-fluorophenyl) pyrimidin-2-amino) methyl) benzamide (compound 100)
The melting point of the product is m.p.219-222 ℃;
1HNMR(DMSO-d6)(δppm)：4.361-3.670(s，3H)，3.903(s，3H)，4.616-4.631(d，2H)，4.901(s，2H)，6.151-6.180(dd，1H)，6.330-6.337(d，1H)，6.968-6.990(d，1H)，7.162-7.277(m，2H)，7.474(m，2H)，7.898-7.944(m，5H)，8.315-8.328(d，1H)，9.474(s，1H)。
n- (2-amino-5-methoxyphenyl) -4((4- (4, 5-difluorophenyl) pyrimidin-2-amino) methyl) benzamide (compound 101)
1HNMR(DMSO-d6)(δppm)：3.63-3.672(s，3H)，4.629-4.644(d，2H)，4.879(s，2H)，6.154-6.182(dd，1H)，6.334-6.341(d，1H)，6.974-6.996(d，1H)，7.217-7.230(d，1H)，7.457-7.580(m，3H)，7.900-7.967(m，4H)，8.121(m，1H)，8.381-8.393(d，1H)，9.450(s，1H)。
N- (2-amino-5-methoxyphenyl) -4((4- (4-bromophenyl) pyrimidin-2-amino) methyl) benzamide (compound 102)
The melting point of the product is m.p.212-215 ℃;
1HNMR(DMSO-d6)(δppm)：3.565-3.673(s，3H)，4.629-4.644(d，2H)，4.833(s，2H)，6.156-6.184(dd，1H)，6.339-6.345(d，1H)，6.980-7.001(dd，1H)，7.177-7.191(d，1H)，7.460-7.77(d，2H)，7.69-7.714(d，2H)，7.900-7.942(m，3H)，8.024-8.045(d，2H)，8.369-8.382(d，1H)，9.451(s，1H)。
Figure GPA00000632129500381
reaction scheme 10
EXAMPLE 10 Synthesis of N- (2-amino-5-methoxyphenyl) -4 ((6-phenylpyrimidin-4-amino) methyl) benzamide (Compound 91)
Step 1. Synthesis of methyl Paraminomethylbenzoate hydrochloride
Weighing 2g of p-aminomethyl benzoic acid, suspending the p-aminomethyl benzoic acid in 100ml of methanol, slowly dropwise adding 2ml of thionyl chloride under ice bath, continuously stirring and reacting for 3 hours at room temperature after the addition is finished, carrying out reflux reaction at 50 ℃ for 3 hours, carrying out plate-dropping reaction to be basically complete, extracting with ethyl acetate, washing with saturated sodium carbonate, drying with magnesium sulfate, concentrating and crystallizing to obtain 2.05g of white solid.
Step 2. Synthesis of methyl 4- ((6-chloropyrimidine-4-amino) methyl) benzoate
9.5g of methyl p-aminomethylbenzoate hydrochloride was dissolved in 250ml of a mixed solution of THF/DMF (5: 1), 20ml of triethylamine was added dropwise to obtain a suspension, 7g of 4, 6-dichloropyrimidine was added thereto, and the mixture was refluxed at 70 ℃ for 15 hours under stirring, whereby a white solid was precipitated, and then the white solid was filtered, washed with water, and dried to obtain 13.8g of a white solid.
Step 3, synthesizing 4- ((6-phenyl pyrimidine-4-amino) methyl) benzoic acid
0.2836g of triphenylphosphine and 0.1214g of palladium acetate are weighed and dissolved in 10ml of 1, 4-dioxane, the mixture reacts for 1 hour at 80 ℃ under the protection of nitrogen, 50ml of acetonitrile/water (═ 3: 2) mixed solvent is added after the reaction of the dotting plate is completed, 1.5g of 4- ((6-chloropyrimidine-4-amino) methyl benzoate, 1.12g of potassium carbonate and 0.1g of sodium bromide are added for the reaction at 90 ℃, 0.79g of phenylboronic acid is added after half an hour for the reaction overnight, the dotting plate is completely reacted, the mixture is cooled to 60 ℃, suction filtration is carried out, suspension evaporation is carried out, hydrochloric acid is used for regulating the pH value to be 5-6 to generate a large amount of solid, and the solid is obtained after suction filtration and drying.
Step 4. Synthesis of N- (2-amino-5-methoxyphenyl) -4 ((6-phenylpyrimidine-4-amino) methyl) benzamide
0.3g of 4- ((6-phenylpyrimidin-4-amino) methyl) benzoic acid and 0.16g N, N-carbonyldiimidazole are dissolved in 8ml of anhydrous tetrahydrofuran, reacted under reflux at 50 ℃ for 1.5h and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 4-methoxy-1, 2-phenylenediamine in 7ml anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.12g trifluoroacetic acid, dropwise adding the reaction solution for later use, stirring at room temperature overnight, after the reaction is finished by TCL, recovering the solvent under reduced pressure, washing the residue with silica gel column and ethyl acetate/ethanol 7: 1, concentrating the eluent, and crystallizing to obtain 0.15g of white solid.
1HNMR(DMSO-d6)(δppm)：3.650-3.677(s，3H)，4.633-4.675(d，2H)，4.895(s，2H)，6.168-6.189(dd，1H)，6.344-6.350(d，1H)，6.989-7.026(d，2H)，7.050-7.502(m，6H)，7.926-8.060(m，6H)，8.515(s，1H)，9.477(s，1H)。
The following compounds 92 to 96, 103 to 119, 123 to 124 were synthesized in the same manner as in example 10 (Compound 91).
N- (2-amino-5-methoxyphenyl) -4((6- (3-methoxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 92)
1HNMR(DMSO-d6)(δppm)：3.647-3.674(s，3H)，3.821(s，3H)，4.655-4.669(d，2H)，4.892(s，2H)，6.165-6.186(dd，1H)，6.339-6.346(d，1H)，6.984-7.038(m，3H)，7.388-7.564(m，5H)，7.919-8.032(m，3H)，8.506(s，1H)，9.471(s，1H)。
N- (2-amino-5-methoxyphenyl) -4((6- (4-methoxyphenyl) pyrimidine-4-amino) methyl) benzamide (compound 93)
1HNMR(DMSO-d6)(δppm)：3.674(s，3H)，3.815(s，3H)，4.644-4.656(d，2H)，4.892(s，2H)，6.165-6.186(dd，1H)，6.339-6.346(d，1H)，6.983-7.052(m，4H)，7.39-7.59(d，2H)，7.917-7.980(dd，5H)，8.460(s，1H)，9.496(s，1H)。
N- (2-amino-5-methoxyphenyl) -4((6- (3-pyridyl) pyrimidin-4-amino) methyl) benzamide (compound 94)
1HNMR(DMSO-d6)(δppm)：3.647-3.674(s，3H)，4.667-4.681(d，2H)，4.892(s，2H)，6.165-6.187(dd，1H)，6.339-6.346(d，1H)，6.984-7.096(m，2H)，7.449-7.527(m，3H)，7.922-7.943(d，2H)，8.130-8.162(t，1H)，8.334-8.353(d，1H)，8.544-8.678(m，2H)，9.196(s，1H)，9.473(s，1H)。
N- (2-amino-5-methoxyphenyl) -4((6- (3, 4-methylenedioxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 95)
1HNMR(DMSO-d6)(δppm)：3.647-3.674(s，3H)，4.641-4.653(d，2H)，4.890(s，2H)，6.092(s，2H)，6.164-6.186(dd，1H)，6.338-6.345(s，1H)，7.004-7.031(m，3H)，7.435-7.541(m，4H)，7.915-7.935(m，3H)，8.450(s，1H)，9.468(s，1H)。
N- (2-amino-5-fluorophenyl) -4 ((6-phenylpyrimidin-4-amino) methyl) benzamide (Compound 103)
1HNMR(DMSO-d6)(δppm)：4.665-4.667(s，2H)，5.205(s，2H)，6.330-6.373(m，1H)，6.516-6.551(dd，1H)，7.026(s，1H)，7.085-7.122(t，1H)，7.478-7.502(m，6H)，7.930-8.066(m，6H)，8.514(s，1H)，9.535(s，1H)。
N- (2-amino-5-fluorophenyl) -4((6- (3-methoxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 104)
1HNMR(DMSO-d6)(δppm)：3.821(s，3H)，4.661-4.673(s，2H)，5.226(s，2H)，6.330-6.373(m，1H)，6.517-6.546(dd，1H)，7.041-7.097(m，3H)，7.392-7.469(m，3H)，7.548-7.567(s，2H)，7.928-7.949(d，2H)，8.057-8.088(t，1H)，8.506(s，1H)，9.556(s，1H)。
N- (2-amino-5-fluorophenyl) -4((6- (4-methoxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 105)
1HNMR(DMSO-d6)(δppm)：3.815(s，3H)，4.646-4.660(s，2H)，5.203(s，2H)，6.328-6.371(m，1H)，6.513-6.548(dd，1H)，6.942-7.119(m，4H)，7.448-7.468(d，2H)，7.924-7.981(m，5H)，8.458-8.3460(s，1H)，9.531(s，1H)。
N- (2-amino-5-fluorophenyl) -4((6- (3-pyridyl) pyrimidin-4-amino) methyl) benzamide (compound 106)
1HNMR(DMSO-d6)(δppm)：4.669-4.682(s，2H)，5.202(s，2H)，6.342-6.349(m，1H)，6.511-6.547(dd，1H)，7.079-7.117(t，2H)，7.454-7.535(m，3H)，7.927-7.948(d，2H)，8.135-8.165(t，1H)，8.334-8.354(d，1H)，8.544-8.674(m，2H)，9.170(s，1H)，9.532(s，1H)。
N- (2-amino-5-fluorophenyl) -4((6- (3, 4-methylenedioxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 107)
1HNMR(DMSO-d6)(δppm)：4.643-4.825(d，2H)，5.201(s，2H)，6.093(s，2H)，6.328-6.371(m，1H)，6.512-6.547(dd，1H)，6.924-7.118(m，3H)，7.446-7.586(m，5H)，7.921-7.974(m，4H)，8.450(s，1H)，9.527(s，1H)。
N- (2-amino-5-fluorophenyl) -4((6- (2, 4-dimethoxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 108)
1HNMR(DMSO-d6)(δppm)：3.818-.083(d，6H)，4.607(s，2H)，5.201(s，2H)，6.330-6.373(m，1H)，6.514-6.655(m，3H)，7.084-7.121(q，2H)，7.436-7.457(d，2H)，7.913-7.964(m，4H)，8.432(s，1H)，9.533(s，1H)。
N- (2-amino-5-methoxyphenyl) -4 ((2-methyl-6-phenylpyrimidine-4-amino) methyl) benzamide (compound 109)
1HNMR(DMSO-d6)(δppm)：2.416-2.505(s，3H)，3.674(s，3H)，4.658(s，2H)，4.892(s，2H)，6.158-6.186(dd，1H)，6.339-6.346(d，1H)，6.822(s，1H)，6.984-7.005(d，1H)，7.463-7.474(m，5H)，7.923-7.993(m，5H)，9.473(s，1H)。
N- (2-amino-5-methoxyphenyl) -4((6- (3-methoxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 110)
1HNMR(DMSO-d6)(δppm)：2.412(s，3H)，3.674(s，3H)，3.815(s，3H)，4.645-4.655(s，2H)，4.890(s，2H)，6.158-6.186(dd，1H)，6.339-6.345(d，1H)，6.813(d，1H)，6.982-7.046(m，2H)，7.388-7.548(m，5H)，7.883-7.941(t，3H)，9.472(s，1H)。
N- (2-amino-5-methoxyphenyl) -4 ((2-methyl-6- (3, 4-methylenedioxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 113)
1HNMR(DMSO-d6)(δppm)：2.401(s，3H)，3.674(s，3H)，4.638(s，2H)，4.890(s，2H)，6.082-6.185(m，3H)，6.338-6.345(d，1H)，6.729(s，1H)，6.982-7.010(q，2H)，7.445-7.576(m，4H)，7.810-7.936(t，3H)，9.467(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((2-methyl-6-phenylpyrimidine-4-amino) methyl) benzamide (Compound 96)
1HNMR(DMSO-d6)(δppm)：2.415(s，3H)，4.652(s，2H)，5.201(s，2H)，6.349(m，1H)，6.511-6.546(dd，1H)，6.781-6.822(s，1H)，7.079-7.117(t，1H)，7.413-7.480(d，6H)，7.905-7.992(m，5H)，9.532(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6- (3-methoxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 111)
1HNMR(DMSO-d6)(δppm)：2.496(s，3H)，3.815(s，3H)，4.646-4.658(s，2H)，5.202(s，2H)，6.328-6.371(m，1H)，6.511-6.546(dd，1H)，6.824-6.835(s，1H)，7.019-7.100(m，2H)，7.369-7.548(m，5H)，7.888-7.947(ds，3H)，9.532(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6- (4-methoxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 112)
1HNMR(DMSO-d6)(δppm)：2.497(s，3H)，3.808(s，3H)，4.632(d，2H)，5.200(s，2H)，6.328-6.370(m，1H)，6.511-6.546(dd，1H)，6.742(s，1H)，7.010-7.166(m，3H)，7.432-7.476(m，2H)，7.924-7.962(t，5H)，9.529(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((2-methyl-6- (3-pyridyl) pyrimidin-4-amino) methyl) benzamide (compound 114)
1HNMR(DMSO-d6)(δppm)：2.497(s，3H)，4.664(s，2H)，5.601(s，2H)，6.328-6.370(m，1H)，6.511-6.546(dd，1H)，6.903(s，1H)，7.080-7.166(t，3H)，7.466-7.513(m，3H)，7.929-8.005(sd，3H)，8.314-8.33(d，1H)，8.643-8.655(dd，1H)，9.144(s，1H)，9.534(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6- (3, 4-methylenedioxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 115)
1HNMR(DMSO-d6)(δppm)：2.492(s，3H)，4.629-4.639(s，2H)，5.200(s，2H)，6.083-6.097(s，2H)，6.321-6.370(m，1H)，6.511-6.546(dd，1H)，6.728(s，1H)，6.990-7.116(td，2H)，7.453-7.576(td，4H)，7.818-7.942(ds，3H)，9.526(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6- (2, 4-dimethoxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 116)
1HNMR(DMSO-d6)(δppm)：2.365(s，3H)，3.810(s，6H)，4.592(s，2H)，5.201(s，2H)，6.331-6.374(m，1H)，6.515-6.551(dd，1H)，6.601-6.633(q，2H)，7.084-7.121(q，2H)，7.444-7.465(d，2H)，7.766-7.780(t，1H)，7.919-7.952(m，3H)，9.537(s，1H)。
N- (2-amino-5-methoxyphenyl) -4- ((6- (2, 4-dimethoxyphenyl) pyrimidin-4-amino) methyl) benzamide (compound 123)
1HNMR(DMSO-d6)(δppm)：3.674(s，3H)，3.818-3.856(s，6H)，4.628(s，2H)，4.923(s，2H)，6.158-6.186(dd，1H)，6.337-6.344(d，1H)，6.625-6.658(m，2H)，6.979-7.001(d，1H)，7.229(s，1H)，7.427-7.447(d，2H)，7.924-7.970(m，4H)，8.434(s，1H)，9.510(s，1H)。
Figure GPA00000632129500421
Reaction formula 11
N- (2-amino-5-fluorophenyl) -4- ((6- (4-methoxyphenyl) pyrazine-2-amino) methyl) benzamide (compound 117)
1HNMR(DMSO-d6)(δppm)：3.799(s，3H)，4.648-4.663(d，2H)，5.196(s，2H)，6.325-6.361(m，1H)，6.511-6.539(dd，1H)，7.011-7.097(td，3H)，7.503-7.523(d，2H)，7.727-7.756(t，1H)，7.899-7.968(m，5H)，8.246(s，1H)，9.521(s，1H)。
N- (2-amino-5-methoxyphenyl) -4- ((6- (4-methoxyphenyl) pyrazine-2-amino) methyl) benzamide (compound 118)
1HNMR(DMSO-d6)(δppm)：3.670-3.677(s，3H)，3.799(s，3H)，4.642-4.657(d，2H)，4.882(s，2H)，6.159-6.188(dd，1H)，6.334-6.341(d，1H)，6.975-7.023(t，3H)，7.491-7.511(d，2H)，7.718-7.748(t，1H)，7.894-7.966(m，5H)，8.242(s，1H)，9.457(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6- (3, 4-methylenedioxyphenyl) pyrazine-2-amino) methyl) benzamide (compound 119)
1HNMR(DMSO-d6)(δppm)：4.638-4.653(d，2H)，5.193(s，2H)，6.066(s，2H)，6.323-6.365(m，1H)，6.507-6.535(dd，1H)，6.978-7.110(m，2H)，7.491-7.535(m，4H)，7.746-7.775(t，1H)，7.909-7.941(t，3H)，8.239(s，1H)，9.519(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6-phenylpyrazin-2-amino) methyl) benzamide (compound 124)
1HNMR(DMSO-d6)(δppm)：4.662-4.676(d，2H)，5.224(s，2H)，6.324-6.366(m，1H)，6.503-6.531(dd，1H)，7.080-70102(q，1H)，7.436-7.529(m，5H)，7.928-8.018(m，6H)，8.315(s，1H)，9.550(s，1H)。
Reaction formula 12
EXAMPLE 12 Synthesis of N- (2-amino-5-methoxyphenyl) -4- ((6, 7-dimethoxyquinazolin-4-amino) methyl) benzamide (Compound 120)
Step 1. Synthesis of methyl Paraminomethylbenzoate hydrochloride
The synthesis was as in step 1 of example 10
Step 2. Synthesis of methyl 2-amino-4, 5-dimethoxybenzoate
Adding 15g of 4, 5 dimethoxy-2-nitrobenzoic acid methyl ester, 0.86g of ferric trichloride and 3g of dried activated carbon into 150ml of ethanol, heating to 80 ℃ under the protection of nitrogen, refluxing for 0.5h, cooling to 60 ℃, slowly dropwise adding 10ml of hydrazine hydrate (85%) into the reaction solution, continuously refluxing for 3h after dropwise adding is finished, thin-layer chromatography shows that the reaction is finished, filtering the reaction solution while hot, concentrating the filtrate under reduced pressure to remove most of ethanol, cooling the residual solution, separating out light yellow solid, filtering, and drying to obtain 8.6g of light yellow solid.
Step 3, synthesizing 6, 7-dimethoxy-3H quinazoline-4-ketone
Adding 7.2g of the product obtained in the step 2 and 7.2g of formamidine acetate into 100ml of ethanol, heating and refluxing for reaction for 4 hours, performing thin layer chromatography to show that the reaction is finished, cooling the reaction liquid, and filtering to obtain a white solid
Step 4, synthesizing 6, 7-dimethoxy-4-chloroquinazoline
Stirring 5.4g of a mixed solution of the product of the step 3, thionyl chloride (30ml) and DMF (2.5ml), heating to 50 ℃ for reaction for 5 hours, performing thin layer chromatography to show that the reaction is finished, removing the thionyl chloride under reduced pressure, washing the obtained solid with ethanol, and drying to obtain the product.
Step 5, synthesizing 4- ((6, 7-dimethoxyquinazoline-4-amino) methyl benzoate
Adding 5.0g of the product of the step 4, 4.4g of the product of the step 1 and 8.6ml of triethylamine into 50ml of DMF, refluxing and reacting the mixed solution at 80 ℃ for 18h under the protection of nitrogen, finishing the reaction through thin layer chromatography, pouring the reaction solution into 100ml of water, adjusting the pH to be 7 by using hydrochloric acid (2N), separating out a solid, filtering and drying to obtain the product.
Step 6, synthesizing 4- ((6, 7-dimethoxyquinazoline-4-amino) methyl) benzoic acid
And (3) stirring a mixed solution of 6.4g of the product of the step 5, 2.3g of lithium hydroxide, 40ml of THF and 20ml of water at 30 ℃ for reacting for 4h, carrying out thin layer chromatography to show that the reaction is finished, carrying out reduced pressure concentration to remove the THF, adjusting the pH of the residual solution to be 3 by using hydrochloric acid (2N), precipitating white solid, filtering and drying to obtain the compound.
Step 7. Synthesis of (2-amino-5-methoxyphenyl) -4- ((6, 7-dimethoxyquinazoline-4-amino) methyl) benzamide
0.4 of the product of step 6, 0.19g of N, N-carbonyldiimidazole was dissolved in 10ml of anhydrous DMF, reacted at 45 ℃ for 1.5 hours, and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 0.19g of 4-methoxy-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.44g of trifluoroacetic acid, dropwise adding a standby reaction solution, stirring at room temperature overnight, performing thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, enabling the residue to flow over silica gel column, eluting with ethyl acetate/ethanol at a ratio of 5: 1, concentrating the eluent, and crystallizing to obtain 0.28g of white solid.
1HNMR(DMSO-d6)(δppm)：3.672(s，3H)，3.902(s，6H)，4.834-4.848(d，2H)，4.915(s，2H)，6.163-6.178(m，1H)，6.335-6.342(dd，1H)，6.999-7.115(m，2H)，7.448-7.469(d，2H)，7.674(s，1H)，7.908-7.929(t，2H)，8.320(s，1H)，8.557-8.589(t，1H)，9.497(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((6, 7-dimethoxyquinazoline-4-amino) methyl) benzamide (compound 121)
1HNMR(DMSO-d6)(δppm)：：3.902(s，6H)，.835-4.850(d，2H)，5.195(s，2H)，6.343-6.350(m，1H)，6.512-6.547(dd，1H)，7.082-7.112(m，2H)，7.458-7.478(d，2H)，7.684(s，1H)，7.912-7.952(t，2H)，8.317(s，1H)，8.536-8.566(t，1H)，9.520(s，1H)。
Figure GPA00000632129500441
Reaction formula 13
EXAMPLE 13 Synthesis of N- (2-amino-5-fluorophenyl) -4- ((2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) methyl) benzamide (Compound 122)
Step 1 Synthesis of methyl 4- ((2-nitrobenzoylamino) methyl) benzoate
Suspending 1.6g of o-nitrobenzoic acid in 15ml of redistilled dichloromethane, slowly adding 1.28g of N, N' -dicyclohexylcarbodiimide in batches under ice bath, then adding 0.66g N-hydroxysuccinimide and a catalytic amount of 4-dimethylaminopyridine, and stirring at room temperature for later use; and taking another reaction bottle, adding 2g of aminomethyl methyl benzoate hydrochloride, 1.47ml of triethylamine and 10ml of redistilled dichloromethane, after half an hour, slowly dropwise adding the standby reaction solution, stirring for two hours at room temperature, after TLC shows that the reaction is complete, stopping the reaction, filtering, collecting filtrate, washing the filtrate for 3 times with acid water, then washing the filtrate for 3 times with saturated sodium carbonate, collecting an organic layer, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain 1.46g of white solid.
Step 2. Synthesis of 4- ((2-nitrobenzoylamino) methyl) benzoic acid
Suspending 1.15g of the product in the step 1 and 0.67g of sodium hydroxide in a 10ml tetrahydrofuran/10 ml water mixed solution, stirring overnight at room temperature, removing the solvent under reduced pressure, adding a proper amount of water into the residue, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, and drying to obtain 0.94g of a white solid.
Step 3. Synthesis of 4- ((2-aminobenzamidoyl) methyl) benzoic acid
Suspending 0.8g of the product of the step 2, 0.13g of ferric trichloride and 0.24g of dry activated carbon in 20ml of absolute ethyl alcohol, heating and refluxing for half an hour, stopping heating, slowly dropwise adding 0.4ml of hydrazine hydrate, continuously refluxing for 2 hours, showing complete reaction by TLC, filtering while hot, collecting filtrate, removing the solvent under reduced pressure, adding appropriate amount of water into the residue, adjusting the pH to about 7, filtering, and drying to obtain 0.68g of white solid
Step 4. Synthesis of 4- ((2- (ethoxycarbonyl) benzoylamino) methyl) benzoic acid
Dissolving 0.62g of the product of the step 3 in 15ml of pyridine, slowly and dropwise adding 0.24ml of ethyl chloroformate in ice bath, continuously stirring for 2h, indicating complete reaction by TLC, adding a proper amount of acid water into the reaction solution to make the pH acidic, extracting with dichloromethane for a plurality of times, combining organic layers, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain light yellow solid, and recrystallizing with ethyl ester/ethanol to obtain 0.63g of white solid.
Step 5 Synthesis of 4- ((2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) methyl) benzoic acid
Suspending 0.50g of the product in the step 3 in a mixed solution of 10ml of methanol and 10ml of water, adding 0.074g of NaOH, heating and refluxing for 12 hours, performing TLC to show that the reaction is complete, filtering, collecting filtrate, removing the solvent under reduced pressure, adding a proper amount of water into the residue, adjusting the pH to be about 5-6, filtering, and drying to obtain 0.46g of a white solid.
Step 6 Synthesis of N- (2-amino-5-fluorophenyl) -4- ((2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) methyl) benzamide
0.43g of the product of step 5 and 0.24g of N, N-carbonyldiimidazole are dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 50 ℃ under reflux for 1.5h and cooled for further use. Taking another dry 100ml three-necked bottle, dissolving 0.23g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.165g of trifluoroacetic acid, dropwise adding a standby reaction solution, stirring at room temperature overnight, recovering the solvent under reduced pressure, eluting the residue by silica gel column and ethyl acetate/ethanol 10: 1, concentrating the eluent, and crystallizing to obtain 0.25g of a white solid.
1HNMR(DMSO-d6)(δppm)：5.131(s，2H)，5.295(s，2H)，6.942-7.112(m，3H)，7.215-7.348(m，4H)，7.669-7.706(t，1H)，7.845-7.964(m，3H)，9.520(s，1H)，11.425(s，1H)。
The following synthesis procedure for compounds 127 and 128 was the same as in example 13 (compound 122).
N- (2-amino-5-fluorophenyl) -4- ((1- (2- (dimethylamino) ethyl) -2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) methyl) benzamide (compound 127)
1HNMR(DMSO-d6)(δppm)：2.271(s，6H)，5.134(s，2H)，5.301(s，2H)，6.944-7.113(m，3H)，7.216-7.350(m，4H)，7.670-7.706(t，1H)，7.853-7.969(m，3H)，9.532(s，1H)。
N- (2-amino-5-fluorophenyl) -4- ((1- (2-morpholinoethyl) -2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) methyl) benzamide (compound 128)
1HNMR(DMSO-d6)(δppm)：2.389-2.401(t，4H)，3.671-3.680(t，4H)，5.131(s，2H)，5.295(s，2H)，6.942-7.112(m，3H)，7.215-7.348(m，4H)，7.669-7.706(t，1H)，7.845-7.964(m，3H)，9.522(s，1H)。
Example 9 growth inhibition of tumor cells by Compounds disclosed in the invention
And (4) detecting by using an MTT method, and carrying out an experiment when the state of the cultured cells is good. The cells were prepared as a uniform suspension and seeded into 96-well plates at a certain density. Add 100. mu.L of cell suspension per well to give the number of cells per well10000-. Different drug concentration groups of 0-500 mu M are set, and a blank control group and a solvent control group are additionally set. Each concentration is three repeated holes, 10 mu L of the medicine is added into each hole, the medicine is sequentially added according to the concentration from low to high, and the medicine is uniformly mixed when the medicine is added. The 96-well plate was sealed, leaving a small convection gap to reduce errors due to evaporation of the cell culture medium. After adding medicine and stimulating for 48h, cell proliferation is detected by an MTT method. Detecting absorbance value at 570nm wavelength, and performing mathematical statistical analysis to obtain GI50Values (concentration of compound that inhibits cell growth by 50%).
TABLE 2 proliferation inhibitory Activity of Compounds on tumor cells
Figure GPA00000632129500461
Figure GPA00000632129500471
Positive control drug: n- (2-aminophenyl) -4- ((3, 4-dimethoxyphenyl) aminomethyl) benzamide (the compound disclosed in WO2005092899, which we have synthesized according to the procedure disclosed therein)
Cell source:
SMMC-7721: human liver cancer cell HepG 2: human liver cancer cell
MCF-7: human breast cancer cell MDA-MB-231: human breast cancer cell
HL-60: human myeloid leukemia cell Jurkat: human T lymphocyte leukemia
CCD-1059 SK: normal fibroblast
The result shows that the compound disclosed by the invention has obvious anticancer activity, particularly the compound 6 is 29 times and 13 times higher than MS-275 for human breast cancer cells MDA-MB-231 and MCF-7 respectively; for leukemia cells HL60 and Jurkat, the compound 6 is 3 times and 2 times higher than that of MS-275 respectively; compared with MS-275, the compound 6 is 5 times and 1 time higher in human liver cancer cells SMMC-7721 and HepG 2. The proliferation inhibitory activity of compound 4 on tumor cells was comparable to that of MS-275. The compounds disclosed herein are less toxic to normal cells than MS-275 or the positive control drug (YX).
Preliminary stability test
A. High temperature test
2 parts of each pre-test compound sample is taken, an appropriate amount of each pre-test compound sample is placed in a weighing bottle, a thin layer with the thickness of 5mm is paved, the thin layer is placed in a thermostat with the temperature of 60 ℃ for 10 days, samples are taken respectively in 5 days and 10 days, and the appearance, related substances and content change are inspected, and the results are shown in a table 3.
TABLE 3 table of high temperature stability test results of compounds
And (4) conclusion: after the MS-275 is heated for 10 days, the appearance is changed into white powder, and the content and related substances are obviously changed, which indicates that the product is unstable to high temperature; after the compound is irradiated by strong light for 6-10 days, the appearance, the content and related substances have no obvious change, which shows that the product is stable to high temperature.
B. Test by intense light irradiation
A proper amount of the pre-test compound is taken and spread into a thin layer with the thickness of 5mm, the thin layer is placed under the condition of the illumination intensity of 4500Lx +/-500 Lx for 10 days, samples are taken respectively at 5 days and 10 days, and the appearance, related substances and content change of the samples are inspected, and the results are shown in a table 4.
TABLE 4 stability test results of the preliminary test Compounds under high light irradiation
Figure GPA00000632129500482
Figure GPA00000632129500491
And (4) conclusion: after the contrast is irradiated by strong light for 10 days, the appearance of the contrast is changed into red powder, and the content and related substances are obviously changed, which indicates that the contrast is unstable to the light; after the compound 6 is irradiated by strong light for 10 days, the appearance, the content and related substances have no obvious change, which shows that the product is more stable to the light compared with a reference product (the compound disclosed in WO 2005092899).
N- (2-aminophenyl) -4- ((3, 4, 5-trimethoxyphenylamino) methyl) benzamide (control) was the compound disclosed in WO2005092899, which we synthesized as follows: melting point m.p.164.5-165 deg.C; 1HNMR (DMSO-d6) (δ ppm): 3.646(s, 6H), 3.500(s, 3H), 4.313-4.327(d, 2H), 5.186-5.206(d, 2H), 5.887(s, 2H), 6.138-6.169(t, 1H), 6.331-6.374(m, 1H), 6.515-6.550(dd, 1H), 7.082-7.103(dd, 1H), 7.477-7.498(d, 2H), 7.917-7.938(d, 2H), 9.529(s, 1H).
Industrial applicability
The inventor of the invention proves through experiments that the compound disclosed by the invention has a positive inhibition effect on tumor cell proliferation, the tumor inhibition activity is obviously superior to that of a positive control medicament MS-275, and the compound has lower toxicity on normal cells than MS-275. In addition, the compound disclosed by the invention has more stable physicochemical properties than the positive control drugs MS-275 and the compound disclosed by WO 2005092899.

Claims (8)

1. A compound of the formula, or a pharmaceutically acceptable acid salt thereof,
Figure FSB00000784343600011
here, Ar is:
Figure FSB00000784343600012
2. a compound of the formula, or a pharmaceutically acceptable acid salt thereof,
Figure FSB00000784343600013
here, Ar is:
Figure FSB00000784343600014
3. a compound of the formula, or a pharmaceutically acceptable acid salt thereof,
here, Ar is:
Figure FSB00000784343600016
4. a compound of the formula:
Figure FSB00000784343600017
wherein,
Figure FSB00000784343600018
Figure FSB00000784343600021
5. a compound of the formula:
Figure FSB00000784343600022
wherein,
Figure FSB00000784343600023
6. a compound of the formula:
or a pharmaceutically acceptable acid salt thereof, wherein:
R1＝H R2＝OCH3 R3＝OCH3 R4＝H R5＝H。
7. a pharmaceutical composition comprising 1 or more compounds according to any one of claims 1-6, and a pharmaceutically acceptable carrier.
8. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of psoriasis, leukemia or solid tumours associated with cell proliferation in humans or animals.
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