CN101730703A - 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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CN101730703A
CN101730703A CN200880015929A CN200880015929A CN101730703A CN 101730703 A CN101730703 A CN 101730703A CN 200880015929 A CN200880015929 A CN 200880015929A CN 200880015929 A CN200880015929 A CN 200880015929A CN 101730703 A CN101730703 A CN 101730703A
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compound
formula
optionally substituted
alkoxy
het
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CN101730703B (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 anti-proliferative activity, pharmaceutical preparations thereof
Benzamide derivatives with antiproliferative activity and pharmaceutical preparations thereof
Technical Field
The invention relates to a compound for treating diseases related to proliferation, in particular to a novel benzene amide derivative, a preparation method thereof, a salt of the derivative and a medicament taking 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 malignant tumor deaths in China is on the rise year by year, and the cancer prevention and treatment tasks are extremely straightforward. 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 has been 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 human life health still
Satisfactory results have not been achieved.
Chemotherapy drugs in the traditional sense often generate more serious toxic and side effects due to the lack of selectivity of acting on target, 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. The more and more the pharmaciasts and oncologists realize that to improve the curative effect of tumor therapy, the breakthrough progress must be made by starting from the mechanism of tumorigenesis and development so as to fundamentally prevent and treat cancer. Therefore, the antitumor drug is developing from the conventional cytotoxic drug to a novel antitumor drug directed at the multi-link action molecular target of the mechanism. 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 therapeutic effect and low toxic and side effect, and the discovery and clinical application of the molecular targeted drug are shifting the medical treatment of tumor from palliative treatment to # Fanti'.
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 is based on a unique action mechanism of the gene level, and therefore, the gene expression vector draws great attention of researchers at home and abroad.
Chromatin is composed of DNA, histones and non-histones. Nucleosomes are basic repeating units of chromatin, and are composed of octamers of histones H3, H4, H2A, H2B, histone HI located outside the nucleosome, and DNA comprising 146 ciconi pairs wrapped around the same. The acetylation state of histone has important regulation and control function for 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 in relative rest 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 lysine residues at amino terminal ends of several histone components Hl, H2A, H2B, H3 and H4, HDAC can catalyze deacetylation of histones to cause the expression of corresponding genes to be reduced, 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 which influences cell proliferation and regulates the cell cycle is unbalanced, 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 RARa and RARs form heterodimers that bind to retinoic acid-responsive elements on DNA. In the case of acid deficiency in vitamin , SIN3/HDAC3 can be recruited by nuclear co-repressor and the receptor silencing regulator of the gonadal receptor of vitamin acid , thereby inhibiting transcription.
HAT is widely present in cells from yeast to mammalian organisms, and various HAT activities have been foundThere are various classification methods for protein molecules according to structure and function. Mammalian HDACs, on a molecular level, can be classified as type 3: HDAC of type I/II is Zn2+Dependent, HDAC type III is Nicotinamide Adenine Dinucleotide (NAD) dependent. Class I includes HDACs 1,2, 3, 8, 11, all located intranucleally, with a relative molecular weight of 4200055000.
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 Bing Liu Aijun Cheng, et al, "three-dimensional quantitative structure-activity relationship of sulfonamide hydroxamic acid HDAC inhibitors". Proc. physio. Chem. 2005, 21(3): 333-.
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: the (1) can directly act on the key link of the abnormal expression of the gene, thereby inhibiting and correcting the over-proliferation, escape apoptosis and differentiation capacity reduction of tumor cells, which is different from the defect that the traditional antitumor drug only aims at the single phenotype of the over-proliferation of the cells and has weaker effect on other phenotypes caused by the abnormal expression of the gene; 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. And (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 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 may be used during the initial treatment period to increase the sensitivity of tumor cells to target DNA or etoposide, a chemotherapeutic agent for topoisomerase II. 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 together with the HDAC inhibitor LAQ824, was able to inhibit 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 54% and 60%, respectively, and the tumor growth is reduced by % 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 and Scriptaid, (3) cyclotetraphthalide structures containing epoxy ketone groups such as trapoxin B and HC-Toxin; (4) cyclic tetrapeptide structures which do not contain an epoxy keto group, such as FK228, (5) benzene amides, such as MS-275 (EP 0847992A1, 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 acid such as butyric acid; (2) Has great side effect, the hydroximic acid compound is Zn2+For binding targets, many Zn-containing organisms are known2+Protein, and therefore hydroxamic acid compounds, have greater side effects(ii) a (3) the cost is high, the cyclotetra structure containing epoxy ketone groups and the cyclotetra peptide structure without epoxy ketone groups are prepared by a biological method, are separated and purified by high performance liquid chromatography, are not suitable for conventional 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 physical and chemical properties of the benzene amide are unstable because the benzene diamine structure is contained. 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 under development, in order to obtain HDAC inhibitors with high anticancer activity, less side effects and more stability.
Disclosure of Invention
It is an object of the present invention to provide novel derivatives of the formula < CHEM > amide 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 benzene amide derivative, which has a structure shown in a formula (I):
x2or 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;
g is selected from a bond, T, L-T, T-L or T-L-T;
wherein 1^ is 8,0, C =0 or N (R!) in the presence of L, where 1 is selected from hydrogen, alkyl, hydroxyalkyl and tert-butoxycarbonyl;
t is d-C when present4An 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 =0 in formula I);
y is NH2Or OH;
X X2、 X3each independently selected from hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), d-C4Alkyl or ^ alkoxy, and specify x!, x2、 x3At least one of which is not hydrogen.
Preferred compounds of formula I according to the invention are those selected from the group consisting of fluorine, d-C4Alkoxy radical, X3Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, d-C4Alkyl or d-C4An alkoxy group.
Preferred compounds of the formula I according to the invention are those in which X2Is fluorine, d-C4Alkoxy radicals, Xi, x3Both are 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-Gi is
Preferred compounds of formula (I) of the present invention have the structure shown in formula (I A):
R2is hydrogen or-C4 alkyl;
y is-NH2or-OH;
X2selected from fluoro or-C4 alkoxy;
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 (I A) of the present invention have the structure of formula (I A-1):
wherein: l is NH or S;
p, Q, M, G and U are each independently CH or N and M, Q, U cannot be N at the same time, provided that 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 CrC4An alkyl group;
X2selected from fluorine or.1-。4A alkyl group;
the groups A and B may be the same or different and are independently selected from hydrogen, halogen, d-C4Alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy, heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, amido, aminomethyl radical or
、 o>、 -c -
Preferred compounds of formula (I A) of the present invention have the structure of formula (IA-2):
wherein:
l is S or NH;
R2is hydrogen or-alkyl;
X2selected from fluorine or d-C4An alkoxy group;
a and B are as defined for compounds of formula (I A-1).
Preferred compounds of formula (I A) of the present invention have the structure shown in formula (IA-3):
wherein:
is S or NH;
X2selected from fluorine or CrC4An alkoxy group;
A. b is as defined for the compound of formula (I A-1).
Preferred compounds of formula (I A) of the present invention have the structure shown in formula (I A-4):
wherein:
l is S or NH;
d is N-R3 or S;
e is N or C-A;
R2and R3Each independently is hydrogen or CrC4An alkyl group; x is the number of2Selected from fluorine or C! -alkoxy;
a and B are as defined for the compound of formula (IA-1).
Preferred compounds of formula (I A) of the present invention have the structure shown in formula (IA-5):
( I A-5)
wherein:
l is NH;
X2selected from fluorine or C, -C4An alkoxy group;
a and B are as defined for compounds of formula (I A-1).
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IA-6):
、 I A-0
wherein:
a is hydrogen or CrC4An alkyl group;
b is as defined for compounds of formula (I A-I);
X2selected from fluorine or d-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 the compound of formula (I A-1);
X2selected from fluorine or Ci-C4An alkoxy group;
preferred compounds of formula (I) of the present invention have the structure shown in formula (IB):
( I B)
wherein:
01is 1\ L-T or T-L, where 1^ is 8,0 or NH T is-CH2-;
Z iota is 0, S, NH or CH2;
Z2Is N or CH;
X2selected from fluorine or d-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 in compound (I A-1); het may also be optionally substituted with 1,2 or 3 groups independently selected from alkoxy, -substituted alkoxy, acyl, morpholino or alkoxy optionally substituted phenyl.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (I C):
wherein:
01is 1\ L-T or T-L;
LS, O or NH;
t is-CH2-;
Z2Is N or CH;
Σ,0, S, NH, or C microspheres;
X2selected from fluorine or-C4An alkoxy group;
het is selected from phenyl, pyridyl, sneezyl or benzothiazolyl, and may be substituted with A and/or B, A and B are as defined in formula (I A-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 (I D):
wherein
Het is:
X2selected from fluorine or-C4An alkoxy group. Preferred compounds of formula (I) of the present invention have the structure shown in formula (IE):
y is-OH or-NH2;
X2Selected from fluorine or ^ -alkoxy;
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 d-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:
-CN 、 、 、 ο 、。 - -、。
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, a bond, -C microspheres-, -0-CH2-、 -S-CH2-、 -S-CH(CH3) -or-NiR-CH ^ more preferred compounds of formula (I) in which G is2Is indolyl or indolinyl; is-0 microspheres-or-N ^ -CHr;
het is:
in preferred compounds of the formula (I), G3Is absent;
G2is phenylene;
gi is-S-C microspheres or-S-C (CH)3)(H)-;
Het is:
x-or wherein J is selected from the following groups:
preferred compounds of formula (I) of the present invention have the structure shown In Formula (IF):
wherein:
y is-OH or-N microspheres;
X2selected from fluorine or d-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:
preferred structures of the invention are of formula (IF):
y is-NH2;
X2Selected from fluorine or d-C4An alkoxy group;
a is as defined for formula (I A-l).
Preferred compounds of formula (I) of the present invention have the structure shown in formula (IG):
wherein: „
Het, G, Y are as defined in formula (I), X2Selected from fluorine or alkoxy groups.
Preferred compounds of formula (I) of the present invention have the structure shown in formula (I H):
l is S or-NH-;
X2selected from fluoro or C, -C4 alkoxy;
A. b is as defined in the structure of formula (I A-1).
Preferred compounds of formula (I H) 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):
| A Is 0 or-NH;
X2selected from fluoro or Ci-C4 alkoxy;
r4 is hydrogen or CrC6An alkyl group.
The invention also provides a novel benzene amide derivative, which has a structure shown in a formula II:
or a salt of a pharmaceutically acceptable acid.
Hetl is an aryl or heteroaryl group, optionally substituted, each of which may be optionally fused to one or more aryl or heterocyclyl groups, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclyl groups, each of which may be optionally substituted;
Xi X2、 X3and Y is as defined for formula (I); d is a covalent bond C0-C4Hydrocarbyl radical, C0-C4-hydrocarbyl- (CO) -C0-C4-hydrocarbyl, C0-C4-hydrocarbyl- (NR5) -C0-C4-a hydrocarbon radical, C. -C4-hydrocarbyl- (S) -C. -C4-a hydrocarbyl group, C. -C4A hydrocarbon group- (good) -C. -C4-menstrual radical, CQ-C4-hydrocarbyl- (SO) - -C4-hydrocarbon radical, CQ-C4-hydrocarbyl- (SO) -CQ-C4Alkyl, CG-C4-alkyl- (NH) - (CO) -CQ-C4-hydrocarbyl, Co-C4-hydrocarbyl- (CO) - (N)H)- C0-C4-hydrocarbyl, -NH-CO-NH-, -NH-CS-NH-, -O-CO-O-, -O-CS-O-, -NH-C (NH) -NH-, -S (0)2-N(R5)-， -N(R5)- S(0)2-, -NH-C (0) -0-, or-O-C (O) -NH-, where R5 may be hydrogen, d-C5Alkyl, aryl, aralkyl, heterocyclyl, heterocyclylaryl, S02-alkyl, S02-aryl, CO-alkyl, CO-aryl, CO-NH-alkyl, CO-NH-aryl, CO-0-alkyl or CO-0-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, sulfonate and the like; examples of the inorganic acid salts include hydrohalic acid salts, sulfuric acid salts, phosphoric acid salts, and nitric acid salts.
For example, with lower alkyl sulfonic acids, such as sulfonic acid, trifluoro sulfonic acid, and the like, sulfonate, trifluoro sulfonate can be formed; with aryl sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid to form p- benzenesulfonate, benzenesulfonate; 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 acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, or phosphoric acid, and the like.
The solvate of the benzamide derivative is also in the protection scope of the invention, and the solvent is preferably water, ethanol or alcohol.
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:
(I) wherein Het and G in the compound of formula III2、 G3Is as defined for compounds of formula I, and compounds of formula IV wherein Y is-NH 2, or OH, beta2、 X3Each independently selected from hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), d-C4Alkyl or-Ct alkoxy and specifying beta iota, X2、 X3At 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 organic solvents such as chloroform, dichloro alkane, tetrahydrofuran, dioxane, 1, 2-bis oxyethane, xylene, toluene, dimethyl sulfoxide, triethylamine and the like; the reaction temperature is-30- +80 deg.c, and if necessary, alkali such as sodium hydroxide, triethylamine, pyridine, etc. and acid such as hydrochloric acid, acetic acid, trifluoroacetic acid, etc. may be added.
Het, G of the compound of the formula III1 ¾G2、 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, Hetl, G, Z, n, beta, X2、 X3The definition of "Y" is the same as that of the compound of formula (II). The invention also provides a pharmaceutical composition containing the benzene amide compound or the salt or solvate thereof. In the above-mentioned medicineThe 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 medicament can be prepared into various forms such as tablets, powders, granules, capsules, oral liquid, injection and the like, and the medicaments of all the forms can be prepared according to the conventional method in the field of pharmacy. 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 benzene amide 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 physical and chemical properties of the compound disclosed by the invention are more stable than those of the positive control drugs MS-275 and the compound disclosed by WO 2005092899.
Best mode for carrying out the inventionexamplesthe implementability of the present invention is illustrated below by way of examples, and it will be understood by those skilled in the art that modifications or substitutions of corresponding technical features are made in accordance with the teachings of the prior art, and still fall within the scope of the claimed invention.
EXAMPLE 1 Synthesis of N- (2- -5-fluorophenyl) -4((4- (pyridin-3-yl) pyrimidin-2-ylmethyl) phenylmethyl Sfc amine (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-di -yl amide, adding 5ml of N, N-dimethyl -amide diacetal into the solution, heating to 110 ℃ after the addition is finished, reacting for 3 hours, displaying the reaction completion by thin layer chromatography, recovering N, N-dimethyl amide under reduced pressure, placing the residual solution in a refrigerator overnight, precipitating yellow solid, filtering, washing with ethyl acetate/petroleum in a ratio of 1:1, and obtaining 2.05g of yellow solid.
The melting point of the product is m.p.82-83. C;
step 2, synthesizing 4-guanidino -benzene acid, dissolving 2g of methyl isothiourea sulfate in 10ml of lmol/L sodium hydroxide aqueous solution, slowly dripping 2.15g of 4-aminomethyl benzoic acid under ice bath, stirring at room temperature for reacting overnight after the addition is finished, separating out white solid, filtering and drying to obtain the white solid
2.56g。
Step 3. Synthesis of 4- [ (4-pyridin-3-yl-pyrimidin-2-yl-amino) -methyl ] benzenepropanoic 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 1.87g is obtained after cooling, filtration and drying.
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) yl) benzene amide (Compound 1)
Lg 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 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, carrying out thin layer chromatography to show that the reaction is finished, recovering the solvent under reduced pressure, washing residues by silica gel column and ethyl acetate/petroleum ether/ethanol 2:1:2, concentrating the 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) (5ppm): 4.640-4.654(d,2H), 5.212(s,2H), 6.338-6.354(m, lH), 6.506-6.54 l (dd, lH), 7.069-7.107(t, lH), 7.262-7.274(d, lH), 7.492-7.53 l (m,3H), 7.910-8.044(m,3H), 8.407-8.420(d,2H), 8.680-8.690(d, lH), 9.246 (s, lH), 9.515-9.532 (d, lH). The following compounds 2 to 4, 9Synthesis of-17, 51 to 55, 125 to 126 was carried out as in example 1 (Compound 1)
N- (2-i ^ -5-L L phenyl) -4((4- (pir -2-yl) pyrimidine-2-methyl) benzyl S ^ J & (Compound 2)
The melting point of the product is m.p. 206-207 ℃;
'HNMR(DMSO-d6) (5ppm)： 4.653-4.667(d,2H) , 5.208(s,2H) , 6.337-6.344(m,lH) , 6.503-6.539(dd,lH) , 7.066-7.104(t,lH) , 7.494-7.520(m,4H) , 7.908-7.997(m,4H) , 8.317-8.337(d,lH), 8.442-8.455(d,lH), 8.692-8.703(d,lH), 9.525(s,lH)。
n- (2-Fa-5-fluorophenyl) -4((4- (pyridin-4-yl) pyrimidin-2- yl) benzyl (compound 3)
The melting point of the product is m.p. 206-207 ℃;
' HNMR (DMSO-d6) (delta rho iota η): 4.647-4.662(d,2H), 5.192(s,2H), 6.324-6.367(m, lH), 6.508-6.543(dd, lH), 7.073-7.1 l l (m, lH), 7.284-7.297(d, lH), 7.486-7.494(d,2H), 0.89(t,3H), 7.909-8.074(m,5H), 8.460-8.472(d, lH), 8.720-8.734(d,2H) 9.510(s, lH). melting point of the product m.p. 209-209.5 ℃;
'HNMR(DMSO-d6) (5ppm): 3.831(s,3H), 4.676(s,2H), 6.349-6.392(m, lH), 6.528-6.563(dd, lH), 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, lH), 9.539(s, lH). N- (2-J ^ -5-fluorophenyl) -4((4- (4-bromophenyl) pyrimidin-2-11) methyl) benzyl S! t ^ (compound 9)
lHNMR(DMSO-d6) (6ppm):4.632-4.645(d,2H) ， 5.223(s,2H) , 6.330-6.367(m,lH) ， 6.514-6.549(dd,lH), 7.075-7.112(t,lH), 7.186-7.200(d,lH), 7.481(s,2H), 7.698-7.717(d,2H), 7.912-8.050(m,5H), 8.372-8.384(d,lH), 9.540(s，lH)。
N- (2-J ^ -5-fluorophenyl) -4((4- (3, 4-difluorophenyl) pyrimethanil-2-atmosphere) methyl) benzene gfc amine (compound 10)
'HNMRCDMSO-de) (6ppm)： 4.631-4.654(d,2H) ， 5.189(s,2H) , 6.337-6.344(m,lH) , 6.507-6.542(dd,lH) ， 7.071-7.108(t,lH) ， 7.218-7.230(d,lH) ， 7.487-7.579(m,3H) ， 7.904-7.974(m,4H), 8.120-(s,lH), 8.381-8.393(d,lH), 9.509(s,lH)。
N- (2-IL ^ -5-fluorophenyl) -4((4- (2, 4-dimethylthiazol-5-yl) pyrimidin-2-11 ^) methyl) benzoic compound 11)' HNMRCDMSO-de) (6ppm): 2.614(s,6H), 4.558-4.574(d,2H), 5.192(s,2H), 6.326-6.36 l (m, lH), 6.509-6.544(dd, lH), 6.826-6.839(d, lH), 7.075-7.112(t, lH), 7.440-7.459(d,2H), 7.899-7.919(d,3H), 8.317-8.329(d, lH), 9.507(s, lH).
N- (2- ^ 5-fluorophenyl) -4((4- ((2- (pimeliyl) ethylHg phenyl) mi i-2- ^) methyl) benzyl SUfe (Compound 12)
'HNMR(DMSO-d6) (5ppm): 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,lH), 6.511-6.540(dd,lH), 7.072-7.129(m,4H), 7.464-7.483(d,2H), 7.802(t,lH), 7.903-7.923(d,2H), 8.068-8.090(d,2H), 8.300-8.321(d,lH), 9.512 (s,lH)。
N- (2- ^ 5-fluorophenyl) -4((4- (3-fluoro-4- (m) phenyl) sneezemethyl) phenylmethylSfe amine (compound 13) (6ppm) 2.505(s,3H), 4.625-4.640(d,2H), 5.188(s,2H), 6.337-6.366(m, lH), 6.507-6.542(dd, lH), 7.072-7.110(q, lH), 7.199-7.212(d, lH), 7.423-7.485(m,3H), 7.904-7.966(m, 5H), 8.354-8.366(d, lH), 9.508 (s, lH).
N- (2-J-5-fluorophenyl) -4((4- (3-radon-4- (Methylol J-phenyl) pyrimidin-2-methyl) phenylmethyl (Compound 1)
1HNMR(DMSO-d6) (5ppm) ： 3.904(s,3H) , 4.621-4.635(d,2H) , 5.213(s,2H) , 6.326-6.369(m,lH) ， 6.508-6.543(dd,lH) ， 7.070-7.107(t,lH) ， 7.161-7.173(d,lH) ， 7.254-7.296(t,lH), 7.483(s,2H), 7.908-7.928(m,5H), 8.316-8.329(d,lH), 9.534 (s,lH)。 N-(2- J>-5-fluorophenyl) -4((4-0 fc ~ -2-yl) pyrimidinylmethyl) phenylmethyl SUft (Compound 15)
'HNMR^DMSO-ds) (6ppm) ： 4.673(d,2H) , 5.215(s,2H) ， 6.338-6.35(m,lH) ， 6.503-6.538(dd,lH), 7.065-7.101 (t,lH), 7.451-7.53 l(m,3H), 7.915-7.935(dd,2H), 8.159(s,lH), 8.503-8.515(d,lH), 8.785(s，2H), 9.451 (s，lH)， 9.539 (s，lH)。
N- (2- ^ -5-fluorophenyl)) -4((4- (4- (karen-3-yl)) sneez-2-methyl) benzyl (compound 16)' Η Ν k (o m 8 o- ά)6)(δρριη):4.602-4.618(ά,2Η), 5.190(s,2H), 6.337-6.366(m,lH),
6.514-6.542(dd,lH), 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,lH)。
N- (2-J-5-fluorophenyl) -4((4- (4-methylthienyl) pyrimidinylmethyl) phenylmethyl bffc fe (Compound 17)
'HNMRCDMSO-de) (5ppm): 2.51 l(s,3H), 4.627-4.642(d,2H), 5.192(s,2H), 6.325-6.367(m,lH),6.518-6.546(dd,lH) , 7.090-7.149(m,2H)， 7.344-7.488 (q,4H) , 7.832-8.040(m,5H) , 8.320-8.333(d,lH), 9.508(s，lH)。
N- (2-IL ^ -5-L phenyl) -4((4- (4- (2-morpholinoethylphenyl) pyrimidinylmethyl) benzyl Stjfe (Compound 51)
MS(FAB):543 (M+l)
N- (2-tJ-5-fluorophenyl) -4((4- (4-ethyl) pyrimidin-2- |1^) methyl) benzyl SUfe (compound 52)
'HNMR(DMSO-d6) (5ppm): 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,lH), 6.51-6.55(dd,lH), 7.01-7.1 l(q,4H), 7.47-7.49(d,2H), 7.76-7.79(m,lH), 7.90-7.92(d,2H), 8.03-8.05(d,2H), 8.28-8.29(d,lH), 9.51(s，lH)。
N- (2-J ^ -5-fluorophenyl) -4((4- (4-butylphenyl) pyrimidinylmethyl) benzyl ^ (compound 53)
'HNMR(DMSO-d6) (5ppm): 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,lH), 6.50-6.54(dd,lH), 7.02-7.1 l(q,4H), 7.46-7.48(q,2H) , 7.80-7.83(m,lH), 7.90-7.92(d,2H), 8.03-8.05(d,2H) ， 8.28-8.29(d,lH) , 9.53(s,lH)。
N- (2-J ^ -5-I L phenyl) -4 ((4-phenyl) pyrimidine-2-I Delta-methyl) benzyl Sjfe (compound 54)
'HNMR(DMSO-d6) (6ppm): 4.64-4.65(d, 2H), 5.2 l(s, 2H), 6.33-6.36(q,lH), 6.51-6.54 (dd，lH)， 7.07-7.1 l(m,lH), 7.17-7.19(d,lH), 7.50(s,5H), 7.91-7.93(m,3H), 8.08-8.09(d,2H), 8.35-8.37(d，lH), 9.53(s,lH)。
N- (2-J5-fluorophenyl) -4 ((4-ring SJ ^ yl) pyrimidine-2-methyl) benzyl SU ^ (compound 55)
'HNMRiDMSO-de) (6ppm): 1.59-1.71(q, 6H), 1.94-1.99(q, 2H), 4.62-4.63(d,2H), 4.88-4.91 (m,lH), 5.21(s,2H), 6.34-6.37(q,lH), 6.51-6.53(dd,lH), 6.98-7.10(q,4H), 7.46-7.48(d,2H), 7.79-7.82(q,lH), 7.90-7.92(d,2H), 8.02-8.04(d,2H)， 8.28-8.29(d,lH) , 9.53(s,lH)。
N- (2-tJ ^ 5-fluorophenyl) -4((4- (3-methylphenyl) pyrimidin-2-ylmethyl) benzene SUfe (compound 125)
'HNMR(DMSO-d6) (5ppm): 3.814(s， 3H)， 4.623-4.638(d, 2H), 5.187(s,2H), 6.322-6.343 (m,lH) , 6.512-6.54 l(dd，lH)， 7.059-7.179(m,3H) , 7.382-7.647(m,5H) , 7.877-7.92 l(t,3H), 8.345-8.358(d,lH), 9.504(s,lH)。
N- (2-H ^ -5-fluorophenyl) -4((4- (3, 4-methylenedill ^ phenyl) pyrimidinylmethyl) phenylmethyl SUfe (Compound 126)
1HNMR(DMSO-d6) (5ppm): 4.615-4.630(d, 2H), 5.190(s, 2H)， 6.096(s,2H), 6.336-6.344 (m,lH) , 6.506-6.541(dd,lH) , 7.077-7. l l l(m,3H), 7.457-7.477(d,2H) , 7.625-7.620(m,5H), 8.282-8.295(d,lH), 9.507(s,lH)。
R!=H R2=OCH3R3=H R4=H R5= H compound 5
RfH R2=OCH3R3=OCH3R4=H R5= H compound 6
R,=OCH3R2=OCH3R3=OCH3R4=H R5= H Compound 7
R!=H R2=OCF3R3=H R4=H R5= H compound 18
0、
R1，R2=<R3=H R4=H R5= H compound 19
O
R2=H R3=H R4=H R5= H compound 82
Ri=H R2=H R3=H R4=H R5= H compound 83
R,=H R2=CH3R3=H R4=H R5= H compound 84
R!=H R2=OC2H5R3=H R4=H R5= H compound 85R4=H R5= H compound 86
R,=H R2=Br R3=H R4=H R5= H compound 87
Rj=H R2=H R3-CF3 R4=H R5= H compound 88
R]=H R2=H R3=H R4=CH3 R5= H compound 89
Rj=H R2=H R3=H R4=Cl R5=CH3Compound 90
^2
Example 2 Synthesis of N- (2-4L ^ -5-fluorophenyl) -4- ((4-formoxyphenyl) methyl) benzamide (Compound 5) step 1 Synthesis of esters of p-benzoic acid
Dissolving 2.0g of p-aldehyde benzene acid in 20ml of methanol, slowly dripping 1.81ml of thionyl chloride in a water bath, heating and refluxing for 3 hours after the addition is finished, displaying the end of the reaction by thin layer chromatography, 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
Dissolving 1.59g of p-aminoanisole and 2.13g of the product obtained in the step 1 in 15ml of alcohol, adding 3.07g of NaBH4 in batches under ice bath, dropwise adding glacial acetic acid to keep the pH of a 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 acidity with 2N hydrochloric acid, precipitating a large amount of white solid, filtering, and drying to obtain 2.89g of white solid. Step 33. Synthesis of 44- - ((((44-methoxymethoxyphenylalkylphenylamino)) methyl)) benzoic acid
Suspending the product obtained in step 11 of step 22..6677gg in 88mmll tetrahydrofuran/88 mmll water, adding 00..5533 gg lithium hydroxide, stirring overnight at room temperature, thin-layer chromatography, recovering solvent, dissolving the residual substance in 2200mmll water, adjusting PPHH to about 55 with 11NN hydrochloric acid, standing, filtering to obtain white solid 22..1177 gg. .
The melting point of the 55-product is mm.. pp., 117788- -118800..55 deg.C CC;
step 44. Synthesis of NN- - ((22- -amino- -55- -fluorobenzophenyl)) - - -44- - (((((44- - Oxyloxyphenylalkylanilinylamino)) methyl) benzamide ((Compound 55))
Dissolving the product 22..1177gg, Ν -carbonoyl diimidazole 11..3399gg produced in step 33 in 1100mmll anhydrous tetrahydrofurofurans, reacting at 4455 ° ° CC for 11..55hh, and cooling. . Dissolving 11..3344gg 44-fluoro-11, 22-phenylenediamine in anhydrous tetrahydrofuran under nitrogen protection, dripping 00. 9988gg trifluoro fluoro acetic acid, adding dropwise the reaction liquid, stirring at room temperature, reacting overnight, collecting thin layer, separating layer, collecting solvent, passing the residue through silica gel column, washing ethyl acetate/petrolic acid 11: (22 deg.C), eluting, concentrating, crystallizing, and obtaining white solid 11..0055 gg. .
The melting point of the product is mm.. pp., 220055.. 55-220066 degree CC;
((δδρρρριιηη)):: 33..660033((ss,,33HH)),, 44..228844--44..229999((dd,,22HH)),, 55..221144((ss,,22HH)),, 55..993399--55..996699((tt,,llHH)),, 66..332299--66..337722((mm,,llHH)) ,, 66..449966--66..553399((mm,,33HH)) ，， 66..666600--66..668833((dd,,22HH)) ，， 77..007733--77..11 ll ll((qq,,llHH)) ,, 1155 77..444488--77..446699((dd,,22HH)),, 77..990000--77..992200((dd,,22HH)),, 99..552299((ss,,llHH))。。
the sub-synthesis step of the following compound 66-77, 1188-1199, 8822-9900 is as described in the example 22 (the compound 55).
NN- - ((22- - [ SP ] -
The melting point of the product is mm.. pp., 113355..55- -113366..55 degree CC;
2200 ''HH MMRR((DDMMSSOO--dd66)) ((66ppppmm)):: 33..558899((ss,,33HH)),, 33..665599((ss,,33HH)),, 44..229922--44..330066((dd,,22HH)),, 55..119922 ((ss,,22HH)),, 55..996688--66..000099((mm,,22HH)) ,, 66..332244--66..335522((mm,,22HH)) ，， 66..551177--66..666655((mm,,22HH)) ,, 77..008811--77..111188((tt,,llHH)) ，， 77..446600--77..448800((dd，，22HH))，， 77..009977--77..779900((dd,,22HH)),, 99..552211((ss，，llHH))。。
NN- - ((22- -JJ- -55- -Fluorofluorophenyl phenyl)) - - - (44- - ((((33, 44, 55- -TrimethylHH ^ SS ^ methyl)) phenylmethylSStt amine ((Compound 77))
The melting point of the product is mm.. pp., 116666- -116677 degree CC;
2255 ''HHNNMMRR((DDMMSSOO--dd66)) ((55ppppmm)):: 33..449955((ss,,33HH)),, 33..662244((ss,,33HH)),, 33..664433((ss,,33HH)),, 44..331133--44..332288((dd,,22HH)),, 55..222299((ss,,22HH)) ,, 55..888822((ss,,22HH)) ,, 66..333322--66..337755((mm,,22HH)) ,, 66..551122--66..554488((dddd,,llHH)) ,, 77..007755--77..009977((qq,,llHH)) ,, 77..447799--77..449999((dd,,22HH)),, 77..991199--77..993399((dd,,22HH)),, 99..555511((ss,,llHH))。。
NN- - ((22- - -55- - -iLL phenylphenyl)) - - - (44- - ((((44-trifluoro-fluoromethyl-ttJJ:: methyl group ^) phenyl SSUufefe) ((chemical compound 1188))
' 'HHNNMMRRCCDDMMSSOO--ddee)) ((55ppppmm)):: 44..440088--44..442233((dd,,22HH)),, 55..223344((ss,,22HH)),, 66..333333--66..337755((mm,,llHH)),, 3300 66..551144--66..554422((dddd,,llHH)),, 66..779977--66..889944((mm,,44HH))，， 77..007766--77..226666((mm,,22HH)),, 77..446655--77..448866((dd,,22HH)),, 77..993311 --77..9955 ll((dd,,22HH)),, 99..556622((ss,,llHH))。。
N- - ((22- - · F- - -55- -fluorophenylphenyl)) - - - (44- - ((((33, 44- -methylenebisHHJJ ^ ggyl)) phenylmethylSStt amine ((chemical compound 1199))
1H1HNNMMRR((DDMMSSOO--dd66))((SSppppmm))::44..227777--44..229922((dd,,22HH))，，55..223300((ss,,22HH))，，55..880044((ss,,22HH))，，55..995566--55..997799((dddd，，llHH)) ,, 66..001166--66..113377((tt,,llHH)) ,, 66..225577--66..226622((dd,,llHH)) ，， 66..333366--66..337744((mm,,llHH)) ,, 66..551122--66..662277((mm,,22HH)) ，， 3355 77..009900--77..111122((qq,,llHH)),, 77..444455--77..446655((dd,,22HH)),, 77..990077--77..992288((dd,,22HH)),, 99..554433((ss，，llHH))。。
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EXAMPLE 3 Synthesis of 4- (((phenethyl) (2-hydroxyethyl) methyl) -N- (2-a-5-fluorophenyl) benzamide (Compound 8)
Step 1, synthesizing 4- ((phenethylamino) radical) benzene acid ester hydrochloride
Dissolving 1.43ml of phenethylamine and 1.46g of p-aldehyde benzene acid ester in 10ml of alcohol, adding 2.5g of sodium borohydride in batches in ice bath, dropwise adding glacial acetic acid to keep the pH of a reaction solution at 5-6, performing thin layer chromatography to show that the reaction is finished, decompressing and removing the solvent, distributing residues in ethyl acetate/water, adjusting the residues to be acidic by using 2N hydrochloric acid, precipitating a large amount of white solid, filtering, and drying to obtain 2.06g of the white solid.
Step 2 Synthesis of 4- (((2- (tert-butyldi -silyloxy) ethyl) (phenethyl) amino) -yl) benzoic acid ester
Taking a 100ml dry three-necked bottle, dissolving 2.06g of 4- ((phenethylamino) yl) benzene methyl ester hydrochloride in 20ml of anhydrous bis yl 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) bis silane after solid is dissolved, heating to 60 ℃, reacting at constant temperature for 24h, carrying out thin layer chromatography to show that the reaction is finished, distributing the reaction liquid in ethyl acetate/water, collecting an ethyl ester layer, recycling the solvent under reduced pressure, passing the concentrated solution through a silica gel column, eluting with ethyl acetate/petroleum ether 1: 6, and concentrating under reduced pressure to obtain 1.53g of light yellow oily matter.
Step 3 Synthesis of 4- (((2- (tert-butyldi -silyloxy) ethyl) (phenethyl) amino) -yl) benzene acid (IV)
1.53g of the product of step 2 was dissolved in 6ml of THF/6 ml 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-butyldi -silyloxy) ethyl) (phenethyl) amino) methyl) -N- (2-amino-5-fluorophenyl) phenyl -carboxamide (Compound 8)
1.02g of the product of step 3, 0.44g of Ν, Ν -carbonyldiimidazole were dissolved in 7ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5h and cooled for further use. Taking another 100ml dry three-necked bottle, dissolving 0.35g of 4-fluoro-1, 2-phenylenediamine in 5ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.26g 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, and passing the residue through a silica gel column, wherein the weight ratio of ethyl acetate: washing with petroleum ether at a ratio of 1:2, concentrating the eluate, and crystallizing to obtain white solid 0.34g
Step 5. Synthesis of 4- (((phenethyl) (2-hydroxyethyl) amino) yl) -N- (2-amino-5-fluorophenyl) benzamide (Compound 8) A100 ml dry three-necked flask was taken, dry nitrogen was introduced, 0.34g of the product of step 4 and 5ml of anhydrous tetrahydrofuran were added at-20 ℃ to dissolve, 0.17g of tetrabutylammonium fluoride was slowly dropped, after the addition, was slowly raised to room temperature, the reaction was stirred overnight, thin layer chromatography showed the reaction was completed, the solvent was recovered under reduced pressure, the residue was passed through a silica gel column, ethyl acetate/petroleum ether 1: 4 was eluted, the eluate was concentrated and crystallized to obtain 0.102g of a white solid
The melting point of the product is m.p. 100.0-101.5 ℃;
'HNMRCDMSO-cU) (6ppm)： 2.593-2.746(m,6H)， 3.611-3.750(q,4H) , 5.182(s,2H)，
6.317-6.359(m,lH) , 6.502-6.537(dd,lH) , 7.063-7.391(m,8H) , 7.873-7.893(d,2H) ，
9.521(s,lH)。
the following synthetic procedures for compounds 20-21 were the same as in example 3 (compound 8).
4- (((4-Methylmethyl) (2-hydroxyethyl) methyl) -N- (2-5-L-phenyl) phenylmethyl SUfe (Compound 20)nHNMR(DMSO-d6) (5ppm)： 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,lH), 6.513-6.548(dd,lH), 6.879-6.90 l(d,2H), 7.077-7.115(q,lH), 7.263-7.285(d,2H), 7.469-7.490(m,2H) , 7.922-7.943(d,2H) , 9.563(s，lH)。
4- (((3, 4-difluorobenzyl) (2-hydroxyethyl) methyl) -N- (2- | ^ -5-Lphenyl) phenylmethyl SUfe (Compound 21)nHNMR(DMSO-d6) (Sppm)： 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,lH), 6.520-6.552(dd,lH), 7.095-7.108(q,lH), 7.231-7.233(d,lH), 7.368-7.395(d,lH), 7.487-7.539(m,3H), 7.930-7.95 l(d,2H), 9.569(s，lH)。
2728293031606162 formula 4 example 4 Synthesis of 4- (2-Fluorobenzyl microspheres J-N- (2- ^ 5-fluorophenyl) benzyl « Jfe (Compound 22)
Step 1, synthesizing 4- (2-fluorobenzylamino) benzene acid
Dissolving 2-fluorobenzaldehyde 1.59g and aminobenzene acid 2.13g in 4-amino benzene ml, adding NaBH4 3.07g in batches in 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, reducing pressure to remove the solvent, adding a proper amount of water into the residue, adjusting the residue to be acidic by using 2N hydrochloric acid, precipitating a large amount of white solid, filtering, and drying to obtain 2.89g of white solid.
The melting point of the product is m.p.178-180.5' C;
step 2 Synthesis of N- (2-amino-5-fluorophenyl) -4- ((4-methoxyphenylamino) yl) benzamide (Compound 22)
Dissolving 2.17g of the product obtained in the step 1, N-carbonyl diimidazole 1.39g in 10ml of anhydrous tetrahydrofuran, reacting at 45 ℃ for 1.5h, and cooling for later use. Dissolving 1.34g of 4-fluoro-1, 2-phenylenediamine in anhydrous tetrahydrofuran under the protection of nitrogen in another three-necked bottle, 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 1:2, concentrating the eluent, (Hl's) Z.i 6 XllZ ^ iS L-M L
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EXAMPLE 5 Synthesis of N- (2-IL ^ -5-fluorophenyl) -4((4- (3, 4-difluorophenyl) pyrimidin-2-) methyl) benzyl BU microspheres (Compound 32)
Step 1. Synthesis of 3, 3-bis Aminoamino-mini (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 for reaction for 3 hours after the addition is finished, recovering the 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 acid at a ratio of 1:1 to obtain 1.86g of yellow solid.
The melting point of the product is m.p.79-8rC;
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, adding a proper amount of water into the residue to dissolve, adjusting the pH value to be weakly acidic by using 1N hydrochloric acid, precipitating a large amount of yellow solid, filtering and drying to obtain the sodium-containing copper sulfate.
Step 3, synthesizing ester of 4- ((4- (3, 4-difluorophenyl) pyrimidine-2-thio) - -yl) benzene acid, 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 ester of 4-chloro -yl benzene acid after half an hour, reacting for 6 hours at room temperature, adding appropriate amount of water into a reaction bottle after TCL shows that the reaction is finished, precipitating a large amount of solid, filtering, and drying to obtain 1.76g of colored solid.
The melting point of the product is m.p.l02.5-104 ℃;
step 4. Synthesis of 4- ((4- (3, 4-difluorophenyl) pyrimidin-2-sulfanyl) - -yl) benzoic acid
Suspending 1.5g of the product of the step 3 in 15ml of alcohol 15/ml of water, adding 0.52g of lithium hydroxide, stirring at room temperature of 25785, standing 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 to 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-sulfanyl) methyl) benzamide (Compound 32)
G of the product from 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 0.42 g 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, after TCL shows that the reaction is finished, recovering the solvent under reduced pressure, leaning residues on silica gel, washing ethyl acetate/petroleum at a ratio of 2:1, concentrating eluent, and crystallizing to obtain 0.29g of white solid.
' HNMRCDMSO-c ^ Xappm): 4.573-4.587(d,2H), 5.221(s,2H), 6.324-6.367(m, lH), 6.508-6.536(dd, lH), 7.071-7.093(q, lH), 7.849-7.929(m,3H), 8.104-8.291(m,2H), 8.737-8.750(d, lH), 9.530 (s, lH). The synthesis stages for the following compounds 33-38, 63-69 were the same as in example 5 (compound 32).
N- (2-J ^ -5-fluorophenyl) -4((4- (3-fluoro-4-methoxyphenyl) sneeze-2- « ^) methyl) benzyl (compound 33)
'HNMR(DMSO-d6)(6ppm)： 3.934(s，3H)， 4.575(s,2H) , 5.205(s,2H), 6.495-6.515(m,lH) , 6.712-6.741(dd,lH) ， 7.152-7.189(q,lH) ， 7.317-7.361(t,lH) , 7.600-7.62 l(d,2H) , 7.774-8.076(m,5H), 8.654-8.668(d,lH), 9.528 (s，lH)。
N- (2-J-5-fluorophenyl) -4((4- (4-methoxy-1) pyrimidine-2-microspheres) methyl) benzoic acid A-diol (Compound 34)
1HNMR(DMSO-d6)(6ppm): 2.550(s,3H)， 4.571-4.954(s,2H), 5.202(s,2H), 6.335-6.363(m,lH), 6.504-6.532(dd,lH) , 7.069-7.090(q,lH) , 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,lH), 9.522 (s,lH)„
N- (2- ^ -5-fluorophenyl) -4((4- (thiophen-3-yl) pyrimidin-2-) methyl) phenylmethyl SUfe (compound 35)
'HNMR(DMSO-d6) (5ppm): 4.557(S,2H), 5.232(S,2H), 6.321-6.364(m, lH), 6.499-6.535(dd, lH), 7.061-7.099(q, lH), 7.593-7.614(d,2H), 7.672-7.686(d, lH), 7.735-7.755(q, lH), 7.841-7.920 (m,3H), 8.552-8.560(m, lH), 8.647-8.660(d, lH), 9.548(S, lH). N- (2-iJ 5-fluorophenyl) -4((4- (4-bromophenyl) pyrimidin-2-) methyl) benzyl BtJfe (compound 36)
1HNMR(DMSO-d6)(5ppm) ： 4.574(s,2H) , 5.168(s,2H) , 6.361-6.395(m,lH) ， 6.531-6.566(dd,lH) , 7.086-7.102(d,lH) , 7.602-7.62 l(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,lH), 9.580 (s,lH)。6Z
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EXAMPLE 6 Synthesis of N- (2-E-5-L-phenyl) -3- (4- ((4-A LJ ^) methyl) phenyl-allylene (Compound 39)
Step 1, synthesizing 3- (4- ((4-methoxyphenyl amino) radical) phenyl) acrylic acid ester hydrochloride
Dissolving 2g of p-aminoanisole and 3.09g of 4-aldehyde cinnamic acid ester in 15ml of alcohol, adding 3.07g of NaBH4 in batches under ice bath, dropwise 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, decompressing and removing the solvent, distributing residues in ethyl acetate/water, adjusting the acidity with 2N hydrochloric acid, precipitating a large amount of white solid, filtering, and drying to obtain 3.10g of white solid.
Step 2, synthesizing 3- (4- ((4- oxyphenylamino) radical) phenyl) acrylic acid
Suspending 3.10g of the product obtained in the step 2 in 8ml of THF/8 ml of water, adding 0.66 g of lithium oxide, stirring at room temperature overnight, performing thin layer chromatography to indicate 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, synthesizing N- (2-amino-5-fluorophenyl) -3- (4- ((4- oxyphenylamino) methyl) phenylacrylamide (compound 39), dissolving 2.50g of the product in the step 3 and 1.44g of N, N-carbonyldiimidazole in 10ml of anhydrous tetrahydrofuran, reacting at 45 ℃ for 1.5h, cooling 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 l.Olg of trifluoroacetic acid, dropwise adding the spare reaction liquid, 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 precipitating '(H is less'b) 6S-0 Ethyl ' im ^ iYL-WL ' (ΐ ^ 6' ί - ς ' ί ' (H ' P ^ OHO ' A ' (H Γ Pi) ς 8.9. ΐ 8.9 ' (H b) is less than 9'9-0S 9' (H Γ Pi)&) ·9·εε·9 '(HZ^LZ^ '(ΗΓΡ)ΐε "0£ (9p-OSWa)¾iMNHl£
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EXAMPLE 7 Synthesis of 6- (4-nail, North, N- (2-J-5-fluorophenyl) -nicotinic acid (Compound 42)
Step 1. Synthesis of 6- (4- -oxybenzylamine) nicotinic acid
G of 6-chloronicotinic acid, 1.26g of p- oxybenzylamine, 1.3g K2C03Adding 20ml of anhydrous DMF into a reaction bottle, heating to 150 ℃, reacting for 6h, after the reaction is finished by thin layer chromatography, adding a proper amount of water into the reaction bottle, extracting once by using ethyl acetate, adjusting the pH of a water layer to 6-7 by using 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. C;
step 2. Synthesis of 6- (4-methoxybenzylamino) -N- (2-amino-5-fluorophenyl) -nicotinic acid amide (Compound 42)
Lg of the product of step 1, 0.64g N, N-carbonyldiimidazole was dissolved in 8ml of anhydrous tetrahydrofuran, reacted at 45 ℃ for 1.5h, and cooled for use. Taking another dry 100ml three-neck bottle, under the protection of nitrogen, dissolving 0.6g of 4-fluoro-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran, dropwise adding 0.44g 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 at a ratio of 3:2, concentrating the eluent, and performing crystallization to obtain 0.31g of white solid.
' HNMRCDMSO-de) (6ppm): 3.715(S,3H), 4.529-4.543(d,2H), 5.266(S,2H), 6.302-6.345(m, lH), 6.487-6.522(dd, lH), 6.623-6.654(q, lH), 6.862-6.883(d,2H), 7.011-7.049(q, lH), 7.248-7.269(d,2H), 8.191-8.207(m,2H), 8.516(t, lH), 9.554(S, lH). Synthesis of the following Compounds 43-44, 76 lemon as in example 7 (Compound 42)
N- (2-5-L phenyl) -6- ((3, 4-methylenebis HS ^ yl) methyl SJ nicotinic SUfe (Compound 43)
1HNMR(DMSO-d6) (5ppm) ： 4.512-4.526(d,2H) ， 5.253(s,2H) ， 5.961(s,2H) ， 6.305-6.348(m,lH) , 6.491-6.656(m,2H) , 6.814-7.059(m,4H) , 8.187-8.203(m,2H)， 8.491-8.519(t,lH), 9.543(s,lH)。
N- (2-iJ > -5- | Lphenyl) -6- (2- (1H-indol-3-yl) ethyl J ^ nicotinic StJfe (compound 44)
'HNMRCDMSO-deXappm)： 2.964-2.983(t,2H) , 3.690-3.704(q,2H) , 5.222(s,2H) , 6.316-6.359(m,lH) , 6.498-6.620(m,2H), 6.964-7.172(m,4H) , 7.313-7.333(d,lH) ,7.573-7.593(d,lH), 8.114-8.288(m,3H), 9.486(s,lH), 10.796(s，lH)。
6- (2-benzyl) ethyl ^ -N- (2-5-fluorophenyl) -nicotinic Sfe fe (compound 76)
'HNMR(DMSO-d6) (8ppm)： 2.853-2.871(m,2H) , 3.633-3.648(t,2H) , 5.28(s,2H) , 6.331-6.334(q,lH) , 6.599-6.630(q,2H), 7.253-7.285(q,6H) ， 8.213-8.225(q,3H) , 9.499(s，lH)。
cl¾cl
Compound 79
Compound 77
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Compound 78
Compound 81
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Example 8 Synthesis of Ν - (2- | ^ -5-fluorophenyl) -5- ((3, 4-methylene-two-phenyl) methyl a ^ -l) -benzofuran-2-a su amine (Compound 45)
Step 1. Synthesis of 5-nitrobenzofuran-2- acid Ethyl ester
1.0g of 2-hydroxy-5-nitrobenzene aldehyde and 1.65 g of K2C03Dissolving in 20ml of N, N-dimethylformamide, stirring at room temperature for reaction for lh, then slowly dropwise adding 0.67 ethyl bromoacetate, heating to 80 ℃ after the addition, reacting for 3h, carrying out chromatography on a thin layer to show that the reaction is finished, cooling, adding water to dilute the reaction solution, and filtering to obtain 1.53g of a yellow gray solid.
Step 2. Synthesis of 5-Aminophenylfuran-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 added20 and 0.15ml of 30% HC1, after addition, the temperature is raised to 100 ℃ and the mixture is refluxed lh. Maintaining the temperature, adding 1.5g of ethyl 5-nitrobenzofuran-2- (product of step one), 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, and collecting anhydrous MgS04Drying, filtering and recovering ethyl acetate under reduced pressure to obtain 1.16g of a light yellow oily substance, step 3, synthesizing ethyl 5- ((3,4- dioxyphenyl) ylamino) benzofuran-2- acid hydrochloride
Dissolving 3,4- dioxybenzene aldehyde 1.10g and the product of the step 2 1.50g in ml of alcohol, adding NaB 3.07g in batches in 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 pH to be acidic by 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- acid
Suspending 1.56g of the product of the step 3 in 8ml of tetrahydrofuran/8 ml of water, adding 0.53 g of lithium hydroxide, stirring overnight at room temperature, 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 to 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-fluorophenylyl) -5- ((3, 4-phenylene dioxyphenyl) ylamino) -benzofuran-2- amide (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 the temperature of 45 ℃, and cooled for later use. Taking another three-necked flask, dissolving 0.33 g 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 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 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 ℃;
'HNMR(DMSO-d6) (Sppm): 4.195-4.210(d,2H), 5.253(s,2H), 5.971(s,2H), 6.150-6.180(t, lH), 6.338-6.381(m, lH), 6.520-6.556(dd, lH), 6.727-6.733(d, lH), 6.848-6.874(m,3H), 6.953-6.955(d, lH), 7.099-7.137(q, lH), 7.376-7.398(d, lH), 7.422(s, lH), 9.656(s, lH). The following Synthesis procedures for Compounds 46-50, 77-81 were carried out as in example 8 (Compound 45)
N- (2- -5-fluorophenyl) -5- (4- (dimethylbenzyl-2-methylfuroate-2-methyl-SUfe (Compound 46)
nHNMR(DMSO-d6) (Sppm)： 2.854(s,6H) , 4.145-4.159(d,2H)， 5.250(s,2H) , 6.007-6.035(t,lH) , 6.338-6.373(m,lH)， 6.521-6.549(dd,lH)， 6.686-6.738(q,3H) , 6.855-6.883(dd,lH), 7.101-7.224(m,3H), 7.362-7.384(d,lH), 7.439(s,lH), 9.649(s，lH)。
N- (2-J ^ -5-fluorophenyl) -5- (4-peaceful benzyl-benzofuroyl-2-methyl (compound 47)
HNMR(DMSO-d6) (Sppm) : 4.280-4.294(d,2H) , 5.253(s,2H) , 6.221 -6.25 l(t,lH) , 6.338-6.380(m,lH) , 6.521-6.556(dd,lH) , 6.726-6.731(d,lH) , 6.856-6.885(dd,lH) , 7.099-7.175(m,3H), 7.382-7.448(m,4H), 9.657(s,lH)。
N- (2-g ^ -5-fluorophenyl) -5- (2-fluorobenzyl) -benzofuran-2-carboxamide (Compound 48)
1HNMR(DMSO-d6) (δρριη)： 4.34-4.35(d,2H) , 5.25(s,2H) , 6.17-6.20(t,lH) , 6.35-6.38(m,lH), 6.52-6.55(dd,lH), 6.75-6.76(d,lH), 6.88-6.90(dd,lH), 7.11-7.45(m,7H), 9.66(s,lH)。
N- (2- -5-fluorophenyl) -5- (2-chlorobenzoic acid benzofuran-2-carboxylic acid sodium salt (Compound 49)
1HNMR(DMSO-d6) (Sppm)： 4.37-4.38(d,2H) , 5.25(s,2H)， 6.29-6.36(m,2H)， 6.52-6.55(dd,iH), 6.67-6.20(d,lH), 6.87-6.89(dd,lH), 7.1 l-7.13(q,lH), 7.28-7.48(m,6H),9.66(s，lH)。
N- (2- -5-fluorophenyl) -5- (2, 4-dichlorobenzyl benzofuran-2-methyl StJfe (Compound 50)
'HNMR(DMSO-d6) (5ppm) ： 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,lH), 7.10-7.14(q,lH), 7.41-7.45(m,4H), 7.63-7.64(d,lH), 9.67(s,lH)。
N- (2- -5-fluorophenyl) -5- (3, 4-difluorophenylbenzofuran-2-methyl-SUfe (Compound 77)
'HNMRCDMSO-de) (8ppm)： 4.292-4.306(d,2H) , 5.271(s，2H) , 6.317-6.377(q,2H) , 6.513-6.548(dd,lH) , 6.714-6.720(d,lH)， 6.847-6.875(dd,lH)， 7.086-7.123(t,lH) , 7.248(s,lH), 7.378-7.450(q,4H), 9.688(s，lH)。
N- (2-J ^ -5-fluorophenyl) -5- (2-methylbenzene J-benzofuoron-2-methyl (Compound 78)
•HNMRCDMSO-de) (6ppm) ： 3.853(s,3H) ， 4.246-4.261 (d,2H) ， 5.250(s,2H), 6.024-6.054(m,lH) , 6.339-6.381(q,lH) , 6.522-6.557(dd,lH) , 6.687-6.692(d,lH) , 6.859-6.902(q,2H) ， 7.002-7.022(d,lH) ， 7.100-7.138(t,lH) ， 7.212-7.296(q,2H) , 7.379-7.44 l(q,2H), 9.658(s,lH).
N- (2-J > -5-fluorophenyl) -5- (4-methyl-1 ^ a) -benzofuroate-2-methyl-SUfe (compound 79)
1HNMR(DMSO-d6) (5ppm) ： 3.724(s,3H) ， 4.207-4.222(d,2H) , 5.275(s,2H), 6.150-6.179(m,lH) , 6.338-6.381(q,lH) , 6.518-6.553(dd,lH) , 6.723-6.728(d,lH) , 6.855-6.909(q,3H), 7.092-7.130(t,lH), 7.307-7.443(q,4H)， 9.686(s,lH)。
N- (2-i-5-elephant-phenyl) -5- (3, 4-dimethyl L ^ L jia ^ -benzofuxue-2- SUfe (Compound 80)
'HNMR(DMSO-d6) (5ppm) ： 3.737(s,6H) ， 4.201 -4.215(d,2H) ， 5.276(s,2H), 6.156-6.157(m,lH) , 6.352-6.359(q,lH) , 6.515-6.550(dd,lH)， 6.740-6.745(d,lH) , 6.885-6.91 l(q,3H) , 7.015-7.016(d,lH) ， 7.090-7.128(t,lH) , 7.379-7.45 l(q,2H) , 9.687(s,lH)。
N- (2-J-5-fluorophenyl) -5- (pyridin-3-yl-methyl ^) -benzofuran-2-methyl SUfe (Compound 81)
'HNMRCDMSO-d^ (5ppm): 4.332-4.347(d,2H), 5.276(s,2H), 6.309-6.358 (q,2H) , 6.513-6.549(dd,lH) , 6.764-6.770(d,lH) , 6.868-6.898(dd,lH) ， 7.087-7.125(t,lH), 7.356-7.45 l(q,3H), 7.780-7.800(q,lH), 8.443-8.455(dd,lH), 8.622-8.627(d,lH), 9.694(s，lH).
Compound 97 compound 98 compound 100 compound 102
^9
Example 9 Synthesis of Ν - (2- | ^ -5-Methylofenap-phenyl) -4((4- (py-3-yl) pyrimidin-2- | methyl) benzamide (compound 97)
Step 1. Synthesis of 3, 3-bis -ylamino-1-pyridin-3-yl-propenone
2g of 3-acetylpyrazine1Microspheres: dissolving in 5ml of anhydrous DMF, adding 5ml of DMAPDMA into the solution, heating to 110 ℃ for reaction for 3 hours after the addition is finished, reducing pressure to recover DMF after the reaction is finished by thin layer chromatography, putting the residual solution in a refrigerator overnight to precipitate yellow solid, performing suction filtration, and washing with ethyl acetate/petroleum ether at a ratio of 1:1 to obtain 2.05g of yellow solid.
Melting point of the product m.p.82-83 ℃ MS (FAB);
step 2. Synthesis of 4-guanidinomethyl-benzene acid
2g of -yl isothiourea sulfate was dissolved in 10ml of Imol/LNaOH aqueous solution, 2.15g of 4-amino benzoic acid was slowly dropped under ice bath, and after the addition was completed, the reaction was stirred at room temperature overnight to precipitate a white solid, which was then filtered and dried to obtain 2.56g of a white solid.
Step 3 Synthesis of 4- [ (4-pyridin-3-yl-pyrimidin-2-yl-amino) - -yl ] benzene acid
Dissolving 1.57g of the product of the step 1 and 1.88g of the product of the step 2 in 10ml of isopropanol, adding 1.26g K2C03, heating and refluxing for 12h after the addition is finished, and performing thin layer chromatography to show that the reaction is finished, cooling, filtering and drying 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) yl) benzoyl compound 1) lg of the product of step 3, 0.54g of N, N-carbonyldiimidazole were 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 a standby reaction solution, stirring at room temperature overnight, displaying the end of the reaction by thin layer chromatography, recovering the solvent under reduced pressure, washing residues by silica gel column and ethyl acetate/petroleum gel/ethanol 2:1:2, concentrating the eluent, and crystallizing to obtain 0.28g of white solid.
The melting point of the product is m.p. 165-167 ℃;
lHNMR (DMSO-d6) (ppm) 3.641-3.670 (d,3H), 4.636-4.649 (d,2H), 5.212(s,2H), 6.150-6.178 (dd, lH), 6.330-6.337 (d, lH), delta 6.969-6.991 (d, lH), 7.262-7.274(d, lH), 7.492-7.531(m,3H), 7.901-8.045(m,3H), 8.407-8.420(d,2H), 8.680-8.690(d, lH), 9.246 (s, lH), 9.475 (d, lH) the compounds of examples 98-102 were synthesized according to the procedure of example 9
N- (2- · Lambda-5-methyl radon phenyl) -4((4- (4-ethyl) pyrimidylmethyl) benzene (compound 98)
The melting point of the product is m.p.215-217 ℃;
'HNMR(DMSO-d6) (5ppm) ： 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,lH), 6.334-6.340(d,lH),
6.997-7.104(m,4H), 7.453-7.473(d,2H), 7.751-8.048(m，5H), 8.277-8.289(d,lH), 9.443(s，lH)。
n- (2-microspheres of Lambda-5-methoxyphenyl) -4((4- (4-methylphenyl) pyrimidin-2-ylmethyl) benzene SUfe (compound 99) product melting point m.p.83-186 ℃;
'HNMRCDMSO-de) (δρριη) ： 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,lH) , 6.333-6.339(d,lH) , 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，lH)。
n- (2-J ^ -5-methyl phenyl) -4((4- (4-fluorophenyl) pyrimidine-2-1 ^) methyl) benzene SUfe (compound 100) product melting point m.p.219-222 ℃;
1HNMR(DMSO-d6) (δρριη) ： 4.361-3.670(s,3H), 3.903(s,3H), 4.616-4.63 l(d,2H), 4.901 (s,2H), 6.151-6.180(dd, 1 H),6.330-6.337(d, 1 H)， 6.968-6.990(d, 1 H)，
7.162-7.277(m,2H), 7.474(m,2H), 7.898-7.944(m,5H), 8.315-8.328(d,lH),
n- (2-IL ^ -5-methoxyphenyl) -4((4- (4, 5-difluorophenyl) pyrimidin-2-methyl) phenyl SUfe (compound 101)
1HNMR(DMSO-d6) (5ppm)： 3.63-3.672(s,3H), 4.629-4.644(d,2H), 4.879(s,2H), 6.154-6.182(dd,lH), 6.334-6.341(d,lH), 6.974-6.996(d,lH), 7.217-7.230(d,lH), 7.457-7.580(m,3H), 7.900-7.967(m,4H), 8.121(m,lH), 8.381-8.393(d,lH),
N- (2-J ^ -5-methoxyphenyl) -4((4- (4-bromophenyl) pyrimidylmethyl) benzene SU ^ (compound 102)
The melting point of the product is m.p.212-215 ℃;
'HNMR(DMSO-d6) (Sppm) : 3.565-3.673 (s,3H) , 4.629-4.644(d,2H) , 4.833 ( s,2H ) ， 6.156-6.184(dd,lH), 6.339-6.345(d，lH)， 6.980-7.00 l(dd,lH), 7.177-7.191 (d,lH), 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,lH), 9.451(s,lH)。
compound 96 Ar = X2=F A=CH3Compound 103 Ar = X2= F A = H compound 104 Ar = X2= F A = H compound 105X2=F A=H
Compound 106 Ar = X2=F A=H
Compound 107 Ar = X2= F A = H compound 108 Ar = X2=F A=H
MeO'^OMe
Compound 109 Ar = Or X2=OCH3A=CH3
Compound 110 Ar = X2=OCH3A=CH3
OMe
Compound 111 Ar = X2=F A=CH3Compound 112 Ar = X2=F A=CH3Compound 113 Ar = X2=OCH3A=CH3
Compound 114 Ar = X2=F A=CH3
Compound 115 Ar = X2=F A=CH3
Compound 116 Ar = X2=F A=CH3
MeOA^OMe
Compound 123 Ar = X2=OCH3A=H
MeO^^OMe
Formula 10
Example 10 Synthesis of N- (2-IL ^ -5-Methylphenyl) -4 ((6-phenylpyrimidine-4-J methyl) benzyl SUfe (Compound 91) step 1 Synthesis of methyl Paraminobenzoate hydrochloride
Weighing 2g of p-amino -phenyl acid, suspending the p-amino -phenyl acid in 100ml of alcohol, slowly adding 2ml of thionyl chloride dropwise in ice bath , continuously stirring at room temperature for reaction for 3 hours after the addition is finished, and then 5(TC refluxing reaction for 3 hours, point-plate reaction is basically complete, ethyl acetate extraction, saturated sodium carbonate washing, magnesium sulfate drying, concentration and crystallization are carried out to obtain 2.05g of white solid.
Step 2. Synthesis of ester of 4- ((6-chloropyrimidin-4-amino) -yl) benzene acid
9.5g of p-aminobenzene -ylbenzene acid ester hydrochloride was dissolved in 250ml of a mixed solution of THF/DMF (=5: l), 20ml of triethylamine was added dropwise to obtain a suspension, 7g of 4, 6-dichloropyrimidine was added to the suspension, the suspension was stirred at 70 ℃ and refluxed for reaction for 15 hours, and a precipitated white solid was precipitated, and the precipitate was filtered, washed with water, and dried to obtain 13.8g of a white solid.
Step 3. Synthesis of 4- ((6-phenylpyrimidine-4-amino) methyl) benzoic acid
0.2836g of triphenylphosphine and 0.1214g of palladium acetate are weighed and dissolved in 10ml of 4-dioxane, the mixture reacts for 1 hour at 80 ℃ under the protection of nitrogen, 50ml of mixed solvent of ethyl 1/water (= 3: 2) is added after the reaction of spotting plates is completed, 1.5g of 4- ((6-chloropyrimidine-4-amino) -yl) benzene methyl ester, 1.12g of potassium carbonate and 0.1 g of sodium bromide are added for the reaction at 90 ℃, 0.79g of phenylboronic acid is added after half an hour, the reaction is carried out overnight, the spotting plates are completely reacted, the mixture is cooled to 60 ℃, is subjected to suction filtration and suspension evaporation, hydrochloric acid is used for regulating pH =5-6 to generate a large amount of solid, and the product is obtained after the suction filtration and drying.
Step 4 Synthesis of N- (2-amino-5- -oxyphenyl) -4 ((6-phenylpyrimidin-4-amino) -yl) benzamide
Dissolving 4g of- ((6-phenylpyrimidine-4-J yl) benzene acid and 0.16g N, N-carbonyldiimidazole in 8ml of anhydrous tetrahydrofuran, carrying out reflux reaction at 50 ℃ for 1.5h, cooling for later use, taking another dry 100ml three-necked bottle, dissolving 0.14g of 4- oxy-1, 2-phenylenediamine in 7ml of anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.12g of trifluoroacetic acid, dropwise adding the later used reaction liquid, stirring at room temperature overnight, recovering the solvent under reduced pressure, washing residues with silica gel column, ethyl acetate/ethanol 7:1, concentrating eluent, and crystallizing to obtain 0.15 g of white solid.
'HNMR(DMSO-d6) (6ppm) 3.650-3.677 (s,3H), 4.633-4.675 (d,2H), 4.895(s,2H), 6.168-6.189(dd, lH), 6.344-6.350(d, lH), 6.989-7.026 (d,2H), 7.050-7.502(m,6H), 7.926-8.060(m,6H), 8.515(s, lH), 9.477 (s, lH). The following synthesis procedures for compounds 92-96, 103-119, 123-124 were the same as in example 10 (compound 91).
N- (2-J-5-formol phenyl) -4((6- (3-methyl) sneeze-4-methyl) benzyl) SUfe (compound 92)
'HNMRCDMSO-d^) (5ppm): 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,lH)， 6.339 -6.346(d,lH) , 6.984-7.038(m,3H) , 7.388-7.564(m,5H), 7.919-8.032(m,3H), 8.506(s,lH), 9.471(s，lH)。
N- (2-J ^ -5-methoxyphenyl) -4((6- (4-methyl) pyrimidin-4-HJ methyl) benzyl SUfe (compound 93)
'HNMRCDMSO-de) (5ppm)： 3.674 (s,3H) , 3.815(s,3H) , 4.644-4.656 ( d,2H ) ， 4.892(s,2H)， 6.165-6.186(dd,lH)， 6.339-6.346(d,lH)， 6.983-7.052 (m,4H)， 7.39-7.59(d,2H), 7.917-7.980(dd,5H), 8.460(s,lH), 9.496(s,lH)。
N- (2- · 5-methoxyphenyl) -4((6- (3-piri- ^) pyrim-4-methyl) benzyl StJ ^ (compound 94)
1HNMR(DMSO-d6) (6ppm): 3.647-3.674 (s,3H)， 4.667-4.68 l(d,2H) , 4.892 ( s,2H ) , 6.165-6.187(dd,lH), 6.339 -6.346(d,lH), 6.984-7.096 (m,2H)， 7.449-7.527(m,3H),7.922-7.943(d,2H), 8.130-8.162(t,lH), 8.334-8.353(d,lH) , 8.544-8.678(m,2H) ， 9.196 (s,lH) , 9.473 (s，lH)。
N- (2-J ^ -5-methyl radon phenyl) -4((6- (3, 4-methylene-phenyl) pyrimidine-4-) methyl) benzyl (compound 95)
'HNMRCDMSO-de) (5ppm): 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,lH) , 6.338-6.345 (s,lH)， 7.004-7.03 l(m,3H) , 7.435-7.541(m，4H)， 7.915-7.935(m,3H), 8.450 (s，lH) , 9.468(s，lH)。
N- (2-H ^ -5-L phenyl) -4 ((6-phenylpyrimidin-4-methyl) benzyl BUfe (compound 103)
1HNMR(DMSO-de) (6ppm): 4.665-4.667 (s,2H), 5.205(s,2H) , 6.330-6.373 ( m,lH ) , 6.516-6.55 l(dd,lH) , 7.026(s,lH) ， 7.085-7.122(t,lH) , 7.478-7.502(m,6H) , 7.930-8.066(m,6H), 8.514(s,lH), 9.535(s，lH)。
N- (2-J > -5-fluorophenyl) -4((6- (3-methoxy | J. yl) pyrimidin-4-ylmethyl) benzoic acid anhydride (Compound 104)
'HNMR(DMSO-d6) (5ppm): 3.821(s,3H), 4.661-4.673 (s,2H), 5.226 (s,2H), 6.330-6.373(m, lH), 6.517-6.546(dd, lH), 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, lH), 8.506 (s, lH), 9.556 (s, lH). N- (2-5-fluorophenyl) -4((6- (4-methyl) pyrimidin-4-ylmethyl) benzyl ^ (compound 105)
'HNMR(DMSO-d6) (5ppm)： 3.815(s,3H) , 4.646-4.660 (s,2H) , 5.203 ( s,2H ) , 6.328-6.371(m,lH) , 6.513-6.548(dd,lH) , 6.942-7.119(m，4H) , 7.448-7.468(d,2H) , 7.924-7.98 l(m,5H), 8.458-8.3460(s,lH), 9.531(s,lH)。
N- (2-J-5-L-phenyl) -4((6- (3-pyranyl) pyrimidylmethyl) phenylmethyl Sfc amine (Compound 106)
1HNMR(DMSO-d6) (5ppm)： 4.669-4.682(s，2H) , 5.202(s,2H) , 6.342-6.349(m,lH) , 6.511-6.547(dd,lH), 7.079-7.117(t,2H) , 7.454-7.535(m,3H)， 7.927-7.948(d,2H) , 8.135-8.165 (t,lH), 8.334-8.354 (d,lH) ， 8.544-8.674(m,2H), 9.170 (s,lH) ， 9.532 (s,lH)。
N- (2- | Fahrenheit-5-fluorophenyl) -4((6- (3, 4-methylenedili ^ yl) pyrimidine-4-J methyl) benzoic acid (Compound 107) 1HNMR (DMSO-d6) (6ppm): 4.643-4.825(d,2H), 5.201 (s,2H), 6.093(s,2H), 6.328-6.371(m, lH), 6.512-6.547(dd, lH), 6.924-7.118(m,3H), 7.446-7.586(m,5H), 7.921-7.974(m,4H), 8.450 (s, lH), 9.527(s, lH).
N- (2- ^ -5-fluorophenyl) -4((6- (2, 4-dimethoxyphenyl) pyrimidinylmethyl) benzeneMethylamine (Compound 108)' H MR (DMSO-d)6) (6ppm)： 3.818-.083(d,6H), 4.607(s,2H) ，5.201 ( s,2H ) , 6.330-6.373(m,lH) , 6.514-6.655(m,3H) , 7.084-7.12 l(q,2H)， 7.436-7.457(d,2H) , 7.913-7.964(m,4H), 8.432(s,lH), 9.533 (s,lH) 。
N- (2-5-Methylphenyl ((2-methyl-6-phenylpyrimidine-4-41 ^) methyl) benzyl « Jfe (Compound 109)
1HNMR(DMSO-d6) (5ppm): 2.416-2.505(s,3H), 3.674(s,3H) , 4.658 ( s,2H ) , 4.892(s,2H), 6.158-6.186(dd,lH)， 6.339-6.346(d,lH)， 6.822(s,lH)， 6.984-7.005(d,lH)， 7.463-7.474(m,5H), 7.923-7.993 (m,5H), 9.473 (s,lH) „
N- (2-SJ-5-MethylH ^ yl) -4((6- (3-methylphenyl) -2-methylpyrimidin-4-methyl) benzyl SUfe (Compound 110)
^MRCDMSO-de) (5ppm): 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,lH), 6.339-6.345(d,lH), 6.813(d,lH), 6.982-7.046(m,2H), 7.388-7.548 (m,5H),。 7.883-7.941(t,3H) , 9.472(s,lH) 。
N- (2-amino-5-methoxyphenyl) -4 ((2-methyl-6- (3, 4-methylenedioxyphenyl) pyrimidin-4-amino) methyl) phen-yl St-amine (compound 113)
^MRCDMSO-de) (6ppm): 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,lH) , 6.729(s,lH) , 6.982-7.010(q,2H) , 7.445-7.576(m,4H), 7.810-7.936(t,3H), 9.467 (s，lH) 。
N- (2-lL ^ -5-fluorophenyl) -4- ((2-methyl-6-phenylpyrimidine-4-J methyl) benzathine (Compound 96)
^MRCDMSO-de) (6ppm) : 2.415(s,3H) , 4.652(s,2H) , 5.201(s,2H), 6.349(m,lH) , 6.511-6.546(dd,lH) , 6.781-6.822(s,lH) , 7.079-7.117(t,lH) , 7.413-7.480(d,6H) , 7.905-7.992(m,5H), 9.532(s,lH)。
N- (2-amino-5-fluorophenyl) -4- ((6- (3-methoxyphenyl) -2-methylpyrimidin-4-amino) methyl) benzamide (compound 111)
1HNMR(DMSO-d6) (δρρπι): 2.496(s,3H), 3.815(s,3H), 4.646-4.658(s,2H), 5.202(s,2H), 6.328-6.371(m,lH) , 6.511-6.546(dd,lH) , 6.824-6.835(s,lH)， 7.019-7.100(m,2H) , 7.369-7.548(m,5H), 7.888-7.947 (ds,3H), 9.532(s,lH)。
N- (2-amino-5-fluorophenyl) -4- ((6- (4-methoxyphenyl) -2- -ylpyrimidin-4-amino) yl) benzamide (compound 112)
, (5ppm)： 2.497(s,3H) , 3.808(s,3H) , 4.632(d,2H), 5.200(s,2H)， 6.328-6.370(m,lH) , 6.511-6.546(dd,lH) ， 6.742(s,lH) , 7.010-7.166(m,3H) , 7.4-32-7.476(m,2H), 7.924-7.962(t,5H), 9.529(s,lH)。
N- (2-E-5-fluorophenyl) -4- ((2-methyl-6- (3-pyrazoyl) pyrimidine-4-a) methyl) benzamide (compound 114) tamRCDMSO-dg) (5ppm) 2.497(s,3H), 4.664(s,2H), 5.601 (s,2H), 6.328-6.370(m, lH), 6.511-6.546(dd, lH), 6.903(s, lH), 7.080-7.166(t,3H), 7.466-7.513(m,3H), 7.929-8.005(sd,3H), 8.314-8.33(d, lH), 8.643-8.655(dd, lH), 9.144(s, lH), 9.534(s, lH).
N- (2-5-fluorophenyl) -4- ((6- (3, 4-methylenebis _ North' en phenyl) -2-methylpyrimidine-4- methyl) benzamide (Compound 115)
^MRCDMSO-de) (5ppm) ： 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,lH), 6.511-6.546 (dd,lH), 6.728 (s,lH) ,6.990-7.116 (td,2H), 7.453-7.576(td,4H), 7.818 -7.942 (ds,3H), 9.526(s,lH)。
N- (2-J ^ -5-fluorophenyl) -4- ((6- (2, 4-dimethylphenyl) -2-methylpyrimidine-4-J ^ methyl) benzamide (compound 116)
^MRCDMSO-de) (5ppm) : 2.365(s，3H) , 3.810(s,6H) , 4.592 (s,2H), 5.201(s,2H) , 6.331-6.374(m,lH) , 6.515-6.551(dd,lH) , 6.601 -6.633(q,2H) , 7.084-7.121 (q,2H) ,7.444-7.465 (d,2H)， 7.766-7.780 (t,lH), 7.919-7.952(m,3H), 9.537(s,lH)。
N- (2-J ^ -5-methylphenyl) -4- ((6- (2, 4-dimethyl H > phenyl) sneeze-4-peaceful methyl) benzyl SU ^ (compound 123)
^MRCDMSO-de) (8ppm): 3.674(s,3H), 3.818-3.856(s,6H), 4.628(s,2H), 4.923(s,2H), 6.158-6.186(dd,lH)， 6.337-6.344(d,lH) , 6.625-6.658(m,2H)， 6.979-7.00 l(d,lH) , 7.229(s,lH), 7.427-7.447(d,2H), 7.924-7.970(m,4H) , 8.434(s,lH), 9.510(s，lH)。
Formula 11
N- (2-H ^ -5-fluorophenyl) -4- ((6- (4-methyl HJ ^ yl) 2-11^) yl) benzyl Stife (compound 117)
'HNMR(DMSO-d6) (5ppm) ： 3.799(s,3H) , 4.648-4.663(d,2H) ， 5.196 (s,2H), 6.325-6.361(m,lH) , 6.511-6.539(dd,lH) , 7.011-7.097(td,3H) , 7.503-7.523(d,2H) , 7.727-7.756(t,lH), 7.899-7.968 (m,5H), 8.246(s,lH), 9.521 (s，lH)。
N- (2-5-methoxyphenyl) -4- ((6- (4-methyl) methoxy-2-methyl) benzoic acid StJfe (Compound 118)' HNMRCDMSO-de) (delta rho η iota): 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, lH), 6.334-6.34 l (d, lH), 6.975-7.023(t,3H), 7.491-7.51 l (d,2H), 7.718-7.748(t, lH), 7.894-7.966(m,5H), 8.242(s, lH), 9.457(s, lH).
N- (2-amino-5-fluorophenyl) -4- ((6- (3, 4-methyleneradonylphenyl) combing oxazin-2-yl) methyl) benzamide (compound 119)
•HNMRCDMSO-de) (5ppm) ： 4.638-4.653(d,2H) ， 5.193(s,2H) , 6.066(s,2H), 6.323-6.365(m,lH) , 6.507-6.535(dd,lH) , 6.978-7.110(m,2H) , 7.491-7.535(m,4H) , 7.746-7.775(t,lH), 7.909-7.94 l(t,3H), 8.239(s,lH), 9.519(s，lH)。
N- (2-tJ-5-fluorophenyl) -4- ((6-phenylfc 2-J methyl) phenylmethyl SUft (Compound 124)
'HNMRiDMSO-de) (6ppm)： 4.662-4.676(d,2H) , 5.224(s,2H) , 6.324-6.366(m,lH), 6.503-6.53 l(dd,lH) , 7.080-70102(q,lH) , 7.436-7.529(m,5H) , 7.928-8.018(m,6H) ,8.315(s,lH), 9.550(s,lH)。
SOC1,
COOH CH3OH H HCC11 ^COOMe R R 1
I N
COOMe HN LiOH
SOCl2COOMe
DMF NEt, /DMF THF / H20
Compound 120X2=OCH3R!=R2=OCH3Compound 1212=F R!=R2=OCH3^ 12
EXAMPLE 12 Synthesis of N- (2-H ^ -5-methyl HJJ ^ yl) -4- ((6, 7-dimethylquinacrifylmethyl) benzyl (Compound 120)
Step 1. Synthesis of p-aminomethyl benzene acid ester hydrochloride
The synthesis was as in step 1 of example 10
Step 2, synthesizing 2-amino-4, 5-di oxyphenol acid ester
15g of ester of 4, 5-bis -oxy-2-nitrophenyl -carboxylic acid, 0.86g of ferric chloride and 3g of dried activated carbon were added
Heating to 80 ℃ in 150ml of ethanol under the protection of nitrogen, refluxing for 0.5h, cooling to 60 ℃, slowly dripping 10ml of hydrazine hydrate (85%) into of the reaction solution, continuously refluxing for 3h after dripping, showing that the reaction is finished by thin layer chromatography, filtering the reaction solution while the reaction solution is 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 the light yellow solid.
Step 3, synthesizing 6, 7-di oxy-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-di oxy-4-chloroquinazoline
Stirring 5.4g of a mixed solution of the product of the step 3, thionyl chloride (30 ml) and DMF (2.5 ml), 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 compound. Step 5, synthesizing 4- ((6, 7-di oxoquinoline-4-amino) group) benzoic acid ester
Adding 5.0g of the product obtained in the step 4, 4.4g of the product obtained in 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 =7 by using hydrochloric acid (2N), separating out a solid, filtering and drying to obtain the product. Step 6 Synthesis of 4- ((6, 7-bis oxoquinazolin-4-amino) yl) benzene carboxylic acid
And (3) stirring and reacting the mixed solution of 6.4g of the step 5 product, 2.3g of lithium hydroxide, 40ml of THF and 20ml of water at 30 ℃ for 4h, displaying the end of the reaction by thin-layer chromatography, concentrating under reduced pressure to remove THF, adjusting the pH of the residual solution to be =3 by using hydrochloric acid (2N), precipitating white solid, and filtering and drying to obtain the lithium ion battery.
Step 7, synthesizing (2-amino-5- oxyphenyl) -4- ((6, 7-dimethoxyquinazoline-4-amino) group) benzamide,
0.4 of the product of step 6, 0.19g of N, N-carbonyldiimidazole, was dissolved in 10ml of anhydrous DMF and cooled for 1.5h at 45 ℃. Taking another dry 100ml three-necked bottle, dissolving 0.19g4- oxy-1, 2-phenylenediamine in 7ml anhydrous tetrahydrofuran under the protection of nitrogen, dropwise adding 0.44g 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, eluting the residue by silica gel column and ethyl acetate/ethanol 5:1, concentrating the eluent, and crystallizing to obtain 0.28g of white solid. To
^MRCDMSO-de) (5ppm): 3.672 ( s,3H ) ,3.902(s,6H), 4.834-4.848(d,2H), 4.915 (s,2H), 6.163-6.178(m,lH) , 6.335-6.342(dd,lH) , 6.999-7.115(m,2H) , 7.448-7.469(d,2H) , 7.674(s,lH), 7.908-7.929(t,2H), 8.320(s,lH), 8.557-8.589(t,lH), 9.497(s,lH)。
N- (2-IL ^ -5-fluorophenyl) -4- ((6, 7-di ^ quinturyl) benzathine (compound 121)
^MRCDMSO-de) (Sppm) ： ： 3.902(s,6H) , .835-4.850(d,2H) , 5.195 (s,2H), 6.343-6.350(m,lH) , 6.512-6.547(dd,lH) , 7.082-7.112(m,2H) , 7.458-7.478(d,2H) , 7.684(s,lH)， 7.912-7.952(t,2H), 8.317(s,lH)， 8.536-8.566(t5lH), 9.520(s,lH)。
Compound 122R = HX2=F
l3C.N〜、
Compound 127R = compound 128R =
^ 13
EXAMPLE 13 Synthesis of N- (2- ^ -5-fluorophenyl) -4- ((2, 4-dioxo-1, 2-dihydroquina # - [ 3 (4H) -yl) methyl) phenylmethyl StJfe (Compound 122)
Step 1 Synthesis of methyl 4- ((2-nitrobenzoylamino) methyl) benzene carboxylate
Suspending 1.6g of o-nitrobenzene acid in 15ml of redistilled alkane, slowly adding 1.28 g N, N-dicyclohexyl carbodiimide in batches under ice bath, then adding 0.66 g N-hydroxysuccinimide and a catalytic amount of 4-dimethylaminopyridine, and stirring at room temperature for later use; adding 2g of ammonia -phenylbenzene acid ester hydrochloride, 1.47ml of triethylamine and 10ml of redistilled dichloro alkane into another reaction bottle, slowly dripping the mixture into the standby reaction solution after half an hour, stirring the mixture at room temperature for two hours, indicating that the reaction is complete by TLC (thin layer chromatography), stopping the reaction, filtering, collecting filtrate, washing the filtrate with acid water for 3 times, then washing the filtrate with saturated sodium carbonate for 3 times, collecting an organic layer, drying anhydrous ^ L magnesium oxide, filtering, and concentrating the filtrate under reduced pressure to obtain 1.46g of white solid.
Step 2, synthesizing 4- ((2-nitrobenzene amido) methyl) benzene acid
The product of step 1 of U5g, 0.67g sodium hydroxide, was suspended in a 10ml tetrahydrofuran/10 ml water mixture, stirred overnight at room temperature, the solvent was removed under reduced pressure, the residue was added with an appropriate amount of water, adjusted to pH 5-6 with dilute hydrochloric acid, filtered and dried to give 0.94g of a white solid.
Step 3 Synthesis of 4- ((2-aminobenzene amido) yl) benzene acid
Suspending 0.8 g of the product of the step 2, 0.13 g 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, synthesizing 4- ((2- (ethoxycarbonyl) benzene amido) methyl) benzoic acid
Dissolving 0.62 g of the product of the step 3 in 15ml of pyridine, slowly and dropwise adding 0.24ml of ethyl chloride 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 for several times by using -dichloro-alkane, combining organic layers, drying anhydrous magnesium carbonate, filtering, concentrating under reduced pressure to obtain light yellow solid, and recrystallizing by using ethyl ester/ethanol to obtain 0.63g of white solid.
Step 5 Synthesis of 4- ((2, 4-dioxo-1, 2-dihydroquinolin-3 (4H) -yl) -yl) benzene acid
Suspending 0.50g of the product of the step 3 in 10ml of alcohol/10 ml of water mixed solution, 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 about 5-6, filtering, and drying to obtain 0.46g of white solid.
Step 6 Synthesis of N- (2-amino-5-fluorophenyl) -4- ((2, 4-dioxo-1, 2-dihydroquinazolin-3 (4H) -yl) yl) benzene amide
0.43g of the product of step 5 and 0.24g of 0.24g N, N-carbonyldiimidazole are dissolved in 8ml of anhydrous tetrahydrofuran and reacted at 50 ℃ for 1.5h with reflux and cooled until 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 after TCL shows that the reaction is finished, pouring the residue on silica gel column, eluting with ethyl acetate/ethanol 10:1, concentrating the eluent, and crystallizing to obtain 0.25 g of white solid.
1HNMR(DMSO-d6) (5ppm) ： 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, lH), 7.845-7.964(m,3H), 9.520(s, lH), 11.425(s, lH). The synthesis steps for compounds 127,128 are as in example 13 (compound 122).
N- (2-J ^ -5-fluorophenyl) -4- ((1- (2- (dimethyiazolyl) -2, 4-dioxo-1, 2-dihydroperazol 3 (4H) -yl) methyl) phenylmethylSfc amine (Compound 127)
'HNMR(DMSO-d6) (5ppm): 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,lH), 7.853-7.969(m,3H), 9.532(s,lH)„
N- (2-tJ 5-fluorophenyl) -4- ((l- (2-morpholinoethyl) -2, 4-two-peaches-1, 2-dihydrofluquinazol (4H) -yl) methyl) benzyl Bfe ^ (compound 128)
'HNMR(DMSO-d6) (5ppm): 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,lH) , 7.845-7.964(m,3H) , 9.522(s,lH)。
Example 9 growth inhibition of tumor-inhibiting sperm deer by the Compound disclosed in the present 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. A suspension of O.mu ί cells was added to each well in such a way that the number of cells per well was 10000-50000 cells/well. Different drug concentration groups of 0-500 mu m are set, and a blank control group and a solvent control group are additionally set. And (3) each concentration is provided with three repeated holes, I & ltmu & gt I & lt ^ medicaments are added into each hole, the medicaments are sequentially added according to the concentration from low to high, and the medicaments are uniformly mixed at the time of adding the medicaments. 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 GI5. Values (concentration of compound that inhibits cell growth by 50%).
TABLE 2 proliferation inhibitory Activity of Compounds on tumor cells
GI of Compound tumor cells5o (M) of normal cells. I50(μΜ)
HL60 Jurkat HepG2 SMMC-7721 MCF-7 MDA-MB-231 CCD-1059SK
MS-2750.15561.981921.100016.43643.42984.230468.4250 Compound 0.04340.713510.71122.97440.24930.1435107.38236
Compound 0.35241.645750.311311.99812.23501.448091.56744
Compound 0.1231.4603.150012.76551.40680.4817115.67011 compound 0.1971.667116.40808.97380.36841.7916120.580
9
Compound 0.0860.89345.40125.44950.94602.850386.08532
Compound 0.0750.76952.983710.86590.71081.2895140.78037
Compound 0.0940.978216.12499.78451.85483.4760102.35733
Compound 0.0560.95878.02336.15660.95611.562499.12393
Compound 0.1120.789212.36547.26550.86481.5772101.25596
Compound 0.0780.754816.12555.26130.98751.048882.165103
Compound 0.12530.988411.25658.46581.25641.254890.254104
Compound 0.18790.97248.26549.26451.80122.0566100.987105
Compound 0.09550.85429.21568.12561.56483.4698120.546107
Compound 0.09250.77859.56565.02550.78542.4869100.748110
Compound 0.06651.25635.16627.02350.45680.456187.012
111
Compound 0.05230.55248.20216.45561.25542.455685.021
1 12
Compound 0.08740.64588.8688.16651.04551.5554130.254116
Compound 0.07890.87426.6635.17420.87560.1514110.223117
Positive 0.18232.450025.375020.15474.29033.790057.6937 control drug
Thing (YX)
Positive control drug: n- (2-aminophenyl) -4- ((3, 4-dimethoxyphenyl) amino yl) benzene amide (a compound disclosed in WO2005092899, which we have synthesized according to the procedure disclosed therein)
Cell source: SMMC-7721 human liver cancer cell HepG2 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-1059SK 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).
③ preliminary stability test
A. High temperature test
2 parts of each sample of the pre-test compound are taken, an appropriate amount of each sample is placed in a weighing bottle, a thin layer with the thickness of 5mm is paved, the mixture is placed in a constant temperature box 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
Content (%) of the material at the time of radish observation
(day) control compound 6
White powder 0.2099.75
0 0.46 99.58
Powder
Light red pink white powder 0.3199.48
5 2.30 97.24
Red powder, white powder 0.4399.35
10 5.73 94.10
Powder
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 are not obviously changed, 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 ℃; lHNMR (DMSO-d6) (5ppm) 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, lH), 6.331-6.374 (m, lH), 6.515-6.550(dd, lH), 7.082-7.103(dd, lH), 7.477-7.498(d,2H), 7.917-7.938(d,2H), 9.529(s, lH).
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 (31)

  1. Claims book
    1. A compound of formula (I):
    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;
    gi is selected from a bond, T, L-T, T-L or T-L-T;
    wherein 1^ in the presence of L is 8,0, C =0 or N (R!), selected from hydrogen, alkyl, hydroxyalkyl and tert-butoxycarbonyl;
    t is d-C when present4An 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 =0 in formula I);
    y is NH2Or OH;
    X,、 X2、 X3each independently selected from hydrogen, halogen, CrC4Alkyl or d-C4Alkoxy groups and specify beta iota, x2、 x3At least one of which is not hydrogen.
  2. 2. The compound of claim 1, wherein X2Selected from fluorine or-C4 alkoxy, Xi, X3Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, d-C4Alkyl or d-C4An alkoxy group.
  3. 3. The compound of claim 2, wherein X2Is fluorine, oxy, X! X3Both are hydrogen.
  4. 4. According to the rightThe compound of claim 1, wherein G3Is absent.
  5. 5. The compound of claim 1, wherein G2Is phenylene, and
    het-d is
  6. 6. The compound of claim 1, wherein said compound has the structure of formula (I A):
    wherein:
    l is S, O or N (R1) wherein is hydrogen or-C4An alkyl group;
    R2is hydrogen or CrC4An alkyl group;
    y is-NH2or-OH;
    X2selected from fluoro C C4 alkoxy;
    het is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzimidazolyl or benzotriazolyl, each of which may be optionally substituted.
  7. 7. The compound of claim 6, wherein said compound has the structure of formula (IA-1):
    wherein:
    l is NH or S;
    p, Q, M, G and U are each independently CH or > < Lambda > and 1^1, Q, U cannot be N at the same time, as long as no more than 2 of P, Q, M, G and U are N, S or O of one ring is not adjacent to S or O on the other ring in rings containing P, Q, M, G and U;
    R2is hydrogen or d-C4An alkyl group;
    X2selected from fluorine or-C4An alkoxy group;
    the groups A and B may be the same or different and are independently selected from hydrogen, halogen, d-C4 alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy, heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio, amido, amino acyl or Z
    00S000/800ZN3/X3d ss bursa OAV
  8. 8. The compound of claim 6, wherein said compound has the structure of formula (IA-2):
    l is S or NH;
    R2is hydrogen or CrC4An alkyl group;
    X2selected from fluoro or-C4 alkoxy;
    a and B are as defined in claim 7.
  9. 9. The compound of claim 6, wherein the compound has the structure of formula (IA-3):
    l is S or NH;
    X2selected from fluoro or-01 alkoxy;
    a and B are as defined in claim 7.
  10. 10. The compound of claim 6, wherein the compound has the structure of formula (IA-4):
    wherein:
    l is S or NH;
    d is ^ -or S;
    e is N or C-A;
    R2and R3Each independently is hydrogen or d-C4An alkyl group;
    X2selected from fluorine or C, -C4An alkoxy group;
    a and B are as defined in claim 7.
  11. 11. The compound of claim 7, wherein said compound has the structure of formula (I A-5):
    wherein
    t is NH;
    X2selected from fluorine or d-C4An alkoxy group;
    a and B are as defined in claim 7.
  12. 12. The compound of claim 7, wherein said compound has the structure of formula (I A-6):
    a is hydrogen or CrC4An alkyl group;
    b is as defined in claim 7;
    X2selected from fluorine or d-C4An alkoxy group;
  13. 13. the compound of claim 7, wherein said compound has the structure of formula (I A-7):
    wherein
    P is CH, N;
    b is as defined in claim 7;
    X2selected from fluorine or d-C4An alkoxy group;
  14. 14. the compound of claim 1, wherein said compound has the structure of formula (I B):
    wherein:
    01is 1\ L-T or T-L, where 1 is 8,0 or NH; t is-CH2-;Z]Is 0, S, NH or CH2;
    Z2Is N or CH;
    X2selected from fluorine or d-C4An alkoxy group;
    het is selected from phenyl, pyridyl, pyrimidine1Microspheres comprising an aryl group, an heteroaryl group, and optionally substituted by A and 1 or B; a. B is as defined in claim 7; or Het is further optionally substituted with 1,2 or 3 groups independently selected from alkoxy, haloalkoxy, acyl, morpholino or alkoxy optionally substituted phenyl.
  15. 15. The compound of claim 1, wherein said compound has the structure of formula (I C):
    wherein:
    01is 1\ L-T or T-L;
    1^ is 8,0 or NH;
    t is-C micros-;
    Z2is N or CH;
    o, S, NH or CH2;
    X2Selected from fluorine or d-C4An alkoxy group;
    het is selected from phenyl, pyridinyl, pyrimidinyl or benzothiazolyl, and is optionally substituted by A and/or B, A, B are as defined in claim 7; or Het is further optionally substituted by 1, one or 3 groups independently selected from alkoxy, haloalkoxy, acyl, morphinyl or an optionally substituted phenyl.
  16. 16. The compound of claim 1, wherein said compound has the structure of formula (I D):
    wherein:
    het is:
    X2selected from fluorine or Ci-alkoxy.
  17. 17. The compound of claim 1, wherein said compound has the structure of formula (IE):
    y is-OH or-NH2;
    X2Selected from fluoro or-alkoxy;
    het is a heterocycle or heteroaryl, each ring containing at least one nitrogen atom as part of the ring and being optionally substituted.
  18. 18. The compound of claim 15, wherein Y is-NH2; X2Is fluorine; het is a heterocycle or heteroaryl, each ring containing at least one nitrogen atom as part of the ring and being optionally substituted by 1 or 2 substituents selected from a or B, A, B being as defined in claim 7. .
  19. 19. A compound according to claim 15, wherein Het is optionally substituted with 1 or 2 substituents independently selected from:
  20. 20. the compound of claim 1, wherein G2Is phenylene, indolyl or indolylenyl, each of which may be optionally substituted, G is a bond, -CH2-、 -0-CH2-、 -S-CH2-, -S-CH (C microspheres) -or-N (Ri) -CH2-。
  21. 21. The compound of claim 18, wherein G2Is indolyl or indolinyl;
    g is-CH2-or-N ^ -CHr;
    het is:
    MeO-or
    MeO 、
  22. 22. The compound of claim 18, wherein G3Is absent;
    G2is phenylene;
    g is-S-CH2-or-S-C (CH)3)(H)-;
    Het is:
    wherein:
    j is selected from the following groups:
    、
  23. 23. the compound of claim 1, wherein said compound has the structure of formula (I F):
    wherein:
    y is-OH or-NH2;
    X2Selected from fluorine or d-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. A compound according to claim 21, wherein Het is:
  24. 25. the compound of claim 1, wherein the compound has the structure of formula (I F-1):
    wherein:
    y is-NH2;
    X2Selected from fluoro or C! -Ct alkoxy;
    a is as defined in claim 7.
    The compound of claim 1, wherein the compound has the structure of formula (I G):
    wherein:
    het, G, Y are as defined in claim 1, X2Selected from fluorine or CrC4An alkoxy group.
  25. 27. The compound of claim 1, wherein said compound has the structure of formula (I H):
    wherein:
    l is 8, O or-NH-;
    X2selected from fluorine or CrA C4 alkoxy group;
    A. b is as defined in claim 7.
  26. 28. The compound of claim 25, wherein A is optionally substituted pyridine or optionally substituted phenyl and B is hydrogen or halogen.
  27. 29. The compound of claim 1, wherein the compound has the structure of formula (I-I):
    wherein:
    l A S, O or-NH;
    X2selected from fluorine or d-C4An alkoxy group;
    r4 is hydrogen or d-C6An alkyl group.
  28. 30. A compound of formula II:
    or a salt of a pharmaceutically acceptable acid.
    Het, which 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 ring optionally substituted;
    X, , X2、 X3y is as defined in claim 1;
    g, is a covalent bond, Co-C4-hydrocarbyl, Co-C4-hydrocarbyl- (CO) -Co-C4-hydrocarbyl, Co-C4-hydrocarbyl- (NR)5)-Co-C4-hydrocarbon radical, Co-C4-hydrocarbyl- (S) -C0-C4-hydrocarbyl, Co-C4-hydrocarbyl- (0) -C. -C4-a hydrocarbyl group, C. -C4-hydrocarbyl- (SO) -C0-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (SO) -Co-C4-hydrocarbyl, Co-C4-hydrocarbyl- (NH) - (CO) -Co-C4-a hydrocarbon radical, C0-C4-hydrocarbyl- (CO) - (NH) -C0-C4-hydrocarbyl, -NH-CO-NH-, -NH-CS-NH-, -0-CO-O-, -0-CS-O-, -NH-C (NH) -NH-, -S (0)2-N(R5)-， -N(R5)- S(0)2-, -NH-C (0) -0-, or-O-C (O) -NH-, wherein R5Possibly hydrogen, d-C5Alkyl, aryl, aralkyl, heterocyclyl, heterocyclylaryl, S02-alkyl, S02-aryl, CO-alkyl, CO-aryl, CO-NH-alkyl, CO-NH-aryl, CO-0-alkyl or CO-0-aryl;
    n is 0, 1,2, 3 or 4;
    z is N or CH;
    y is N microspheres or OH.
  29. 31. A process for the preparation of a compound as claimed in any one of claims 1 to 28, which comprises the reaction of:
    wherein the groups are as defined in the claims.
  30. 32. A pharmaceutical composition comprising 1 or more compounds according to any one of claims 1-28, and a pharmaceutically acceptable carrier.
  31. 33. Use of a compound according to any one of claims 1 to 28 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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