CN111943906A - Amidine derivative, preparation method thereof, pharmaceutical composition and application - Google Patents

Abstract

The invention discloses a class of amidine derivatives, a preparation method thereof, and pharmaceutical compositions and uses thereof. Specifically, it relates to the amidine derivatives represented by the general formula I, their pharmaceutically acceptable salts, their stereoisomers and their preparation methods, compositions containing one or more of these compounds, and the use of such compounds in the treatment and treatment of Use in IDO1-related diseases such as cancer, infectious diseases, and autoimmune diseases.

Description

Amidine derivatives, their preparation methods, pharmaceutical compositions and uses

technical field

The invention discloses a class of amidine derivatives, a preparation method thereof, and pharmaceutical compositions and uses thereof. Specifically, it relates to the amidine derivatives represented by the general formula I, their pharmaceutically acceptable salts, their stereoisomers and their preparation methods, compositions containing one or more of these compounds, and the use of such compounds in the treatment and treatment of Use in IDO1-related diseases such as cancer, infectious diseases, and autoimmune diseases.

Background technique

With the deepening of tumor immunity research, it has been found that the tumor microenvironment can protect tumor cells from being recognized and killed by the immune system. The immune escape of tumor cells plays a very important role in the occurrence and development of tumors. In 2013, the journal Science listed tumor immunotherapy as the first of the ten breakthroughs, which once again made immunotherapy the "focus" in the field of tumor treatment. Indoleamine-2,3-dioxygenase 1 (indoleamine 2,3-dioxy-genase 1, IDO-1) is a naturally occurring immunomodulatory enzyme in the body, and the isoenzyme indoleamine-2,3- Dioxygenase 2 (indoleamine 2,3-dioxygenase 2, IDO-2), tryptophan 2,3-dioxygenase (tryptophan 2,3-dioxygenase, TDO) together form the IDO family.

Human IDO-1 consists of 403 amino acid residues and has a relative molecular mass of about 42,000. Its gene is located on chromosome 8 and is about 15 kb in length, including 10 exons and 9 introns. It is a single-copy gene. IDO-1 is widely distributed in extrahepatic tissues, mainly in the thymus medulla and secondary lymphoid organs, and in immune-privileged tissues such as placenta, epididymis, anterior chamber and gastrointestinal mucosa. IDO-1 is expressed in various cells such as fibroblasts and B cells, but the cells with the highest expression are antigen-presenting cells, such as dendritic cells (DC) and macrophages.

Tryptophan is an essential amino acid with the lowest content in the human body. About 1% of the tryptophan ingested in food is converted into an important neurotransmitter serotonin, and about 95% enters the metabolic pathway of kynurenine (Kyn). The IDO family is a rate-limiting enzyme in the kyn metabolic pathway, which catalyzes the metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD ⁺ ) or complete oxidation to generate energy. NAD ⁺ is involved in important cellular responses such as ATP production and DNA repair. Intracellular NAD ⁺ levels are critical for maintaining cellular homeostasis, function, and survival. IDO _- mediated _Kyn pathway metabolite NAD ₊ in human astrocytes protects cells from oxidative damage by H2O2.

The physiological function of IDO-1 is achieved by regulating the concentration of tryptophan and its metabolites. For example, tryptophan depletion can inhibit the occurrence of lethal immune rejection, inhibit the growth of bacteria, viruses and parasites, reduce the biosynthesis of protein and serotonin, and inhibit the proliferation and differentiation of T cells. For another example, the immunologically active kynurenine produced by metabolism can promote immune response and maintain immune homeostasis.

Numerous studies have found that IDO-1 is constitutively highly expressed in various tumor tissues. Brandacher et al. used immunohistochemical detection methods and found that 39.2% (56/143) of colon cancer patients were accompanied by high expression of IDO-1. These patients are often clinically characterized by a high incidence of liver metastases, poor prognosis and 5-year survival rate. Low. Pan et al. detected that 35.5% (49/138) of liver cancer patients had high expression of IDO-1, increased cancer metastasis rate and decreased survival time. Okamoto et al. detected high expression of IDO-1 in 70.8% (17/24) ovarian cancer patients by means of biochips and immunohistochemistry, and showed resistance to platinum compounds in clinical treatment. In addition, Nakamura, Mansfield et al. detected IDO-1 in acute myeloid lymphoma, breast cancer, melanoma, pancreatic cancer, non-small cell lung cancer, renal cell carcinoma, cervical cancer, endometrial cancer and nasopharyngeal cancer by similar methods. It is highly expressed in other tumors, and is clinically accompanied by unfavorable indications of high degree of malignancy, strong invasiveness, poor prognosis and low survival rate.

Muller and others believe that IDO-1 forms an immunosuppressive state in the microenvironment by inhibiting the functions of T cells and natural killer cells. Tumor cells can use this negative immune regulation to escape the recognition and killing of the immune system, and then continue to develop and kill. transfer. IDO-1 may inhibit T cell proliferation and promote T cell apoptosis, thereby activating and enhancing the immunosuppressive function of regulatory T cells on the one hand, and inhibiting the function of effector T cells on the other hand, promoting the body's immunity to tumor-specific antigens tolerance. IDO-1 is highly expressed in antigen-presenting cells, especially plasmacytoid dendritic cells, which leads to local tryptophan depletion of cells and induces T cells to stagnate in G1 phase, thereby inhibiting the proliferation of T cells and downregulating the body's immune capacity. . IDO-1-dependent degradation of tryptophan leads to increased levels of kynurenine and also induces oxygen radical-mediated T cell apoptosis. Therefore, by inhibiting IDO-1, the recognition and killing of tumor cells by the immune system can be effectively improved. IDO-1 has been proven to be a new target for inhibiting the formation of malignant tumors and improving the effect of tumor immunotherapy. As a potential drug for related treatment, IDO inhibitors have very broad application prospects.

Although a number of small molecule IDO-1 inhibitors have been discovered and several are in clinical research, it is found that the clinical effect of IDO-1 inhibitor monotherapy is not ideal, and the combination with other immune checkpoint inhibitors has a synergistic effect . A recent article reported that IDO-1 enzymatic activity in non-tumor cells is required for the benefit of immune checkpoint inhibitors in tumor therapy (Brain, Behavior, and Immunity, 62 (2017) 24–29). By selectively inhibiting the activity of IDO-1 in tumor tissue, it may have the best synergistic effect in combination with other immune checkpoint inhibitors.

At present, tumor is still a major disease that seriously threatens human life and health. Regardless of tumor chemotherapy, molecular targeted therapy or the recently developed tumor immunotherapy, there are serious side effects on the human body. How to specifically target tumor tissue and reduce or eliminate damage to normal human tissue is the goal pursued by medical researchers.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide an amidine derivative having the general structural formula I, as well as its stereoisomer and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its preparation for prevention or treatment and IDO1 Use in medicines for diseases related to enzymes and signaling pathways.

In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

The first aspect of the technical solution of the present invention is to provide amidine derivatives as shown in general formula I, stereoisomers thereof, and pharmaceutically acceptable salts thereof,

In the formula,

R ₁ and R ₂ are independently selected from: hydrogen, halogen, C _1-4 alkyl, trifluoromethyl, C _1-4 alkoxy, methanesulfonyl, cyano, nitro;

_R3 is selected from:--- _NH2 ,--- _NHCH3 ,--- _NHCH2CH3 ,--- _NHCH2CH2CH3 ,--- _{NHCH ( CH3 ) 2} ,--- NHCH ₂ CH ₂ CH ₂ CH ₃ ,---NHC(CH ₃ ) ₃ ,---NH CH(CH ₃ )CH ₂ CH ₃ ,---NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,-- -NH CH(CH ₂ CH ₃ )CH ₂ CH ₃ ,---NH-(CH ₂ ) _n -NH-SO ₂ NH ₂ ,---NH-(CH ₂ ) _n -NH-S(NH)ONH ₂ ,---NH-(CH ₂ ) _n -NH-S(NCN)ONH ₂ ,---NH-(CH ₂ ) _n -NH-SO ₂ CH ₃ ,---NH-(CH ₂ ) _n -SO ₂ NH ₂ ,---NH-(CH ₂ ) _n -S(NH)ONH ₂ ,---NH-(CH ₂ ) _n -S(NCN)ONH ₂ ,---NH-(CH ₂ ) _n -SO ₂ CH ₃ ,---NH-(CH ₂ ) _n -S(NH)OCH ₃ ,---NH-(CH ₂ ) _n -S(NCN)OCH ₃ ,---NH-( CH ₂ ) _n -NH-S(NH)OCH ₃ ,---NH-(CH ₂ ) _n -NH-S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -NH -SO ₂ NH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NH)ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NCN )ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-SO ₂ CH ₃ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NH)OCH ₃ , ---NH(CO)NH-(CH ₂ ) _n -NH-S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -SO ₂ CH ₃ ,---NH(CO )NH-(CH ₂ ) _n -S(NH)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -SO ₂ NH ₂ ,---NH(CO)NH-(CH ₂ ) _n -S(NH)ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -S(NCN)ONH ₂ ,

Wherein, n=2, 3, 4 or 5;

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;

A is selected from: unsubstituted or substituted benzene ring, unsubstituted or substituted five-membered heteroaryl, or unsubstituted or substituted six-membered heteroaryl, the above-mentioned five-membered or six-membered heteroaryl contains 2- 5 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and the unsubstituted or substituted substituents are selected from: hydrogen, methyl, ethyl, isopropyl, fluorine, bromine, chlorine, Methoxy, cyano, methanesulfonyl.

R ₁ and R ₂ are each independently more preferably selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neobutyl, trifluoromethyl, methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, neo-butoxy, cyano, nitro;

R ₃ is more preferably selected from: ---NHCH ₃ , --- NHCH ₂ CH ₃ , --- NH CH ₂ CH ₂ CH ₃ , --- NH CH(CH ₃ ) ₂ , --- NHCH ₂ CH ₂ CH ₂ CH ₃ ,---NH C(CH ₃ ) ₃ ,---NH CH(CH ₃ )CH ₂ CH ₃ ,---NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,---NH CH(CH ₂ CH ₃ ) CH ₂ CH ₃ ,

R ₄ and R ₅ are each independently more preferably selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;

A is selected from: unsubstituted or substituted benzene ring, unsubstituted or substituted furan ring, unsubstituted or substituted thiophene ring, unsubstituted or substituted thiazole ring, unsubstituted or substituted pyrrole ring, unsubstituted or substituted pyridine Ring, unsubstituted or substituted imidazole ring, unsubstituted or substituted pyrazole ring, unsubstituted or substituted oxazole ring, the substituents in said unsubstituted or substituted are selected from: hydrogen, methyl, ethyl, iso Propyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Said compound is characterized by being represented by formula ii:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ;

_{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl;

R ₆ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Described compound is characterized in that as shown in formula iii:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ;

_{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl;

_R7 is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Said compound is characterized by being represented by formula IV:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ;

_{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl;

R ₈ is selected from hydrogen, methyl;

R ₉ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Said compound is characterized by being represented by formula ⅴ:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ;

_{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl;

R ₁₀ is selected from hydrogen, methyl;

R ₁₁ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Described compound is characterized in that as shown in formula ⅴi:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ;

_{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl;

_R7 is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl.

Preferred compounds include, but are not limited to:

(Z)-N-(3-Bromo-4-fluorophenyl)-N’-(4-nitrobenzyloxy)-4-amino-1,2,5-oxadiazole-3-amidine

(Z)-N'-(1-(4-Nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2,5-oxadiazole -3-Amidine

(Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2, 5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-4-amino-N'-((5-nitrofuran-2-yl)methoxy)-1,2,5-oxadi oxazol-3-amidine

(Z)-N'-(1-(5-Nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2,5- oxadiazole-3-amidine

(Z)-N'-((2-(5-Nitrofuran-2-yl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((1-Methyl-5-nitropyrrol-2-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(1-Methyl-5-nitropyrrol-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(1-Methyl-2-nitroimidazol-5-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((2-(1-Methyl-2-nitroimidazol-5-yl)-propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl) -4-Amino-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(4-nitrobenzyloxy)-4-(2-(aminosulfonamido)ethylamino)-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(4-Nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(aminosulfonamido)ethanamine base)-1,2,5-oxadiazole-3-amidine

(Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(5-nitrofuran-2-yl)-4-(2-(aminosulfonamido)ethylamino)-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-(1-(5-Nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(aminosulfonamido) )Ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N'-((2-(5-Nitrofuran-2-yl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-(2 -(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)propan-2-yl)oxy) -4-(2-(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(methyl) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-sulfamic acid acylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-methanesulfonic acid acylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methylimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methylimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(methanesulfonamido)ethylamino)-1,2, 5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-sulfamoylpropylamino)-1,2,5-oxadi oxazol-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-methanesulfonylpropylamino)-1,2,5-oxadi oxazol-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)propylamino)-1 , 2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoimidosulfonyl) propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)ethylamino)- 1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoimidosulfonyl) propylamino)-1,2,5-oxadiazole-3-amidine

The above-mentioned pharmaceutically acceptable salts include salts and ammonium salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing physiologically acceptable cations; the inorganic acids are selected from hydrochloric acid , hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, medlaric acid, maleic tartaric acid, fumaric acid, citric acid or lactic acid; the alkali The metal ion is selected from lithium ion, sodium ion, potassium ion; the alkaline earth metal ion is selected from calcium ion, magnesium ion; the organic base that can provide physiologically acceptable cations is selected from methylamine, dimethylamine, Trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

The second aspect of the technical solution of the present invention provides a preparation method of the compound described in the first aspect:

In order to prepare the compound described in the general formula I of the present invention, according to the structure of the general formula I, the present invention can choose the following route for preparing the compound of the general formula I:

route 1

route 2

route 3

Route 1: Using hydroxyamidine compound 1 as raw material, react with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under alkaline conditions to generate amidine derivative 1;

Route 2:

(a) using acid chloride oxime compound 2 as raw material, react with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under alkaline conditions to generate oxime ether compound 3;

(b) reacting with aniline derivatives under alkaline conditions to generate amidine derivatives I;

Route 3:

(a) using aldoxime compound 4 as raw material, react with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under alkaline conditions to generate aldoxime ether compound 5;

(b) 5 reacts with NBS to obtain acyl bromoxime ether compound 6;

(c) 6 reacts with aniline derivatives under alkaline conditions to generate amidine derivatives I;

The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and A are the same as those described in any one of claims 1-7.

In addition, the starting materials and intermediates in the above reaction are easily obtained, and each step of the reaction can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art. The compounds of general formula I can exist in the form of solvates or unsolvates, and different solvates may be obtained by crystallization from different solvents. The pharmaceutically acceptable salts of general formula I include different acid addition salts, such as acid addition salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, Trifluoroacetic acid, medlaric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts of general formula I also include different alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organic compounds that can provide physiologically acceptable cations. Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the present invention can be prepared using conventional methods. During the preparation of the compounds of general formula I, solvates and salts thereof, polymorphisms or co-crystals may occur under different crystallization conditions.

The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, the pharmaceutical composition comprising the amidine derivatives and stereoisomers thereof as described in the first aspect of the present invention as active ingredients, as well as their pharmaceutically acceptable ingredients A salt and a pharmaceutically acceptable carrier or excipient are used.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compounds of the present invention can be prepared into common preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to formulate the compounds of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to make the dosage unit into capsules, the active ingredients of the compounds of the present invention can be mixed with diluents and glidants, and the mixture can be directly placed in hard capsules or soft capsules. The compound of the present invention can also be made into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.

To prepare the compounds of the present invention into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvents and appropriate amount of solubilizers, cosolvents, pH adjusters and osmotic pressure adjusters commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjuster can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppant.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention may vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. In general, a suitable daily dosage range of the compounds of the present invention is 0.001-150 mg/Kg body weight, preferably 0.01-100 mg/Kg body weight. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

The fourth aspect of the technical solution of the present invention provides the use of amidine derivatives, stereoisomers and pharmaceutically acceptable salts thereof in the preparation of medicines for preventing and/or treating diseases related to IDO1 enzyme and signaling pathway.

The diseases related to IDO1 enzyme and signaling pathway are selected from cancer, infectious diseases, and autoimmune diseases. The cancer is selected from the group consisting of skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck cancer. The infectious disease is selected from bacterial infection and viral infection. Described autoimmune disease is selected from organ-specific autoimmune disease, systemic autoimmune disease, wherein, described organ-specific autoimmune disease includes chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, Myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritic syndrome, primary biliary cirrhosis, multiple encephalomyelopathy, acute idiopathic polyneuritis, the system Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.

Beneficial technical effects:

The compound of the present invention selectively inhibits IDO1 in tumor tissue; in vivo pharmacodynamic studies show that the compound of the present invention can significantly inhibit the growth of subcutaneous tumors in terms of tumor volume and weight, and the drug effect is better than the corresponding inhibition of IDO1 in the whole body, And low toxicity and side effects.

Detailed ways

The invention will be further described below with reference to the examples, but the scope of the invention is not limited.

Measuring instrument: Vaariaan Mercury 300 nuclear magnetic resonance apparatus was used for nuclear magnetic resonance spectroscopy. Mass spectrometers were used ZAD-2F and VG300 mass spectrometers.

Example 1: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(4-nitrobenzyloxy)-4-amino-1,2,5-oxadiazole-3 -Amidine

Route 1:

Intermediate (Z)-4-amino-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-amidine (500 mg, 1.59 mmol) was mixed with Potassium carbonate (394 mg, 2.85 mmol) was dissolved in DMF (10 mL), and after stirring at room temperature for 30 minutes, p-nitrobenzyl bromide (412 mg, 1.9 mmol) was added, and after stirring at room temperature for 5 h, an appropriate amount of water was added and extracted with ethyl acetate Three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, added with 20 mL of ether, sonicated, and suction filtered to obtain 536.6 mg of an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H, -NH-), 8.24 (d, J=8.6 Hz, 2H, ArH), 7.68 (d, J=8.5 Hz, 2H, ArH ),7.26–7.16(m,2H,ArH),6.89–6.82(m,1H,ArH),6.25(s,2H, _-NH2 ),5.36(s,2H, _-CH2 -).HR-ESI -MS(mz positive):Calcd for C ₁₆ H ₁₂ BrFN ₆ O ₄ [M+H] ⁺ 451.0160, Found: 451.0160.

Route 2: (Z)-4-Amino-N-(p-nitrobenzyloxy)-1,2,5-oxadiazole-3-carbonimidyl chloride

Intermediate (Z)-4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbamidochloride (400 mg, 2.47 mmol) was mixed with anhydrous potassium carbonate (512 mg, 3.7 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 30 minutes, p-nitrobenzyl bromide (640 mg, 3 mmol) was added to the reaction mixture and stirred overnight. An appropriate amount of water was added, extracted with ethyl acetate three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE:EA 3:1) to obtain 175 mg of a pale yellow solid, (Z)-4-Amino-N-(p-nitrobenzyloxy)-1,2,5-oxadiazole-3-carbonimidyl chloride, yield: 23.8%. ¹ HNMR (300MHz, DMSO-d ₆ ) δ 8.28 (d, J=8.8 Hz, 2H, ArH), 7.76 (d, J=8.8 Hz, 2H, ArH), 6.51 (s, 2H, -NH ₂ ) , 5.57(s, 2H, -CH ₂ -). ESI-MS: [M+H] ⁺ =298.

Intermediate (Z)-4-amino-N-(p-nitrobenzyloxy)-1,2,5-oxadiazole-3-carbamidochloride (297 mg, 1 mmol), 3-bromo- 4-Fluoroaniline (285 mg, 1.5 mmol) and 10 ml of ethanol were heated under reflux and stirred for 1 h, then 5 ml of sodium bicarbonate aqueous solution was added, and the stirring was continued at 60 degrees for 10 hours to stop the reaction, remove the ethanol under reduced pressure, and extract with ethyl acetate for 3 Second, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography to obtain (Z)-N-(3-bromo-4-fluorophenyl)-N'-(4- Nitrobenzyloxy)-4-amino-1,2,5-oxadiazole-3-amidine, off-white solid 90 mg, yield: 20%.

Example 2: (Z)-N'-(1-(4-nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2,5 -Oxadiazole-3-amidine

Intermediate (Z)-4-amino-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-amidine (195 mg, 0.62 mmol) was mixed with Potassium carbonate (128 mg, 0.93 mmol) was dissolved in DMF (6 ml), and after stirring at room temperature for 30 minutes, the intermediate 1-(1-bromoethyl)-4-nitrobenzene (170 mg, 0.74 mmol) was added to the reaction and stirred. overnight. Appropriate amount of water was added, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain 115 mg of a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s,1H,-NH-),8.23-8.22(m,2H,ArH),7.65-7.63(m,2H,ArH),7.28-7.21( m, 2H, ArH), 6.89 (m, 1H, ArH), 6.11 (s, 2H, -NH ₂ ), 5.51 (q, J=6.4Hz, 1H, -CH-), 1.52 (d, J=6.6 Hz,3H,-CH ₃ ).HR-ESI-MS(mz positive):Calcd forC ₁₇ H ₁₄ BrFN ₆ O ₄ [M+H] ⁺ 465.0316,Found:465.0316.

Example 3: (Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-amino- 1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-(2-bromoprop-2-yl)-4-nitrobenzene for 1-(1-bromoethyl)-4-nitrobenzene, the operation is the same as

Example 2. A yellow solid was obtained, yield: 32%. ¹ H NMR (500MHz, DMSO-d ₆ )δ9.19(s,1H,-NH-),8.19(d,J=8.5Hz,2H,ArH),7.65(d,J=8.5Hz,2H,ArH ), 7.31–7.19(m, 2H, ArH), 7.00–6.88(m, 1H, ArH), 5.86(s, 2H, -NH ₂ ), 1.66(s, 6H, -CH ₃ ).HR-ESI- MS (mz positive): Calcd for C ₁₈ H ₁₆ BrFN ₆ O ₄ [M+H] ⁺ 479.0472, Found: 479.0470.

Example 4: (Z)-N-(3-Bromo-4-fluorophenyl)-4-amino-N'-((5-nitrofuran-2-yl)methoxy)-1,2, 5-oxadiazole-3-amidine

Substitute the intermediate 2-(bromomethyl)-5-nitrofuran for 1-(1-bromoethyl)-4-nitrobenzene, and the operation is the same as that of Example 2. A pale yellow solid was obtained. ¹ H NMR (400MHz, DMSO-d6)δ9.21(s,1H,-NH-),7.70(d,J=3.7Hz,1H,ArH),7.23-7.15(m,2H,ArH),6.98( d, J=3.7Hz, 1H, ArH), 6.83 (m, 1H, ArH), 6.32 (s, 2H, -NH ₂ ), 5.27 (s, 2H, -CH ₂ -). HR-ESI-MS ( mz positive):Calcd for C ₁₄ H ₁₀ BrFN ₆ O ₅ [M+H] ⁺ 440.9953, Found: 440.9945

Example 5: (Z)-N'-(1-(5-nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1, 2,5-oxadiazole-3-amidine

Substitute the intermediate 2-(1-bromoethyl)-5-nitrofuran for 1-(1-bromoethyl)-4-nitrobenzene, and the operation is the same as in Example 2. A yellow solid was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H, -NH-), 7.70 (d, J=3.8 Hz, 1H, ArH), 7.22-7.17 (m, 2H, ArH), 6.95 (d, J=3.8Hz, 1H, ArH), 6.85 (m, 1H, ArH), 6.25 (s, 2H, -NH ₂ ), 5.50 (q, J=6.7Hz, 1H, -CH-), 1.60 (d,J=6.8Hz,3H,

-CH ₃ ).HR-ESI-MS(mz positive):Calcd for C ₁₅ H ₁₂ BrFN ₆ O ₅ [M+H] ⁺ 455.0109, Found: 455.0112.

Example 6: (Z)-N'-((1-methyl-5-nitropyrrol-2-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino -1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-methyl-2-(bromomethyl)-5-nitropyrrole for 1-(1-bromoethyl)-4-nitrobenzene, and the operation is the same as that in Example 2. A white solid was obtained, yield: 33%. ¹ H NMR(500MHz, DMSO-d ₆ )δ9.06(s,1H,-NH-),8.03(d,1H,ArH),7.23-7.14(m,2H,ArH),6.87-6.78(m, 2H,ArH),6.31(s,2H,-NH ₂ ),5.16(s,2H,-CH ₂ -),3.70(s,3H,-CH ₃ ).HR-ESI-MS(mz positive):Calcd for C ₁₅ H ₁₃ BrFN7O ₄ [M+H] ⁺ 454.0269, Found: 454.0264.

Example 7: (Z)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino -1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-methyl-2-nitro-5-bromomethylimidazole for 1-(1-bromoethyl)-4-nitrobenzene, and the operation is the same as that of Example 2. to give (Z)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1, 2,5-oxadiazole-3-amidine pale yellow solid, yield: 58%. ¹ H NMR(500MHz,DMSO-d6)δ9.15(s,1H,-NH-),7.30(s,1H,ArH),7.20(m,2H,ArH),6.89-6.79(m,1H,ArH) ),6.33(s,2H-NH ₂ ),5.32(s,2H,-CH ₂ -),3.94(s,3H,-CH ₃ ).HR-ESI-MS(mz positive):Calcd for C ₁₄ H _12BrFN8O4 [M ₊ H] ⁺ _455.0222 , Found: 455.0221.

Example 8: (Z)-N'-(1-(1-methyl-2-nitroimidazol-5-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4 -Amino-1,2,5-oxadiazole-3-amidine

The intermediate 1-methyl-2-nitro-5-(1-bromoethyl)imidazole was used instead of 1-(1-bromoethyl)-4-nitrobenzene, and the operation was the same as that in Example 2. to give (Z)-N'-(1-(1-methyl-2-nitroimidazol-5-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino- 1,2,5-oxadiazole-3-amidine was a pale yellow solid, yield: 35%. ESI-MS: [M+H] ⁺ =469.

Example 9: (Z)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)-propan-2-yl)oxy)-N-(3-bromo-4- Fluorophenyl)-4-amino-1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-methyl-2-nitro-5-(2-bromopropan-2-yl)imidazole for 1-(1-bromoethyl)-4-nitrobenzene, and the operation is the same as that in Example 2. gives (Z)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)-propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl) )-4-amino-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 28%. ESI-MS: [M+H] ⁺ = 483.

Example 10: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(4-nitrobenzyloxy)-4-(2-(aminosulfonamido)ethylamino) -1,2,5-oxadiazole-3-amidine

The intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadi Zole-3-amidine (300 mg, 0.69 mmol) and potassium carbonate (195 mg, 0.9 mmol) were dissolved in DMF (10 ml), and after stirring at room temperature for 30 minutes, p-nitrobenzyl bromide (152 mg, 1.1 mmol) was added to the reaction and stirred. overnight. Appropriate amount of water was added, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 217 mg of white solid, yield: 55%. ¹ H NMR (400MHz, DMSO-d6)δ9.23(s,1H,-NH-),8.27-8.23(m,2H,ArH),7.95(s,1H,-NH-),7.71-7.66(m , 2H, ArH), 7.24–7.18 (m, 2H, ArH), 6.89–6.84 (m, 1H, ArH), 6.67 (m, 2H, -NH ₂ ), 6.29 (m, 1H, -NH-), 5.37(s,2H, _-CH2 -),2.89(m,2H, _-CH2 -),2.73–2.72(m,2H, _-CH2 -).HR-ESI-MS(mz positive):Calcd for C ₁₈ H ₁₈ BrFN ₈ O ₆ S[M+H] ⁺ 573.0310, Found: 573.0269.

Example 11: (Z)-N'-(1-(4-nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(aminosulfonamide) yl)ethylamino)-1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-(1-bromoethyl)-4-nitrobenzene for p-nitrobenzyl bromide, and the operation is the same as that of Example 10. A white solid was obtained, yield: 35%. ¹ H NMR (400MHz, DMSO-d6)δ9.17(s,1H,-NH-),8.26-8.19(m,2H,ArH),7.95(s,1H,-NH-),7.68-7.61(m , 2H, ArH), 7.28–7.20 (m, 2H, ArH), 6.90 (m, 1H, ArH), 6.66 (m, 2H, -NH ₂ ), 6.13 (t, J=5.2Hz, 1H, -NH -), 5.55(q, J=6.3Hz, 1H, -CH-), 2.89(m, 2H, -CH ₂ -), 2.73(m, 2H, -CH ₂ -), 1.54(d, J=6.5 Hz,3H,-CH ₃ ).HR-ESI-MS(mz positive):Calcd forC ₁₉ H ₂₀ BrFN ₈ O ₆ S[M+H] ⁺ 587.0466,Found:587.0482.

Example 12: (Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-( 2-(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

Substitute the intermediate 1-(2-bromoprop-2-yl)-4-nitrobenzene for p-nitrobenzyl bromide, and the procedure is the same as in Example 10. A white solid was obtained. ¹ H NMR (400MHz, DMSO-d6)δ9.17(s,1H,-NH-),8.19(d,J=8.9Hz,2H,ArH),7.95(s,1H,-NH-),7.66( d, J=8.9Hz, 2H, ArH), 7.30–7.22 (m, 2H, ArH), 6.97–6.90 (m, 1H, ArH), 6.61 (t, J=6.0Hz, 1H, -NH-), 6.56(m,2H, _-NH2 ),2.89(m,2H, _-CH2 -),2.73(m,2H, _-CH2 -),1.69(s,6H,-( _CH3 ) ₂ ).HR -ESI-MS(mz positive):Calcd for C ₂₀ H ₂₂ BrFN ₈ O ₆ S[M+H] ⁺ 601.0623, Found: 601.0650.

Example 13: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(5-nitrofuran-2-yl)-4-(2-(aminosulfonamido)ethanamine base)-1,2,5-oxadiazole-3-amidine

The intermediate 2-(bromomethyl)-5-nitrofuran was used instead of p-nitrobenzyl bromide, and the operation was the same as that of Example 10 to obtain a yellow oil. ¹ H NMR (400MHz, Acetone-d ₆ ) δ 8.47 (s, 1H, -NH-), 7.48 (d, J=3.7Hz, 1H), 7.28 (dd, J=6.1, 2.7Hz, 1H, ArH )), 7.13(t, J=8.7Hz, 1H, ArH), 7.01-6.99(m, 2H, ArH), 6.99-6.97(m, 1H, -NH-), 6.24(t, J=5.7Hz, 1H, -NH-), 6.09-6.05 (m, 2H, -NH ₂ ), 5.26 (s, 2H, -CH ₂ -), 3.50-3.45 (m, 2H, -CH ₂ -), 3.37-3.33 ( m,2H,-CH ₂ -).HR-ESI-MS(mz positive):Calcd forC ₁₆ H ₁₆ BrFN ₈ O ₇ S[M+H] ⁺ 563.0102,Found:563.0088.

Example 14: (Z)-N'-(1-(5-Nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-( Sulfamido)ethylamino)-1,2,5-oxadiazole-3-amidine

Substitute the p-nitrobenzyl bromide with the intermediate 2-(1-bromoethyl)-5-nitrofuran, and the operation is the same as that of Example 10. A yellow solid was obtained. ¹ H NMR (400MHz, Acetone-d ₆ ) δ 8.42 (s, 1H, -NH-), 7.50 (d, J=3.7Hz, 1H, ArH), 7.32 (dd, J=6.1, 2.7Hz, 1H , ArH), 7.17 (t, J=8.7Hz, 1H, ArH), 7.06–7.01 (m, 1H, ArH), 6.97 (d, J=3.7Hz, 1H, ArH), 6.17 (t, J=5.9 Hz, 1H, -NH-), 6.02 (m, 2H, -NH ₂ ), 5.62 (s, 1H, -NH-), 5.53 (q, J=6.7Hz, 1H, -CH-), 3.50 (m ,2H,-CH ₂ -),3.37(m,2H,-CH ₂ -),1.66(d,J＝6.8Hz,3H,-CH ₃ ).HR-ESI-MS(mz positive):Calcd for C ₁₇ H ₁₈ BrFN ₈ O ₇ S[M+H] ⁺ 577.0259, Found: 577.0246.

Example 15: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 2-(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

Substitute p-nitrobenzyl bromide with the intermediate 1-methyl-2-nitro-5-bromomethylimidazole, and the operation is the same as in Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-( Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 31%. ESI-MS: [M+H] ⁺ =577.

Example 16: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)propan-2-yl )oxy)-4-(2-(aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

Substitute p-nitrobenzyl bromide with the intermediate 1-methyl-2-nitro-5-(2-bromopropan-2-yl)imidazole, and the operation is the same as that in Example 10. gives (Z)-N-(3-bromo-4-fluorophenyl)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)propan-2-yl)oxy )-4-(2-(aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine light yellow solid, yield: 25%. ESI-MS: [M+H] ⁺ = 605.

Example 17: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 3-Sulfamoylpropylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(3-(Sulfamoyl)propylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'- Hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that in Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-( Sulfamoyl)propylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 20%. ESI-MS: [M+H] ⁺ = 576.

Example 18: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 3-Methanesulfonylpropylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(3-(Methylsulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'- Hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that in Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-methyl) Sulfonylpropylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 25%. ESI-MS: [M+H] ⁺ = 575.

Example 19: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 3-(S-Methylimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(3-(S-methylimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl )-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that in Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-( S-methylimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 27%. ESI-MS: [M+H] ⁺ = 574.

Example 20: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 3-(S-methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(3-(S-methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo- 4-Fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-( S-methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 19%. ESI-MS: [M+H] ⁺ = 599.

Example 21: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 2-(S-Methylimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(2-(S-methylimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorobenzene base)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that in Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-( S-methylimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 31%. ESI-MS: [M+H] ⁺ = 560.

Example 22: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-( 2-(S-methyl-N-cyanoimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine

Replacing p-nitrobenzyl bromide with intermediate 1-methyl-2-nitro-5-bromomethylimidazole, intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -4-(2-(S-methyl-N-cyanoimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo -4-Fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-( S-methyl-N-cyanoimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 21%. ESI-MS: [M+H] ⁺ = 585.

Example 23: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(methanesulfonamido)ethylamino)- 1,2,5-oxadiazole-3-amidine

With intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(methanesulfonamido)ethylamino)-1,2,5-oxadi Azole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5 -Oxadiazole-3-amidine, the operation is the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(methanesulfonamido)ethylamino)-1,2 , 5-oxadiazole-3-amidine pale yellow solid, yield: 36%. ESI-MS: [M+H] ⁺ = 572.

Example 24: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-sulfamoylpropylamino)-1,2, 5-oxadiazole-3-amidine

With the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-sulfamoylpropylamino)-1,2,5-oxadiazole-3- Amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole -3-Amidine, the operation is the same as that of Example 10. (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-sulfamoylpropylamino)-1,2,5-oxa Diazole-3-amidine pale yellow solid, yield: 29%. ESI-MS: [M+H] ⁺ = 572.

Example 25: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-methanesulfonylpropylamino)-1,2, 5-oxadiazole-3-amidine

With the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-methanesulfonylpropylamino)-1,2,5-oxadiazole-3- Amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1,2,5-oxadiazole -3-Amidine, the operation is the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-methanesulfonylpropylamino)-1,2,5-oxa Diazole-3-amidine is a pale yellow solid, yield: 38%. ESI-MS: [M+H] ⁺ = 571.

Example 26: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)propylamine base)-1,2,5-oxadiazole-3-amidine

With the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-(S-methylimidosulfonyl)propylamino)-1,2,5 -Oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1, 2,5-oxadiazole-3-amidine, the operation is the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)propylamino)- 1,2,5-oxadiazole-3-amidine was a pale yellow solid, yield: 30%. ESI-MS: [M+H] ⁺ = 570.

Example 27: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoidene Sulfamoyl)propylamino)-1,2,5-oxadiazole-3-amidine

with the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(3-(S-methyl-N-cyanoimidosulfonyl)propylamino)- 1,2,5-Oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethanamine base)-1,2,5-oxadiazole-3-amidine, the operation was the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoimidosulfonyl) ) Propylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 18%. ESI-MS: [M+H] ⁺ = 595.

Example 28: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(S-methylimidosulfonyl)ethane amino)-1,2,5-oxadiazole-3-amidine

With the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(S-methylimidosulfonyl)ethylamino)-1,2, 5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethylamino)-1 , 2,5-oxadiazole-3-amidine, the operation is the same as that in Example 10. gives (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(S-methylimidosulfonyl)ethylamino) -1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 26%. ESI-MS: [M+H] ⁺ = 556.

Example 29: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(S-methyl-N-cyanoidene Sulfamoyl)ethylamino)-1,2,5-oxadiazole-3-amidine

with the intermediate (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(S-methyl-N-cyanoimidosulfonyl)ethylamino) -1,2,5-oxadiazole-3-amidine in place of (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamolamido)ethane amino)-1,2,5-oxadiazole-3-amidine, the operation was the same as that of Example 10. to give (Z)-N-(3-bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(S-methyl-N-cyanoimidosulfonyl) )ethylamino)-1,2,5-oxadiazole-3-amidine pale yellow solid, yield: 22%. ESI-MS: [M+H] ⁺ = 581.

Biological evaluation:

1. Stability test in plasma

The compounds to be tested were prepared into a stock solution of 5 mmol·L ^-1 with DMSO, and then diluted to 0.045 μg·μL ^-1 with PBS (0.01M, pH=7.4) phosphate buffer solution containing 0.5% BSA. Add 200 μL of mouse plasma to a 5 mL graduated test tube with a stopper, pre-warm in a constant temperature shaker at 37°C, and then add 100 μL of the diluted stock solution at a concentration of 0.045 μg·μL ^-1 . In another 5 mL graduated test tube with stopper, 200 μL of 0.5% BSA in PBS (0.01 M, pH=7.4) phosphate buffer solution and 100 μL of the diluted stock solution with a concentration of 0.045 μg·μL ⁻¹ were added as a control group. In another 5 mL test tube with stoppered graduation, 200 μL of mouse plasma and 100 μL of phosphate buffer solution of 0.5% BSA in PBS (0.01M, pH=7.4) were added as blank control. Vortex and mix for 5 min, incubate in a constant temperature constant temperature oscillator at 37 °C, take 60 μL of samples at 0.25, 0.5, 1, 3, and 5 h respectively, add 120 μL of methanol at a ratio of 1:2, vortex for 2 min, and centrifuge at 2000 r for 10 min. 20 μL of the supernatant was subjected to HPLC analysis.

Table 1 Example 1 Stability in plasma

Note: the data in the table is the remaining percentage of the prodrug (Example 1)

2. Lysis of tumor tissue in mice

Under sterile conditions, the NCI-H1975 and NCI-H460 lung cancer tumor tissues that were passaged in the armpits of nude mice were stripped, the fascia was removed, and the tumor tissues were minced and divided into 2-3 mm ³ tumor pieces of uniform size, which were inoculated into BALB/c nude mice. Back of the armpit (inoculated with NCI-H460 under the left armpit and NCI-H1975 under the right armpit). When the average tumor volume reached 600 mm ³ , the animals were randomly divided into groups. The administration group received 80 mg/kg intraperitoneal injection, and the samples were collected at 0.5 h, 1 h and 2 h after administration, with one animal at each time point. When taking the materials, the animals were sacrificed, the tumor tissue was stripped, and normal saline was added to homogenize (tumor tissue: normal saline = 1:3), vortexed for 3 minutes, centrifuged at 2000 r for 5 minutes, and then collected 300 μL of supernatant, added 300 μL of acetonitrile, and vortexed for 1 minute. , 2000r centrifugation for 5min, repeated twice, take 20μL of supernatant for HPLC analysis.

Table 2 Example of lysis in mouse tumor tissue

Note: The data in the table are the percentage of prodrug and original drug respectively

3. Growth inhibitory effect on mouse H22 hepatocellular carcinoma

The well-grown ascites was taken and diluted with sterile normal saline at a ratio of 1:3 to prepare a tumor cell suspension. Each mouse was inoculated with 0.2 mL of tumor fluid on the back of the armpit. The animals were randomly divided into groups and weighed the day after inoculation. The experimental animals were divided into 5 groups, the tumor-bearing solvent control group, the positive control drug 5-FU administration group at 30.0 mg/kg, the Example 1 administration group at 100 mg/kg, and the original drug compound 1 administration group at 100 mg/kg. 5 animals. The 5-FU administration group was administered 30.0 mg/kg on the 1st day, the 4th day, and the 7th day after the inoculation, respectively, for a total of 3 times. The administration volume of control, original drug compound 1 and test compound Example 1 was 0.4 mL per 20 g of mice, administered twice a day, starting on the 4th day after inoculation, and administered for 5 days in total.

After the experiment, the animals were sacrificed by cervical dislocation, weighed, and the tumor tissue was excised and weighed. The tumor inhibition rate (%) was calculated according to the weight, and the body weight and tumor reproducibility were expressed as the mean ± standard deviation (_x ± SD), and the t test between each administration group and the solvent control group was performed.

Table 3 Test results of the growth inhibitory effect of the compounds of the examples on mouse H22 liver cancer

*p<0.05, **p<0.01, ***p<0.001, compared with solvent control group, compound 1=(Z)-4-amino-N-(3-bromo-4-fluorophenyl)-N '-Hydroxy-1,2,5-oxadiazole-3-amidine is the original drug of Example 1.

Claims (17)

1. amidine derivatives shown in general formula I and stereoisomers thereof and pharmaceutically acceptable salts thereof,

In the formula, R ₁ and R ₂ are independently selected from: hydrogen, halogen, C _1-4 alkyl, trifluoromethyl, C _1-4 alkoxy, methanesulfonyl, cyano, nitro; _R3 is selected from:--- _NH2 ,--- _NHCH3 ,--- _NHCH2CH3 ,--- _NHCH2CH2CH3 ,--- _{NHCH ( CH3 ) 2} ,--- NHCH ₂ CH ₂ CH ₂ CH ₃ ,---NHC(CH ₃ ) ₃ ,---NH CH(CH ₃ )CH ₂ CH ₃ ,---NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,-- -NHCH(CH ₂ CH ₃ )CH ₂ CH ₃ ,---NH-(CH ₂ ) _n -NH-SO ₂ NH ₂ ,---NH-(CH ₂ ) _n -NH-S(NH)ONH ₂ ,---NH-(CH ₂ ) _n -NH-S(NCN)ONH ₂ ,---NH-(CH ₂ ) _n -NH-SO ₂ CH ₃ ,---NH-(CH ₂ ) _n - SO ₂ NH ₂ ,---NH-(CH ₂ ) _n -S(NH)ONH ₂ ,---NH-(CH ₂ ) _n -S(NCN)ONH ₂ ,---NH-(CH ₂ ) _n -SO ₂ CH ₃ ,---NH-(CH ₂ ) _n -S(NH)OCH ₃ ,---NH-(CH ₂ ) _n -S(NCN)OCH ₃ ,---NH-(CH ₂ ) _n -NH-S(NH)OCH ₃ ,---NH-(CH ₂ ) _n -NH-S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -NH- SO ₂ NH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NH)ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NCN) ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -NH-SO ₂ CH ₃ ,---NH(CO)NH-(CH ₂ ) _n -NH-S(NH)OCH ₃ ,- --NH(CO)NH-(CH ₂ ) _n -NH-S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -SO ₂ CH ₃ ,---NH(CO) NH-(CH ₂ ) _n -S(NH)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -S(NCN)OCH ₃ ,---NH(CO)NH-(CH ₂ ) _n -SO ₂ NH ₂ ,---NH(CO)NH-(CH ₂ ) _n -S(NH)ONH ₂ ,---NH(CO)NH-(CH ₂ ) _n -S(NCN)ONH ₂ ,

Wherein, n=2, 3, 4 or 5; R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl; A is selected from: unsubstituted or substituted benzene ring, unsubstituted or substituted five-membered heteroaryl, or unsubstituted or substituted six-membered heteroaryl, the above-mentioned five-membered or six-membered heteroaryl contains 2- 5 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and the unsubstituted or substituted substituents are selected from: hydrogen, methyl, ethyl, isopropyl, fluorine, bromine, chlorine, Methoxy, cyano, methanesulfonyl. 2. amidine derivatives and stereoisomers thereof and pharmaceutically acceptable salts thereof according to claim 1, wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neobutyl, trifluoromethyl, methoxy , ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, neo-butoxy, cyano, nitro; _R3 is selected from _: --- _NHCH3 ,--- _NHCH2CH3 ,--- _NHCH2CH2CH3 ,--- _{NHCH ( CH3 ) 2} , _{--- NHCH2CH2CH2} CH ₃ ,---NH C(CH ₃ ) ₃ ,---NH CH(CH ₃ )CH ₂ CH ₃ ,---NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,---NH CH(CH ₂ CH ₃ ) CH ₂ CH ₃ ,

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl; A is selected from: unsubstituted or substituted benzene ring, unsubstituted or substituted furan ring, unsubstituted or substituted thiophene ring, unsubstituted or substituted thiazole ring, unsubstituted or substituted pyrrole ring, unsubstituted or substituted pyridine Ring, unsubstituted or substituted imidazole ring, unsubstituted or substituted pyrazole ring, unsubstituted or substituted oxazole ring, the substituents in said unsubstituted or substituted are selected from: hydrogen, methyl, ethyl, iso Propyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 3. amidine derivatives according to any one of claims 1-2 and stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein the compound is shown in formula ii:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ; _{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl; R ₆ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 4. amidine derivatives according to any one of claims 1-2 and stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein the compound is shown in formula ⅲ:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ; _{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl; _R7 is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 5. The amidine derivatives according to any one of claims 1-2 and their stereoisomers and their pharmaceutically acceptable salts, wherein the compound is shown in formula ⅳ:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ; _{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl; R ₈ is selected from hydrogen, methyl; R ₉ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 6. The amidine derivatives according to any one of claims 1-2 and their stereoisomers and their pharmaceutically acceptable salts, wherein the compound is shown in formula ⅴ:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ; _{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl; R ₁₀ is selected from hydrogen, methyl; R ₁₁ is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 7. amidine derivatives according to any one of claims 1-2 and stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein the compound is shown in formula ⅴi:

Wherein: R ₁ and R ₂ are independently selected from: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ; _{R3 is} selected from:

R ₄ and R ₅ are independently selected from: hydrogen, methyl, ethyl, trifluoromethyl; _R7 is selected from hydrogen, methyl, fluorine, bromine, chlorine, methoxy, cyano, methanesulfonyl. 8. The amidine derivatives and stereoisomers thereof and pharmaceutically acceptable salts thereof according to any one of claims 1-7, the compounds are selected from: (Z)-N-(3-Bromo-4-fluorophenyl)-N’-(4-nitrobenzyloxy)-4-amino-1,2,5-oxadiazole-3-amidine

(Z)-N'-(1-(4-Nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2,5-oxadiazole -3-Amidine

(Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2, 5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-4-amino-N'-((5-nitrofuran-2-yl)methoxy)-1,2,5-oxadi oxazol-3-amidine

(Z)-N'-(1-(5-Nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2,5- oxadiazole-3-amidine

(Z)-N'-((2-(5-Nitrofuran-2-yl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((1-Methyl-5-nitropyrrol-2-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(1-Methyl-5-nitropyrrol-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(1-Methyl-2-nitroimidazol-5-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-amino-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-((2-(1-Methyl-2-nitroimidazol-5-yl)-propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl) -4-Amino-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(4-nitrobenzyloxy)-4-(2-(aminosulfonamido)ethylamino)-1,2 , 5-oxadiazole-3-amidine

(Z)-N'-(1-(4-Nitrophenyl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(aminosulfonamido)ethanamine base)-1,2,5-oxadiazole-3-amidine

(Z)-N'-((2-(4-nitrophenyl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(5-nitrofuran-2-yl)-4-(2-(aminosulfonamido)ethylamino)-1 , 2,5-oxadiazole-3-amidine

(Z)-N'-(1-(5-Nitrofuran-2-yl)ethoxy)-N-(3-bromo-4-fluorophenyl)-4-(2-(aminosulfonamido) )Ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N'-((2-(5-Nitrofuran-2-yl)propan-2-yl)oxy)-N-(3-bromo-4-fluorophenyl)-4-(2 -(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((2-(1-methyl-2-nitroimidazol-5-yl)propan-2-yl)oxy) -4-(2-(Aminosulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(amino) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(2-(methyl) Sulfonamido)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-sulfamic acid acylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-methanesulfonic acid acylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methylimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methylimidosulfonyl)ethylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-((1-methyl-2-nitroimidazol-5-yl)methoxy)-4-(3-(S -Methyl-N-cyanoimidosulfonyl)propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(2-(methanesulfonamido)ethylamino)-1,2, 5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-sulfamoylpropylamino)-1,2,5-oxadi oxazol-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-methanesulfonylpropylamino)-1,2,5-oxadi oxazol-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)propylamino)-1 , 2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoimidosulfonyl) propylamino)-1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methylimidosulfonyl)ethylamino)- 1,2,5-oxadiazole-3-amidine

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-(p-nitrobenzyloxy)-4-(3-(S-methyl-N-cyanoimidosulfonyl) propylamino)-1,2,5-oxadiazole-3-amidine

9. The amidine derivatives and stereoisomers thereof and pharmaceutically acceptable salts thereof according to any one of claims 1-7, wherein the pharmaceutically acceptable salts include compounds with inorganic acids, organic acids, alkali metal ions , alkaline earth metal ions or organic bases that can provide physiologically acceptable cations to form salts and ammonium salts. 10. The amidine derivatives and stereoisomers thereof and pharmaceutically acceptable salts thereof according to claims 1-7, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the The organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, medlaric acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, potassium ion ; Described alkaline earth metal ion is selected from calcium ion, magnesium ion; Described organic base that can provide physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tri(2 - hydroxyethyl)amine. 11. The method for preparing amidine derivatives according to any one of claims 1-7: route 1

route 2

route 3

In order to prepare the compound described in the general formula I, according to the structure of the general formula I, the preparation of the compound of the general formula I is divided into three routes: In route 1, the hydroxyamidine compound 1 is used as a raw material, and the amidine derivative 1 is generated by reacting with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under alkaline conditions; In route 2, (a) takes acyl chloride oxime compound 2 as raw material, reacts with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under basic conditions to generate oxime ether compound 3, (b) in alkali It reacts with aniline derivatives to form amidine derivatives I under neutral conditions; In route 3, (a) takes aldoxime compound 4 as raw material, reacts with nitro-substituted arylmethyl or heteroarylmethyl chloride or bromine or iodine under basic conditions to generate aldoxime ether compound 5, (b) 5 Reaction with NBS to obtain acyl bromoxime ether compound 6, (c) 6 reacts with aniline derivatives under alkaline conditions to generate amidine derivatives I; The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and A are the same as those described in any one of claims 1-7. 12. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the amidine derivatives according to any one of claims 1-7, stereoisomers thereof, and pharmaceutically acceptable salts thereof as active ingredients and a pharmaceutically acceptable carrier or excipient. 13. Use of the amidine derivatives, stereoisomers and pharmaceutically acceptable salts thereof according to any one of claims 1-7, in the preparation of a medicament for preventing and/or treating diseases related to IDO1 enzyme and signaling pathway. 14. The use according to claim 13, wherein the disease related to IDO1 enzyme and signaling pathway is selected from cancer, infectious disease, and autoimmune disease. 15. The application according to claim 14, wherein the cancer is selected from skin cancer, lung cancer, urological tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, neurological Systemic tumor, brain tumor, head and neck cancer. 16. The application according to claim 14, wherein the infectious disease is selected from bacterial infection and viral infection. 17. The application according to claim 14, wherein the autoimmune disease is selected from organ-specific autoimmune disease and systemic autoimmune disease, wherein the organ-specific autoimmune disease comprises chronic lymphocytes Thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebral sclerosis , acute idiopathic polyneuritis, the systemic autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease , Autoimmune hemolytic anemia.