WO2019120199A1 - Quinoline derivatives and bioactivity thereof - Google Patents

Abstract

The present invention provides a quinoline-4-base cyclohexane compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, as well as a preparation method therefor. Said compound alone or in combination with other drugs is used for tretating pathological features of tryptophan metabolic pathway disorders mediated by IDO.

Description

A class of quinoline derivatives and their biological activities Technical field

The present invention relates to a class of quinolin-4-ylcyclohexane compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and processes for their preparation and combinations thereof, alone or in combination with other drugs A disease is used in the treatment of pathological features of the IDO-mediated tryptophan metabolism pathway.

Background technique

Tryptophan is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize proteins and the neurotransmitter serotonin, and the rest is mainly metabolized by the kynurenine pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway. When the expression level of IDO1 is high in tissue cells, a large amount of tryptophan is metabolized by the kynurenine metabolic pathway, and the tryptophan content is decreased, which directly inhibits the activation and proliferation of effector T cells. The metabolites produced by the kynurenine pathway have certain effects on immunity, reproduction and central nervous system. In addition to directly inhibiting the survival of effector T cells, they also inhibit effector T cells by promoting the differentiation of regulatory T cells. Studies have shown that the total uric acid metabolic pathway of tryptophan is an important cause of immune escape in tumor cells.

Recent studies have shown that IDO-mediated kynurenine metabolism is also associated with other diseases. Such as the kynurenine pathway and myelodysplastic syndrome (Leuk Res. 2013; 37 (5): 573-9); neurodegenerative diseases, schizophrenia and depression (Nat Rev Neurosci. 2012; 13 (7): 465 -77); Alzheimer's disease (J Neural Transm (Vienna). 2000; 107(3): 343-53); cataract (Curr Eye Res. 2009; 34(4): 274-81); inflammation and sepsis (Nat. Med 2010; 16 (3): 279-85); AIDS (PLoS One. 2013; 8 (9): e74551);

A large number of experimental data indicate that IDO inhibitors have therapeutic and preventive effects in various diseases such as tumors, and have good application prospects, but existing IDO inhibitors have shown insufficient effectiveness or dose-limiting toxicity in clinical trials, which is required in the art. Development of new IDO inhibitors.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof,

among them:

R ₁ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O ₂ )-C _1-6 alkyl;

X is selected from O or S;

R _{2 is} selected from the group consisting of hydrogen, deuterium, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , - NH ₂ , —NO ₂ , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C _1-4 alkyl;

R ₃ and R ₄ are each independently hydrogen, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl; or

R ₃ and R ₄ together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a -C _1-4 alkyl group. .

In another aspect, the invention provides a compound of formula (II),

among them,

R ₁ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O ₂ )-C _1-6 alkyl;

R _{2 is} selected from the group consisting of hydrogen, deuterium, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , - NH ₂ , -NO ₂ .

In a further embodiment, the invention provides a compound of formula (II), a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

R _{1 is} selected from the following structures:

R _{3 is} selected from fluorine.

Typical compounds of the present invention relating to formula (I)-formula (II) are shown in Table 1, but are not limited to the following examples:

Table 1

definition

As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below. If not defined, all technical and scientific terms used in the specification have the meaning commonly understood by one of ordinary skill in the art.

abbreviation	meaning
IDO	Indoleamine 2,3-dioxygenase
TLC	TLC
R f	Ratio shift
CDI	Carbonyldiimidazole
EDCI	1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
DIC	N,N'-diisopropylcarbodiimide
DCC	Dicyclohexylcarbodiimide
HATU	2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
HBTU	Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate

PyBOP	1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate
MS	Mass spectrometry
IFN-γ	Γ-interferon
EDTA	Ethylenediaminetetraacetic acid
FBS	Fetal bovine serum
EA	Ethyl acetate
PE	Petroleum ether

The term "hydrogen" as used herein refers to -H.

The term "氘" refers herein to -D.

The term "halogen" as used herein refers to -F, -Cl, -Br and -I.

The term "alkyl" as used herein refers to an alkyl group that does not contain a hetero atom. Thus, the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like. The term also includes branched chain isomers of branched alkyl groups, including but not limited to, the following _{groups: -CH (CH 3) 2,} -CH (CH 3) (CH 2 CH 3), - CH (CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -C(CH ₂ CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )(CH ₂ CH ₃ ), - CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ C(CH ₃ ) ₃ , -CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )-CH(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ C(CH ₃ ) ₃ , -CH ₂ CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )CH(CH ₃ )CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(CH ₃ )CH(CH ₃ )(CH ₂ CH ₃ ), and the like. Thus the term alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.

The term "alkenyl" as used herein refers to at least one point of unsaturation in which two adjacent carbon atoms are bonded to the alkyl group defined above by a double bond, wherein the alkyl group is as defined herein.

The term "alkynyl" as used herein refers to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein.

The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and is optionally saturated, partially unsaturated or fully unsaturated. Depending on the structure, the cycloalkyl group is mono- or di-radical (for example, a cycloalkylene group).

The term "heterocycloalkyl" as used herein refers to at least one heteroatom selected from O, N and S and optionally contains one or more double or triple bond non-aromatic cycloalkyl groups. The heterocycloalkyl group as a whole may have 3 to 14 ring atoms and contain 1 to 5 hetero atoms (for example, 3 to 6 ring atoms in the case of a monocyclic heterocycloalkyl group, in the case of a polycyclic heterocycloalkyl group) Has 7-14 ring atoms). Heterocycloalkyl groups can be covalently attached to a defined chemical structure at any hetero atom or carbon atom that results in a stable structure. One or more N or S atoms on the heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide). Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like. Examples of heterocycloalkyl groups also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrroline Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, piperidinyl, azetidine, piperazinyl and the like.

At various points in the specification, substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention encompasses subgroups of each of the members or members of such groups and ranges. The term "C _1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

The term "compound of the invention" (unless otherwise specifically indicated) refers herein to compounds of formula (I)-(II) and all their pure and mixed stereoisomers, geometric isomers, tautomers. , solvates, hydrates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts. The solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate or the like, in combination with a stoichiometric and non-stoichiometric solvent. The compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.

The term "stereoisomer" as used herein refers to a chiralally different compound having one or more stereocenters, including the corresponding isomers and diastereomers.

The compound of the present invention can be used in the form of a salt such as a "pharmaceutically acceptable salt" derived from an inorganic or organic acid. These include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, hydrochloride, 2 -naphthalene sulfonate, oxalate, pectate ester, sulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, sulfur Cyanate, p-toluenesulfonate and decanoate. In addition, basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups. a dialkyl sulfate, including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.

The invention also includes isotopically-labeled compounds of the invention, i.e., identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons. Examples of isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹³¹ I, etc. The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, as well as the compounds of the above forms containing the above isotopes and/or other atomic isotopes, are within the scope of the invention. Certain isotopically-labeled compounds of the invention, such as those labeled with ³ H or ¹⁴ C, can be used in drug tissue distribution assays, and therefore, these ³ H or ¹⁴ C isotopes are particularly preferred for their ease of preparation and detection. In addition, certain compounds of the invention that are replaced by heavier isotopes such as ² H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, ² H is in some It is also preferred in some cases. Isotopically labeled compounds of the formula (I) according to the invention and their presuppositions can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopic labels when carrying out the processes disclosed in the following schemes and/or examples and preparations. Reagents.

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(II), or a pharmaceutically acceptable carrier, diluent or excipient thereof.

The invention further relates to a compound of the formula (I)-(II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for use in the prevention and/or treatment of IDO-mediated tryptophan metabolism The use of a pathway for the pathology of a drug in a disease. The disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorder, nerve Lesions and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, and skin. Cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma , choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor.

The present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune Disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.

The present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer , breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer , brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, Tubal tumors.

Compound or intermediate preparation method

For the purpose of describing the invention, specific embodiments are set forth below. However, it is to be understood that the invention is not limited to the embodiments, and the following examples are merely intended to provide a method of practicing the invention and are not intended to limit the scope of the invention.

The compounds provided herein can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the invention. Starting materials are usually commercially available, for example by Alfa

TCI,

Suiyuan Chemical, An Naiji Chemical, Ester (Chengdu) Biopharmaceutical, Chengdu Best Reagent, Chengdu Huana Chemical Preparation Co., Ltd., Aiqi Kang Pharmaceutical Technology (Shanghai) Co., Ltd., Shanghai Yuxiang Biotechnology Co., Ltd. It is commercially available from companies such as Shanghai WuXi PharmaTech Development Co., Ltd. or by methods well known to those skilled in the art.

The following reaction methods and synthetic procedures provide possible routes for the synthesis of the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the examples below. Those skilled in the art will appreciate that the compounds of the invention may also be obtained by other synthetic routes. While specific starting materials and reagents are used in the reaction schemes below, these starting materials and reagents can be replaced by other similar starting materials or reagents to provide various derivatives. Furthermore, many of the compounds produced by the methods described below can be further modified by conventional chemical methods well known to those skilled in the art under the teachings of the present specification.

The compounds of the invention and the corresponding methods of preparation are further explained and exemplified below by way of examples and preparations. It will be appreciated that while typical or preferred reaction conditions (e.g., reaction temperature, time, molar ratio of reactants, reaction solvent, and pressure, etc.) are given in the specific examples, other reaction conditions can be used by those skilled in the art. Optimum reaction conditions may vary depending on the particular reaction substrate or solvent employed, but such conditions can be determined by one of ordinary skill in the art by routine optimization.

The reaction starting materials, intermediates, and example compounds can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation, etc.).

TLC was extracted from Yantai Huanghai HSGF254 thin-layer chromatography silica gel plate (0.2±0.03 mm) by TLC. The Yantai Yellow Sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm) was purchased from Qingdao Ocean Chemical Plant.

Column chromatography was purchased from Qingdao Ocean Chemical Plant using Yantai Yellow Sea 300-400 mesh silica gel as carrier.

The commercial solvents and reagents used in the test are used without any further explanation after purchase and without further purification or treatment. The reaction conditions (reaction temperature, reaction solvent, reactant molar ratio or/and reaction duration) may be different with reference to other examples or synthetic methods. In general, the progress of the reaction can be monitored by TLC, and the appropriate time is selected to terminate the reaction and post-treat. The purification conditions of the compound may also vary. In general, the appropriate column chromatography eluent is selected according to the _Rf value of TLC, or the corresponding compound is isolated and purified by preparative TLC.

The compound of the formula (I) of the present invention can be produced according to the following Scheme 1. The condensation of A and B gives the compound of formula (I), which typically employs a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like. It will be appreciated that these reaction conditions are not limiting and that the process can be used to prepare compounds of formula (I) by rationally varying the reaction conditions. Wherein R ¹ , R ² , R ³ and R ⁴ have the definitions as described in the present invention.

Process 1

The compound of the formula (I) of the present invention can be produced according to the following Scheme 2. Reaction of A with thionyl chloride in a suitable solvent such as dichloromethane affords intermediate C. Intermediates C and B in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc. in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, In the hexacyclic or the like, the reaction gives a compound of the formula (I). It will be appreciated that these reaction conditions are not limiting and that the process can be used to prepare compounds of formula (I) by rationally varying the reaction conditions. Wherein R1, R2, R3 and R4 have the definitions as described herein.

Process 2

The following examples are intended to illustrate the specific embodiments of the invention, and are not intended to limit the scope of the invention. Those skilled in the art will recognize that the starting materials may vary and additional steps may be employed to generate the compounds encompassed by the present invention, as demonstrated by the following examples. The following examples are for illustrative purposes only and are not intended to be construed as limiting the invention in any way. A person skilled in the art will recognize that variations and modifications can be made without departing from the spirit or scope of the invention.

Example 1. Preparation of Compound 1

Add (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (preparation method WO2016073774A2) 40 mg, 5 mL dichloromethane to a dry reaction flask The mixture was added with 1 ml of thionyl chloride under stirring, and further raised to 40 ° C for 1 hour. After concentration under reduced pressure to dryness and then cooled to room temperature, to the concentrate was added 1.2 equivalents of 4-(methylthio)aniline, 5 mL of dichloromethane, and 0.5 mL of pyridine, and the mixture was stirred at room temperature for 30 minutes and monitored by TLC. After completion of the reaction, the mixture was combined with methylene chloride and EtOAc (EtOAc m. ¹ H NMR (CDCl ₃ , 400 MHz, ppm): δ = 8.82 - 8.81 (d, J = 4.5 Hz, 1H), 8.14 - 8.10 (dd, J = 9.2, 5.8 Hz, 1H), 7.67 - 7.63 (dd, J=10.4, 2.7 Hz, 1H), 7.50-7.48 (m, 2H), 7.34-7.33 (d, J=4.5 Hz, 1H), 7.30 (s, 1H), 7.25-7.23 (m, 2H), 3.31 (br s,1H),2.63-2.57(m,1H), 2.46(s,3H),2.14-2.12(m,1H),1.95-1.60(m,8H),1.30-1.28(d,J=6.8 Hz, 3H). ESI MS (M+H) ⁺ = 423.3.

Example 2, Preparation of Compound 2

The compound of the present invention was synthesized by the method of Scheme 2 to give Compound 2. ESI-MS m/z: 546.1 [M+H] ⁺ .

Biological test

1. Compound test for IDO inhibition activity

HeLa cells were purchased from ATCC and cultured in DMEM containing L-glutamine (2 mM), non-essential amino acids (84 mg/L) and fetal bovine serum (10% FBS) at 95% humidity, 5% CO ₂ , 37 ° C. Incubator. One day before the test, the cells were continuously passaged and grown well. More than 90% of the fused Hela cells were digested with EDTA/trypsin, resuspended in DMEM complete medium, and seeded in 96-well culture plates at a density of 5000/well. Cultivate overnight. On the next day, 96-well plate cell culture medium was replaced, and 200 μl of IFN-γ (final concentration 50 ng/mL, purchased from R&D) and serial dilutions of the compound medium were added to each well. The highest concentration of the compound was 1000 nM, and 7 concentration gradients were diluted 5 times. After the culture plate was returned to the cell culture incubator for 48 hours, 150 μl of the supernatant/well was transferred to a new 96-well plate, 7.5 μl of trichloroacetic acid was added to each well, and the mixture was incubated at 50 ° C for 30 min to produce N. - Formyl kynurenine is hydrolyzed to kynurenine. The precipitate was then removed by centrifugation at 12000 rpm for 10 minutes. The supernatant was analyzed by liquid/triple quadrupole mass spectrometry (LC/MS/MS, LC-20AD high performance liquid chromatography system, Shimadzu, Japan; API4000 triple quadrupole mass spectrometer, Applied Biosystem, USA) for analysis of L-kynurenine concentration. A standard curve was established with a concentration gradient of 2-5000 ng/ml L-kynurenine; the concentration of L-kynurenine in the cell culture supernatant was measured to calculate the activity of each compound to inhibit IDO by fitting with original 7.5. IC ₅₀ of uridine;

The test results of the inhibitory activity of the compound against IDO1 in HeLa cells are shown in Table 1.

The test results indicate that the compound of the present invention has a significantly better inhibitory effect on IDO1 in Hela cells than BMS-986205.

Claims (10)

1. A compound of formula (I):

   

   a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

   R ₁ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O ₂ )-C _1-6 alkyl;

   X is selected from O or S;

   R _{2 is} selected from the group consisting of hydrogen, deuterium, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , - NH ₂ , —NO ₂ , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C _1-4 alkyl;

   R ₃ and R ₄ are each independently hydrogen, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _3-6 cycloalkyl; or

   R ₃ and R ₄ together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a -C _1-4 alkyl group. .
2. A compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, according to claim 1, wherein the compound is as shown in formula (II):

   

   R ₁ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O ₂ )-C _1-6 alkyl;

   R _{2 is} selected from the group consisting of hydrogen, deuterium, halogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , - NH ₂ , -NO ₂ .
3. A compound according to claim 2, which is a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

   R ₁ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O ₂ )-C _1-6 alkyl;

   R _{2 is} selected from the group consisting of hydrogen, helium, and halogen.
4. A compound according to claim 3, which is a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

   R _{1 is} selected from the following structures:

   

   R _{2 is} selected from fluorine.
5. A compound, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, according to any one of claims 1 to 4, which is selected from the group consisting of:

   
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable carrier, diluent or excipient thereof.
7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6, prepared for the prevention and/or treatment of IDO-mediated tryptophan metabolism The use of a pathway for the pathology of a drug in a disease.
8. The use according to claim 7, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, Schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer , bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, Esophageal cancer, renal cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor.
9. A method of treating a disease which prevents and/or treats a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 5 or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.
10. A method of treating a disease which prevents and/or treats a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 5 or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer, breast Cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer, brain Cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, testicular cancer, glioma, maternal glioma, fallopian tube tumor .