WO2019057104A1 - Salt of dioxygenase inhibitor and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a salt of a dioxygenase inhibitor and a preparation method therefor and the use thereof, in particular relates to a salt of (Z)-N-(3-bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinylimine)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine having the structure of general formula (I), a preparation method therefor and the use thereof, and a pharmaceutical composition comprising a therapeutic effective amount of the salt. The salt can be widely used to treat or prevent cancers or tumours, virus infections, depression, neurodegenerative disease, trauma, age-related cataract, organ-graft refection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressors, wherein the definition of each substituent in the general formula (I) is the same as defined in the description.

Description

Salt of dioxygenase inhibitor, preparation method and use thereof Technical field

The invention belongs to the field of medicine and relates to (Z)-N-(3-bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinyl) Salt of imino)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine, preparation method and application thereof, the invention discloses as an IDO inhibitor for treatment A disease having an IDO-mediated pathological feature of a tryptophan metabolism pathway, including cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder, and AIDS.

Background technique

Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reasons are: Ageing, urbanization, industrialization and lifestyle changes. In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.

Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The host's natural defense mechanisms (such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds. The alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan. Fast enzyme, which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein. IDO is closely related to interferon (IFN), interleukin (IL), tumor necrosis factor and other cytokines, and they can activate IDO under certain conditions. In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells; On the other hand, IDO catalyzes the main product produced by the metabolism of tryptophan. Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body. A large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.

(Z)-N-(3-Bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)) is disclosed in PCT Patent Application No. PCT/CN2017/079585 -S-methylsulfinimide)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazol-3-carboxamidine, in the subsequent development, for easy handling of the product, Filtration and drying, seeking suitable storage, long-term stability of the product, etc., the present invention has carried out a comprehensive study on the salt of the above substances, and is committed to obtaining the most suitable salt type.

Summary of the invention

The present invention relates to a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof,

among them:

M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1- Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxynonanoic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-amino Benzoic acid, citric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid , lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, Galactose, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid , malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicin , 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; And

y is an integer of 1, 2 or 3.

A preferred embodiment of the invention is characterized by a salt of the compound shown, a stereoisomer thereof or a mixture thereof, characterized in that it is selected from the group consisting of the salts of the compounds of formula (II):

Wherein: M and y are as defined in the general formula (I).

A preferred embodiment of the invention is characterized by the salt of the compound shown, its stereoisomer or a mixture thereof, characterized in that it is selected from the salt of the compound of formula (II-1):

Wherein: M and y are as defined in the general formula (I).

A preferred embodiment of the invention is characterized in that the salt of the compound of the formula (I), its stereoisomer or a mixture thereof is characterized by its free base crystalline form, characterized by having a ratio of 15.9, 17.2 , 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, 33.6 and 35.5 ± 0.2° diffraction angle 2θ (±0.2°) shows the XRPD of the peak with a melting peak of 176.4 ± 0.5 ° C on the DSC .

A preferred embodiment of the invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein M is selected from the group consisting of phosphoric acid, maleic acid and adipic acid , benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, fumaric acid and L-malic acid.

A preferred embodiment of the present invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein M is selected from adipic acid, benzenesulfonic acid, and para Benzobenzenesulfonic acid, tartaric acid and fumaric acid; preferably benzenesulfonic acid and p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.

A preferred embodiment of the invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein y is 1.

A preferred embodiment of the present invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, characterized in that when M is p-toluenesulfonic acid, it is a pair Methylbenzenesulfonate characterized by having diffraction angles 2θ (±0.2°) at 6.1, 9.6, 10.4, 14.8, 16.0, 17.1, 18.6, 19.4, 20.8, 22.1, 23.3, 24.6, 26.0 and 28.5 ± 0.2°. The XRPD of the peak is shown to have a melting peak of 162.7 ± 0.5 ° C on the DSC;

When M is benzenesulfonic acid, i.e., besylate, it is characterized by having 5.2, 6.1, 7.6, 9.5, 10.4, 10.4, 11.2, 14.1, 15.7, 16.0, 17.0, 18.2, 18.7, 19.4, 21.3, 22.2. , 22.6, 23.0, 23.6, 24.5, 24.9, 26.1, 26.5, 26.9, 28.7, 29.3, 30.6, 33.3, 34.5, 35.6, 36.5 and 41.0 ± 0.2° diffraction angle 2θ (±0.2°) shows the XRPD of the peak, The DSC has a melting peak of 152.3 ± 0.5 °C.

The invention further relates to a preparation scheme for the preparation of a salt of the compound of the formula (I), comprising the steps of:

1) Preparation of stock solution: take the free compound of the general formula, add organic solvent to dissolve, to obtain a clear stock solution, the solution concentration is: 20 ~ 30mg / mL; the organic solvent is preferably ethyl acetate, the solution concentration is preferably 25mg / mL;

2) Preparation of a counter-ion acid solution: adding a counter-acid to an organic solvent to obtain a clear counter-acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 0.25 to 2 mol/liter;

3) Preparation of compound salt: the stock solution is added to the counterion acid solution to obtain a clear salt solution, which is naturally evaporated, and dried under vacuum to obtain a salt of the compound of the formula (I); the vacuum temperature is preferably 60 ° C, and the amount of the counter ion acid is preferably 1 to 1.2 equivalents;

among them:

The organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol ;

The counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.

The invention further relates to a preparation scheme for the preparation of a salt of the compound of the formula (I), comprising the steps of:

1) Weigh an appropriate amount of free base and dissolve it with a benign solvent; the benign solvent is preferably ethyl acetate;

2) weigh 1-3 equivalents of counterion acid, dissolved in an organic solvent; organic solvent is preferably ethanol; the amount of counterion acid is preferably 1.2 equivalents;

3) Combine the above two solutions, and add a poor solvent until turbidity occurs, or stir overnight; the poor solvent is preferably heptane and dichloromethane;

4) standing or blow drying to obtain a salt of the compound of the formula (I);

among them:

The benign solvent is selected from the group consisting of acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate or acetonitrile; preferably ethyl acetate, ethanol, 2 - Butanone, 1,4-dioxane and acetone.

The organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol The above-mentioned benign solvent and organic solution need to be mutually soluble when used;

The poor solvent is selected from the group consisting of heptane, dichloromethane, water, methyl tert-butyl ether, toluene, diisopropyl ether or ethanol; preferably heptane and dichloromethane;

The counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.

The invention further relates to a preparation scheme, wherein the solvent is ethyl acetate or ethanol.

The invention further relates to a preparation scheme, wherein the counter ion acid is benzenesulfonic acid and p-toluenesulfonic acid.

A solution of a composition of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.

According to a preferred embodiment of the present invention, the salt of the compound of the formula (I), the stereoisomer thereof or a mixture thereof, or the composition thereof is prepared for prevention and/or treatment with IDO-mediated The use of the pathological features of the tryptophan metabolic pathway for the use of drugs in disease.

A preferred embodiment of the invention, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease , depression, anxiety, cataract, psychological disorder and AIDS; the cancer is preferably selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor , head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. The method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor Head and neck tumors, leukemias, lymphomas, myelomas and non-small cell lung cancers, preferably fallopian tube tumors, peritoneal tumors, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.

DRAWINGS

Figure 1 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base.

Figure 2 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate.

Figure 3 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate salt.

Figure 4 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt.

Figure 5 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate.

Figure 6 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate.

Figure 7 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate.

Figure 8 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate.

Figure 9 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.

Figure 10 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of tartrate.

Figure 11 is a graphical representation of the fumarate DSC-TGA (differential heat-thermogravimetric analysis).

Figure 12 is a graphical representation of the results of physical stability experiments for p-toluenesulfonic acid.

Figure 13 is a graphical representation of the results of the physical stability test of besylate.

Figure 14 is a graphical representation of the results of a polycrystalline screening experiment for p-toluenesulfonate.

Figure 15 is a graphical representation of the results of polystyrene screening experiments for besylate.

Detailed ways

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

Thermogravimetric Analysis (TGA) refers to a thermogravimetric analysis (TGA) experiment.

"Differential Scanning Calorimetry (DSC)" refers to differential scanning calorimetry (DSC) experiments.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

1.1 Experimental equipment

1.1.1 Some parameters of physical and chemical detection instruments

1.2 liquid phase analysis conditions

1.2.1 Instruments and equipment

equipment name	model
Analytical Balances	Sartorius BSA224S-CW
Pure water machine	Milli-Q Plus, Millipore
High performance liquid chromatography	Agilent1260
Pump	Agilent G1311B
Sampler	G1329B
Column thermostat	G1316A
Detector	G1315D

1.2.2 Chromatographic conditions

Column: Waters X-Bridge (C18, 3.5μm, 4.6*100mm)

Flow rate: 1.0mL/min

Column temperature: 40 ° C

Detection wavelength: 287nm

Injection volume: 5μL

Running time: 15min

Thinner: acetonitrile-water (v/v, 1:1)

Mobile phase: A: water (0.1% trifluoroacetic acid);

B: acetonitrile (0.1% trifluoroacetic acid)

T(min)	B (%)
0	10
12	90
12.1	10
15	90

Example 1: Preparation by natural evaporation method

1.1 Experimental purpose:

Different counterion acids are selected and natural counter-drying methods are used to detect which counter-acids can form compound salts.

1.2 Experimental steps:

1) Instruments and equipment

name	model	source
Analytical Balances	BSA224S-CW	Sartorius
Ultrasonic cleaner	SK5200LHC	Shanghai Science and Technology Ultrasonic Instrument
Pipette	Eppendorf (50mL, 1000μL)	Eppendorf

2) Operating procedures

1 stock preparation

Take the formula compound free base 288.8mg, add ethyl acetate 3 × 3.85mL (using a 5mL pipette),

The solution was sonicated to obtain a clear solution at a solution concentration of 25 mg/mL.

2 salt solution preparation (reverse ion acid addition amount of 1.2 equivalents of free base)

A salt solution of 2 was added to 1 mL of the stock solution 1, and it was naturally evaporated, and dried under vacuum at 60 ° C to obtain a salt of the corresponding compound.

1.2.3DSC-TGA test

Figure 1: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base;

Figure 2: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate;

Figure 3: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate;

Figure 4: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt;

Figure 5: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate;

Figure 6: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate;

Figure 7: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate;

Figure 8: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate;

Figure 9: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.

1.3 Experimental conclusions

Data analysis by DSC-TGA (differential heat-thermogravimetric analysis) and comparison with the data of free base showed that all of the above counterionic acids were able to form compound salts.

Example 2: Preparation by anti-solvent method

2.1 Experimental purpose:

The benign solvent is selected to dissolve the compound, and the compound is crystallized out with a poor solvent.

Benign solvent: acetone, 2-butanone (MEK), tetrahydrofuran (THF), 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile;

Poor solvent: heptane, dichloromethane, water, methyl tert-butyl ether, toluene, diisopropyl ether, ethanol;

Counterionic acid: methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, L-malic acid.

2.2 Experimental steps

1) Instruments and equipment

name	model	source
Analytical Balances	BSA224S-CW	Sartorius
Ultrasonic cleaner	SK5200LHC	Shanghai Science and Technology Ultrasonic Instrument
Circulating water pump	SHB-III	Zhengzhou Great Wall Science and Trade Co., Ltd.

2) Operating procedures

Scheme 1: Free base crystallization good solvent and anti-solvent selection

1 benign solvent: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: water;

2 benign solvents are: acetone, THF, 1,4-dioxane; anti-solvent: heptane, dichloromethane;

3 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: ethanol, isopropanol;

4 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: methyl tert-butyl ether, isopropyl ether;

Specific implementation of free base anti-solvent selection:

50 mg of free base was weighed, dissolved in 2 mL of benign solvent, and the anti-solvent was added dropwise under stirring. When a white precipitate appeared, the dropwise addition was stopped. After standing, the precipitate was collected, dried under vacuum, and XRPD was detected.

The screening of different benign solvents and poor solvents is as follows:

From the above experiments, it is known that ethanol, isopropanol, methyl tert-butyl ether, and isopropyl ether are not ideal anti-solvents in the system composed of the above-mentioned benign solvent and poor solvent.

Scheme 2: Compound salt crystallization good solvent and anti-solvent selection

The benign solvents are: 2-butanone, 1,4-dioxane and ethyl acetate; the anti-solvent is: dichloromethane, n-heptane;

Counterion acid solution solvent: ethanol.

Specific implementation methods for salt preparation of good solvent and anti-solvent:

1) Weigh 150 mg of free base and dissolve it with 6 mL of benign solvent;

2) Weigh 1.2 equivalents of counterion acid and dissolve it with ethanol;

3) the free base solution and the counter ion acid solution are mutually soluble;

4) adding a poor solvent until turbidity occurs, stirring overnight;

5) Allow to stand or blow dry to obtain a solid salt.

The solution of free base and counterion acid is as follows:

The screening of different benign solvents and poor solvents is as follows:

#: The former indicates the amount of the anti-solvent added, expressed by volume or weight, and the latter indicates the phenomenon exhibited by the salt solution after the addition of the anti-solvent to the volume or weight.

Through the above experiments, we can know:

1) In a system where the benign solvent is ethyl acetate and the antisolvent is heptane, phosphate, maleate, adipate, benzenesulfonate, p-toluenesulfonate, citrate, C Diacid salts, tartrate salts, fumarate salts and L-malate salts are all present in large amounts.

2) Under a system in which the benign solvent is 1,4-dioxane and the anti-solvent is dichloromethane, adipic acid, maleic acid, citric acid, and L-malic acid are slightly turbid, and the others are clear solutions.

3) There is a black precipitate formed in hydrobromide, sulfate and nitrate.

XRPD ray diffraction data of free base and various salts

1. XRPD ray diffraction data of adipate:

2. XRPD ray diffraction data of D-tartrate:

3. XRPD ray diffraction data of fumarate:

4. XRPD ray diffraction data of p-toluenesulfonate:

5. XRPD ray diffraction data of besylate:

6. XRPD ray diffraction data of free base:

Example 3: Reaction molar ratio experiment of salt

3.1 Experimental purpose:

The counterions of different molar ratios were added to investigate the stability of the stoichiometric ratio of p-toluenesulfonate to besylate under the established crystallization conditions.

3.2 Experimental plan:

The molar ratio of the counter ion was changed to 0.6 and 2.2 (the molar ratio is the ratio of the number of counterions to the number of moles of free base). The same crystallization process was used to investigate the feasibility of the salt crystallization process and the salt reaction ratio. The mass percentage of free base in the crystalline product was determined by HPLC and external standard method, and compared with the mass percentage of the theoretical reaction ratio.

3.3 Experimental results:

sample name

Free base was measured in the crystal

Theoretical free base in salt

	content%	(1:1 molar ratio) content%
P-toluenesulfonate-0.6	98.2	76.2
P-toluenesulfonate-2.2	94.7	76.2
Benzenesulfonate-0.6	92.0	77.7
Benzenesulfonate-2.2	89.0	77.7

By changing the amount of counterion of the feed, solids can be crystallized out; the solids which are crystallized are subjected to free base quantification, and most of the precipitated crystals are free bases, and a salt having a molar ratio of 1:1 is not formed. When the molar ratio of the counter ion charge is in the range of 1 to 1.2, p-toluenesulfonic acid and benzenesulfonate having a stoichiometric ratio of 1:1 can be formed.

Example 4: Simulating the solubility test in artificial gastrointestinal

4.1 Experimental purpose:

Comparing the solubility of different salts of compounds in simulated artificial gastrointestinal fluids, it provides a basis for the evaluation of salt drug availability.

4.2 Experimental plan:

Approximately 2 mg of the compound was suspended in 1 mL of artificial simulated gastric juice (SGF), fasted artificial simulated intestinal fluid (Fa), non-fasted artificial simulated intestinal fluid (Fe), and pure water for 16 hours, and the compound was determined by HPLC and external standard method. Thermodynamic solubility.

4.3 Experimental results:

From the solubility of the compound and its salt in the simulated intestinal fluid, the solubilization effect of the compound besylate and p-toluenesulfonate compared with the free base is obvious, and it is the primary screening salt.

Example 5: Solid Stability Experiment

5.1 Experimental purposes:

The physicochemical stability of the candidate compound salt under accelerated conditions or influencing factors was investigated to provide a basis for salt screening and compound salt storage.

5.2 Experimental protocol:

1) p-toluenesulfonate:

Take about 10mg of p-toluenesulfonate, sealed in 70 ° C oven, light box (5000lx ± 500lx), open 40 ° C & RH75% (saturated NaCl aqueous solution), RH75% (room temperature) and 30 ° CRH 65% conditions The lower (saturated potassium chromate solution) was examined for 5 days and 10 days, and the salt content was determined by HPLC and external standard method, and the change of the salt-related substance was calculated by the chromatographic peak area normalization method.

2) Benzene sulfonate:

Take about 10mg of benzenesulfonate, seal it in a 70°C oven, light box (5000lx±500lx), open it in 30°C & RH75% (saturated NaCl aqueous solution) for 5 days and 10 days, using HPLC, external standard method. The salt content was determined, and the change in the salt-related substance was calculated by the chromatographic peak area normalization method.

3) Physical stability measurement:

Two salt samples from 10 days were examined and their XRPD was determined and compared to X-day XRPD.

5.3 Experimental results:

1) Physicochemical stability results of p-toluenesulfonate:

The chemical stability results of p-toluenesulfonate:

sample name	content%	Total impurity %	Increase in impurities
P-toluenesulfonate - 0 days	/	0.44	/
P-toluenesulfonate -50 ° C & RH 75% - 5 days	36.05	49.60	49.16
P-toluenesulfonate -50 ° C & RH 75% - 10 days	20.48	67.87	67.43
P-toluenesulfonate -70 ° C - 5 days	100.76	0.47	0.03
P-toluenesulfonate -70 ° C - 10 days	103.21	0.50	0.06
P-toluenesulfonate - light -5 days	97.97	1.84	1.40
P-toluenesulfonate - light -10 days	95.62	2.75	2.31
P-toluenesulfonate -30 ° C & RH 65% - 5 days	99.35	1.07	0.63
P-toluenesulfonate -30 ° C & RH 65% - 10 days	94.08	2.09	1.65
p-toluenesulfonate-RH75%-5 days	98.66	0.56	0.12
p-toluenesulfonate-RH75%-10 days	97.80	0.66	0.22

The compound p-toluenesulfonate was extremely unstable at 50 ° C & RH 75%. After 5 days of storage, the impurity increased by more than 40%. After being placed at 30 ° C & RH 65% for 5 days, the related substances increased by 0.63%, and the RH was 75%. After being placed at room temperature for 5 days and 10 days, the increase of related substances was not obvious, and the impurity increased by 0.22% in 10 days; the compound p-toluenesulfonate was stable under high temperature (70 ° C) for 10 days, and the impurity only increased by 0.06%; Under light conditions, the compound p-toluenesulfonate was slightly degraded for 5 days and 10 days. Therefore, the compound p-toluenesulfonate should be protected from moisture and light.

Physical stability results of p-toluenesulfonic acid:

The test results are shown in Figure 10.

XRPD results showed that p-toluenesulfonate was investigated at 30 ° C & RH 65%, RH 75% (room temperature), light and high temperature for 10 days, and the crystal form did not change compared with the 0 day sample.

1) Physicochemical stability results of besylate:

The chemical stability results of besylate:

sample name	content%	Total impurity %	Increase in impurities
Benzene sulfonate - 0 days	/	1.09	/
Benzene sulfonate -30 ° C & RH 65% - 5 days	96.19	1.03	-0.06
Benzene sulfonate -30 ° C & RH 65% - 10 days	94.40	1.58	0.49
Benzene sulfonate -70 ° C - 5 days	99.67	0.96	-0.13
Benzene sulfonate -70 ° C - 10 days	92.94	13.46	12.37
Benzene sulfonate - light -5 days	79.18	/	/
Benzene sulfonate - light -10 days	77.18	22.88	21.79

Under the condition of 30 °C & RH65%, the compound benzenesulfonate did not increase significantly, but the content decreased significantly. The compound besylate was stable under high temperature (70 °C) for 5 days, and the impurity increased suddenly for 10 days. More than %; under light conditions, the compound p-toluenesulfonate was degraded for 5 days and 10 days.

Physical stability results of besylate:

The test results are shown in Figure 11.

XRPD results showed that the compound besylate was allowed to stand at 30 ° C & RH 65% for 10 days, and the crystal form changed. The compound besylate was observed under light and high temperature for 10 days, and its crystal form was compared with the 0 day sample. The crystal form did not change.

5.4 Summary: The stability of the compound p-toluenesulfonate and benzenesulfonate stability shows that p-toluenesulfonate is superior to benzenesulfonic acid in the condition of moisture-proof and light-proof packaging.

Example 6: Humidity test

6.1 Experimental purpose

The hygroscopicity of the compounds under different relative humidity conditions was investigated to provide a basis for screening and storage of the compound salts.

6.2 Experimental protocol:

The compound salt is placed in saturated water vapor of different relative humidity to achieve a dynamic equilibrium between the compound and the water vapor, and the percentage of moisture absorption and weight gain of the compound after equilibrium is calculated.

6.3 Experimental results:

The p-toluenesulfonate was not wetted under RH 75% conditions (Chinese Pharmacopoeia 2015 edition), and the besylate salt had hygroscopicity under RH 75% conditions. And the p-methylbenzenesulfonate is hygroscopically and desorbed four times under the condition of 0-95% relative humidity, and the XRPD mode is not changed, that is, there is no crystal transformation; the besylate salt crystallizes under the same treatment conditions. Type change.

From the viewpoint of wettability, p-toluenesulfonate is superior to besylate.

Example 7: Polycrystalline screening experiment

7.1 Experimental purpose: Through the polycrystalline screening, the crystal form of the relatively stable compound salt was found.

7.2 Experimental protocol: Select an organic solvent and water with a certain solubility, suspend the compound in a solvent system, stir and beat at room temperature for 1 week, centrifuge, discard the supernatant, and dry the solid at 40 ° C overnight (-0.1 Mpa) overnight. Thereafter, the solid XRPD was determined and compared to the XRPD of the compound salt.

7.3 Experimental results:

1) p-toluenesulfonate results:

The results of the polycrystal screening experiment are shown in FIG.

The compound p-toluenesulfonate can be converted into a free base by beating in water, and besed in other solvents EtOH, DCM, 88% acetone and ethyl acetate. The compound is stable to the methylbenzenesulfonate crystal form and is not converted into other Stable crystal form.

2) Benzene sulfonate results:

The results of the polycrystal screening experiment are shown in FIG.

The compound besylate is not converted to a free form in water except for beating in ethyl acetate, and is converted to a free base in water, and crystal transformation occurs in other solvents.

From the results of polycrystalline screening, p-toluenesulfonate is more stable than the benzsulfonate crystal form.

Example 8: Animal PK Study

8.1 Experimental Objective: To compare the difference in exposure between compound salt and free base in animals by animal PK study.

8.2 Experimental protocol: The free base, p-toluenesulfonate and besylate of the compound were suspended in a CMC-Na (0.5%) aqueous solution containing 0.1% Tween 80, and then administered orally, and the rats were administered. Two rats in parallel were administered at a dose of 100 mg/kg, and the amounts of the compounds were all converted into the same amount of free base.

8.3 Experimental results:

	Free base	Benzene sulfonate	P-toluenesulfonate
T max (h)	2	1	4
C max (ng/mL)	592.5	545.0	705.0
AUC 0-t (ng/mL*h)	2908.5	2419.1	4432.4
AUC 0-∞ (ng/mL*h)	3730.1	2584.5	5914.9
t 1/2 (h)	3.45	1.70	3.34
MRT 0-∞ (h)	5.53	3.49	6.11

The p-toluenesulfonate of the compound significantly increases the exposure of the compound in rats.

Claims (14)

1. a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof,

   

   among them:

   M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1- Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxynonanoic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-amino Benzoic acid, citric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid , lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, Galactose, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid , malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicin , 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; And

   y is an integer of 1, 2 or 3.
2. A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, according to claim 1, characterized in that it is a salt selected from the compound of the formula (II):

   

   among them:

   M and y are as defined in the general formula (I).
3. The compound of the formula (I) according to claim 1 or 2, which is in the form of a free base crystal, characterized by having 15.9, 17.2, 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, The diffraction angle 2θ (±0.2°) of 33.6 and 35.5 ± 0.2° shows the XRPD of the peak with a melting peak of 176.4 ± 0.5 ° C on the DSC.
4. A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to claim 1 or 2, wherein M is selected from the group consisting of phosphoric acid, maleic acid, adipic acid, and benzenesulfonate. Acid, p-toluenesulfonic acid, citric acid, malonic acid, tartaric acid, fumaric acid and L-malic acid.
5. A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 4, wherein M is selected from adipic acid, benzenesulfonic acid, or the like. Methylbenzenesulfonic acid, tartaric acid and fumaric acid; preferably benzenesulfonic acid and p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.
6. A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 5, wherein y is 1.
7. A compound of the formula (I) according to any one of claims 1 to 6:

   When M is p-toluenesulfonic acid, ie p-toluenesulfonate, characterized by having 6.1, 9.6, 10.4, 14.8, 16.0, 17.1, 18.6, 19.4, 20.8, 22.1, 23.3, 24.6, 26.0 with The diffraction angle 2θ (±0.2°) of 28.5±0.2° shows the XRPD of the peak, which has a melting peak of 162.7±0.5° C. on the DSC;

   When M is benzenesulfonic acid, i.e., besylate, it is characterized by having 5.2, 6.1, 7.6, 9.5, 10.4, 10.4, 11.2, 14.1, 15.7, 16.0, 17.0, 18.2, 18.7, 19.4, 21.3, 22.2. , 22.6, 23.0, 23.6, 24.5, 24.9, 26.1, 26.5, 26.9, 28.7, 29.3, 30.6, 33.3, 34.5, 35.6, 36.5 and 41.0 ± 0.2° diffraction angle 2θ (±0.2°) shows the XRPD of the peak, The DSC has a melting peak of 152.3 ± 0.5 °C.
8. A process for the preparation of a salt of a compound of the formula (I) according to any one of claims 1 to 6, comprising the steps of:

   1) Preparation of stock solution: take the free compound of the general formula, add organic solvent to dissolve, to obtain a clear stock solution, the solution concentration is: 20 ~ 30mg / mL; the organic solvent is preferably ethyl acetate, the solution concentration is preferably 25mg / mL;

   2) Preparation of a counter-ion acid solution: adding a counter-acid to an organic solvent to obtain a clear counter-acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 0.25 to 2 mol/liter;

   3) Preparation of compound salt: the stock solution is added to the counterion acid solution to obtain a clear salt solution, which is naturally evaporated, and dried under vacuum to obtain a salt of the compound of the formula (I); the vacuum temperature is preferably 60 ° C, and the amount of the counter ion acid is preferably 1 to 1.2 equivalents;

   among them:

   The organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol ;

   The counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
9. A process for the preparation of a salt of a compound of the formula (I) according to any one of claims 1 to 7, comprising the steps of:

   1) Weigh an appropriate amount of free base and dissolve it with a benign solvent; the benign solvent is preferably ethyl acetate;

   2) weigh 1-3 equivalents of counterion acid, dissolved in an organic solvent; organic solvent is preferably ethanol; the amount of counterion acid is preferably 1.2 equivalents;

   3) Combine the above two solutions, and add a poor solvent until turbidity occurs, or stir overnight; the poor solvent is preferably heptane and dichloromethane;

   4) standing or blow drying to obtain a salt of the compound of the formula (I);

   among them:

   The benign solvent is selected from the group consisting of acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate or acetonitrile; preferably ethyl acetate, ethanol, 2 - butanone, 1,4-dioxane and acetone;

   The organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol The above-mentioned benign solvent and organic solution need to be mutually soluble when used;

   The poor solvent is selected from the group consisting of heptane, dichloromethane, water, methyl tert-butyl ether, toluene, diisopropyl ether or ethanol; preferably heptane and dichloromethane;

   The counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin acid, Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
10. The production method according to claim 8, wherein the organic solvent is ethyl acetate or ethanol.
11. The production method according to claim 8 or 9, wherein the counterionic acid is benzenesulfonic acid and p-toluenesulfonic acid.
12. A pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of the formula (I) according to any one of claims 1 to 7, a stereoisomer thereof or a mixture thereof, and one or A wide variety of pharmaceutically acceptable carriers, diluents or excipients.
13. A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 7, or a composition according to claim 12, which is prepared for prevention and / Use in the treatment of a disease having a pathological feature of the IDO-mediated tryptophan metabolism pathway.
14. The use according to claim 13, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression , anxiety, cataract, psychological disorder and AIDS; the cancer is preferably selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone Cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck Tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

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