TW201815793A - Crystalline form of free alkali of imidazo isoindole derivative and a preparation method thereof - Google Patents

Abstract

The present invention relates a crystalline form of free alkali of imidazo isoindole derivative and a preparation method thereof. In particular, the present invention relates a type A, B, C, D, E, F crystal of formula (I), chemical name of formula (I) is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol. The present invention also relates to preparation method of type A, B, C, D, E, F crystal of formula (I), pharmaceutical use thereof, and type A, B, C, D, E, F crystal of formula (I) and pharmaceutical composition in the preparation of a medicament for treating a disease with a pathological feature of the IDO-mediated tryptophan metabolic pathway. The type A, B, C, D, E, F crystal of formula (I) obtained by the present invention has good stability, and the used crystal-solvent has a low toxicity and residue, which can be better used in clinical treatment.

Description

   Crystal form of free base of imidazoisoindole derivatives and preparation method thereof   

The present invention relates to (S) -2- (4- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a] isoindole-5-yl) piperidin-1-yl) benzene A), B, C, D, E, F crystalline forms of -1) -H-pyrazol-1-yl) ethanol and its preparation method, its application in pharmaceutical composition, and the A, B, C, D, The E and F crystal forms and the medicinal composition thereof are used for preparing and treating diseases having pathological characteristics of tryptophan metabolism pathway mediated by IDO.

Tumor biotherapy is a new therapy using modern biotechnology and related products to prevent and treat tumors. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth model of tumor treatment after surgery, radiotherapy, and chemotherapy. Activate the host's natural defense mechanism (such as inhibiting IDO-mediated tumor immune escape mechanism) or administer naturally occurring highly targeted substances to obtain anti-tumor effects.

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two The folded α -helical domain, the large domain contains a catalytic pocket, and the substrate can interact with IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formine canine urate. It is widely distributed in humans and other mammals (rabbit and rat) in tissues other than the liver. It is the only limit outside the liver that can catalyze tryptophan catabolism. Fast enzyme, and tryptophan is an amino acid necessary for the cell to maintain activation and proliferation, and is also an indispensable important component of protein. IDO is closely related to a variety of cytokines such as interferon (IFN), interleukin (IL), and tumor necrosis factor, and they can start IDO under certain conditions. There is a regulatory point in the cell cycle of T-cells that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to stagnate in the middle of the G1 phase, thereby inhibiting T cell proliferation; On the other hand, IDO catalyzes the production of canine urea, the main product of tryptophan metabolism, which induces changes in intracellular oxidants and antioxidants induced by oxygen free radicals and induces T-cell apoptosis, which is an inherent immunosuppressive mechanism existing in the body. A large number of studies have shown that IDO is highly expressed in leukemia cells, inhibits local T cell proliferation, inhibits T-cell-mediated immune responses, blocks T-cell activation signal transduction, and thereby mediates tumor cells to escape the immune system. attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a promising target for cancer immunotherapy.

Published patent applications for inhibitors that selectively inhibit IDO include WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958, and WO2014066834 and the like.

IDO inhibitors have good application prospects as pharmaceuticals in the pharmaceutical industry. The applicant in the patent application PCT / CN2016 / 079054 (WO2016169421A1, published date 2016-10-27) provides a new type of structure with high efficiency and low toxicity for selective IDO inhibition. Agent compounds, which have excellent effects and effects, especially excellent drug metabolism absorption activity, and its chemical name is (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5, 1-a] isoindole-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol, the structure is shown below

The crystalline structure of a medicinal active ingredient often affects the chemical stability of the drug. Different crystalline forms, preparation methods and storage conditions may cause changes in the crystalline structure of the compound, sometimes accompanied by the generation of other forms. Crystal form. In general, amorphous pharmaceutical products do not have a regular crystalline structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. These differences often lead to scaled-up production. Time difficulties. The stability of existing crystal forms needs to be improved. Therefore, it is necessary to improve the properties of various aspects of the compound. We need to conduct in-depth research to find new crystal forms with higher purity and good chemical stability.

The technical problem to be solved by the invention is to provide a free base (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1- a] Isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol A, B, C, D, E, F crystal form, the crystal has good The crystalline form stability and chemical stability, and the crystallization solvent used has low toxicity and low residue, which can be better applied to the clinic. The technical solution of the present invention is as follows: The present invention provides a crystal form A of a compound represented by formula (I), which is characterized by using Cu-K α radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, It has features at 6.3, 7.7, 9.0, 10.4, 11.0, 12.2, 14.8, 15.2, 16.3, 16.7, 17.3, 17.9, 18.4, 19.5, 19.7, 20.9, 21.2, 21.5, 21.7, 22.1,24.3, 25.6, and 28.9 Peak, the error range of this 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a crystal form A of a compound represented by formula (I), which is characterized in that the crystal form A is at 6.3, 7.4, 8.99, 10.4, 11.0, 12.2, 14.8 , 15.2, 16.3, 16.7, 17.3, 17.9, 18.1, 19.2, 19.7, 20.1.20.9, 21.2, 21.5, 21.7, 22.1,22.8, 24.3, 24.6, 25.6, 26.4, 27.3, 28.9, 30.1, 31.5, 32.2, 32.5 There are characteristic peaks at 34.6, 36.1, 37.3, and 39.0, and the error range of this 2 θ is ± 0.2.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of compound A represented by formula (I), which comprises: adding the compound represented by formula (I) to an organic solvent, performing beating, and filtering. After crystallizing, washing, and drying, the target A crystal form can be obtained. The organic solvent is selected from alcohol solvents, preferably methanol; the beating temperature is selected from 30 ° C to the boiling point of the solvent, and preferably 50 ° C.

In a preferred embodiment of the present invention, the present invention provides a crystal form B of a compound represented by formula (I), which is characterized in that Cu-Kα radiation is used to obtain X-rays represented by a diffraction angle of 2θ. Powder diffraction patterns at 6.2, 7.6, 8.7, 10.011.1, 12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, 21.121.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9 and 31.7 There are characteristic peaks, the error range of this 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a crystal form B of the compound represented by formula (I), which is characterized in that the crystal form B is at 6.2, 6.7, 7.6, 8.7, 10.1, 11.1, There are characteristic peaks at 12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, 21.1,21.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9, and 31.7. The error range of this 2 θ is ± 0.2.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of a compound B represented by formula (I), which includes the following method: dissolving the compound represented by formula (I) in a solvent, and analyzing Crystal, and the target B crystal form can be obtained after filtering and drying, the solvent is selected from halogenated hydrocarbon solvents, preferably dichloromethane; method two, adding the compound represented by formula (I) to an organic solvent, and performing beating, The crystals are filtered and washed, and the target B crystal form is obtained after drying. The organic solvent is selected from the group consisting of nitriles, esters, halogenated hydrocarbons, ethers, alcohols, nitroalkanes, mixed solvents of alcohol and water The nitrile solvent is selected from acetonitrile, the ester solvent is selected from ethyl acetate, the halogenated hydrocarbon solvent is selected from dichloromethane, the ether solvent is selected from tetrahydrofuran, the alcohol solvent is selected from n-propanol, the The nitroalkane solvent is selected from nitromethane, the mixed solvent of alcohol and water is selected from the mixed solvent of isopropanol and water, preferably 5% water to 95% isopropanol; the beating temperature is selected from room temperature ~ The solvent boiling point temperature is preferably 50 ° C, and the room temperature is preferably 15-25 ° C, and more preferably 25 ° C.

In a preferred embodiment of the present invention, the present invention provides a crystal form C of a compound represented by formula (I), which is characterized by using Cu-K α radiation to obtain X- Ray powder diffraction patterns, which are at 6.0, 6.3, 7.6, 8.4, 8.7, 9.0, 10.1, 10.7, 12.1, 12.5, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1.22.6, 23.4 There are characteristic peaks at 24.2, 25.6, 26.4, 27.3 and 28.3, and the error range of this 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a crystal form C of a compound represented by formula (I), which is characterized in that the crystal form C is at 4.1, 6.0, 6.3, 6.5, 7.6, 8.4, 8.7 ), 9.0, 10.1, 10.7, 12.1, 12.5, 14.2, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1,22.6, 23.4, 24.2, 25.6, 26.4, 27.0, 27.3, 28.3, There are characteristic peaks at 28.8, 30.0 and 31.6, and the error range of this 2 θ is ± 0.2.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of the compound represented by formula (I), which comprises: adding the compound represented by formula (I) to an organic solvent, performing beating, and filtering. After crystallizing and washing, the target crystal form can be obtained after drying. The organic solvent is a ketone solvent. The ketone solvent is selected from acetone. The beating temperature is selected from room temperature to the boiling point of the solvent, preferably 50 ° C. The temperature is preferably 15 to 25 ° C, and more preferably 25 ° C.

In a preferred embodiment of the present invention, the present invention provides a D crystal form of the compound represented by the formula (I), which is characterized by using Cu-K α radiation to obtain X- Ray powder diffraction patterns, which have characteristic peaks at 15.1, 16.6, 17.6, 18.2, 19.5, 20.1,20.4, 21.6, 21.9, 22.1,24.6, 26.7, 27.6, and 29.2. The error range of this 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a D crystal form of the compound represented by formula (I), which is characterized in that the D crystal form is at 15.1, 16.6, 17.6, 18.2, 19.5, 20.1.2, 0.4 There are characteristic peaks at 21.6, 21.9, 22.1,24.6, 26.7, 27.6, 29.2, 30.4, and 31.9, and the error range of 2θ is ± 0.2.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of a compound D represented by the formula (I), which comprises: adding the compound represented by the formula (I) into an organic solvent to perform beating, The crystals are filtered, washed, and dried to obtain the target D crystal form. The organic solvent is selected from aromatic hydrocarbon solvents, preferably cumene or xylene. The beating temperature is selected from 30 ° C to the boiling point of the solvent, preferably 50 ° C.

In a preferred embodiment of the present invention, the present invention provides an E crystalline form of a compound represented by formula (I), which is characterized by using Cu-K α radiation to obtain X- Ray powder diffraction patterns with characteristic peaks at 18.2, 18.7, 19.2, 20.1,21.7, 22.8, 24.6, 26.7, 27.7, and 29.2. The error range of this 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form of a compound E of formula (I), which comprises: adding the compound of formula (I) to an organic solvent, performing beating, and filtering. After crystallizing, washing, and drying, the target E crystal form can be obtained. The organic solvent is selected from alcohol solvents, preferably ethanol; and the beating temperature is selected from 30 ° C to the boiling point of the solvent, preferably 50 ° C.

In a preferred embodiment of the present invention, the present invention provides a crystal form F of a compound represented by formula (I), which is characterized by using Cu-K α radiation to obtain X- The ray powder diffraction pattern has characteristic peaks at 18.7, 19.5, 20.2, 21.5, 22.0, 22.6, 24.4, 25.6, 26.6, 27.6, 29.2, and 32.0, and the error range of 2 θ is ± 0.2,

In a preferred embodiment of the present invention, the present invention provides a method for preparing a crystal form F of a compound represented by formula (I), which comprises: adding the compound represented by formula (I) to an organic solvent, performing beating, and filtering. Crystallize and wash, and obtain the target F crystal form after drying. The organic solvent is selected from alcohol solvents, preferably 2-propanol. The beating temperature is selected from 30 ° C to the boiling point of the solvent, preferably 50 ° C.

The present invention further relates to a medicinal composition, which is composed of A-form, B-form, C-form, D-form, E-form, F-form of the compound represented by formula (I) and pharmaceutically acceptable Consisting of a carrier, diluent or excipient.

The invention further relates to a pharmaceutical composition of Form A, Form B, Form C, Form D, Form E, and Form F of a compound represented by formula (I), which is characterized in that the pharmaceutical composition further comprises One or more second therapeutically active agents selected from the group consisting of: anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, anticancer agents, and disease resistance Poison, growth factor regulator, immunomodulator or anti-vascular hyperproliferative compound.

The present invention further relates to a method for preparing the above-mentioned pharmaceutical composition, which is characterized in that the method comprises the following steps: A, B, C, D, E, F The step of mixing the crystalline form with a pharmaceutically acceptable carrier, diluent or excipient.

The present invention further relates to Form A, Form B, Form C, Form D, Form E, Form F, or Form A, B, C, D, E, F of the compound of formula (I). Use of a medicinal composition in the preparation of a disease having pathological characteristics of the tryptophan metabolism pathway mediated by IDO, the disease being selected from cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, Psychological disorders and AIDS, the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 nephroma, head and neck tumor, leukemia, lymphoma, myeloma or Non-small cell lung cancer.

The X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), or dynamic water adsorber (DVS) were used to analyze the A of the obtained compound of formula (I). , B, C, D, E, F crystal structure for structure determination, crystal research, etc.

The crystallization method of the present invention includes room temperature crystallization, cooling crystallization, volatile solvent crystallization, seed crystal induction and the like. The cooling temperature is selected from 40 ° C or lower, preferably -10 ° C to 40 ° C. You can also stir during the process.

Detailed description of the invention

The starting material used in the method for preparing a crystalline form of the present invention may be a compound represented by formula (I) in any form, and the specific form includes, but is not limited to, an amorphous form, an arbitrary crystalline form, and the like.

In the description and the scope of the patent application of this application, unless otherwise stated, scientific and technical terms used herein have the meaning commonly understood by those skilled in the art. However, in order to better understand the present invention, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in this application are not consistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

The “beating” described in the present invention refers to a method for purifying by utilizing the characteristics of poor solubility of a substance in a solvent but good solubility of the impurities in a solvent. Purification can be used to remove color, change crystal form, or remove a small amount of impurities.

The “halo” in the present invention means being replaced by a “halogen atom”, and the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.

The “hydroxyl, cyano, nitro, etc.” in the present invention refers to groups such as —OH, —CN, and —NO ₂ .

The “C _1-6 alkyl group” in the present invention means a linear or branched alkyl group containing 1-6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl , N-butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl Group, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.

The “ester solvent” in the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to, acetic acid Ethyl, isopropyl or butyl acetate.

The “ether solvent” in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran, or 1 , 4-dioxane.

The "alcoholic solvent" in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C _1-6 alkyl" with one or more "hydroxy", and the "hydroxy" and "C _{1 "-6} alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, n-propanol, or 2-propanol.

The "aromatic hydrocarbon solvent" in the present invention refers to a general term for a carbocyclic compound and a derivative thereof having a closed ring conjugated system in which the number of π electrons conforms to the Shocker rule. Specific examples include, but are not limited to: iso Propylbenzene or xylene.

The “halogenated hydrocarbon solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C _1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” And "C _1-6 alkyl" are as defined above, and specific examples include, but are not limited to, methyl chloride, methylene chloride, chloroform, or carbon tetrachloride.

The "nitrile solvent" in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C _1-6 alkyl group" with one or more "cyano groups". The "cyano group" and ""C _1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

The "nitroalkane solvent" in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C _1-6 alkyl" with one or more "nitro", and the "nitro" And "C _1-6 alkyl" are as defined above, and specific examples include, but are not limited to, nitromethane.

The “mixed solvent” in the present invention refers to a solvent in which one or more different kinds of organic solvents are mixed according to a certain ratio, or a solvent in which organic solvents and water are mixed according to a certain ratio, and the certain ratio is 0.05: 1 ~ 1: 0.05, preferably 19: 1; the mixed solvent is preferably a mixed solvent of an alcohol solvent and water; the mixed solvent of the alcohol solvent and water is preferably a mixed solvent of isopropanol and water, the alcohol The solvent is as defined above.

The "X-ray powder diffraction pattern or XRPD" in the present invention refers to 2d sin θ = n λ according to the Bragg formula (where λ is the wavelength of X-rays, λ = 1.54056Å, and the order of diffraction n is any positive An integer, generally taking the first-order diffraction peak, n = 1). When X-rays are incident on a crystal or part of a crystal sample with a grazing angle θ (the coincidence of the angle of incidence, also known as the Bragg angle) with a d-lattice plane spacing When the atomic plane is satisfied, the Bragg equation can be satisfied, and the X-ray powder diffraction pattern of this group is measured.

The “differential scanning calorimetry or DSC” in the present invention refers to measuring the temperature difference and heat flow difference between the sample and the reference during the temperature rising or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase transition information of the sample.

The “2θ or 2θ angle” in the present invention refers to a diffraction angle, and θ is a Bragg angle, and the unit is. Or degrees.

The "crystal plane spacing or crystal plane spacing (d value)" in the present invention means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect adjacent lattice points, and The array is divided into juxtaposed parallelepiped units, called the crystal plane spacing. The space lattice is divided according to the determined parallelepiped unit connection, and a set of straight grids is obtained, which is called a space lattice or a lattice. The lattice and the lattice reflect the periodicity of the crystal structure with geometric points and lines, respectively. Different crystal planes have different interplanar distances (that is, the distance between two adjacent parallel crystal planes); the unit is Å Or Egypt.

The invention also relates to a pharmaceutical composition comprising the A, B, C, D, E, F crystal forms of the compound represented by formula (I), and optionally one or more pharmaceutically acceptable carriers and / or diluents. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the A, B, C, D, E, F crystalline forms or pharmaceutical preparations of the present invention can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections) , Sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays.

In addition, the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment by any suitable method of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or oral liquid preparations, such as oral solutions, oral suspensions, etc. Agents, syrups, etc. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When injectable, the pharmaceutical composition can be produced by conventional methods in the existing pharmaceutical field. When an injection is formulated, the pharmaceutical preparation may be added without an additional agent, or a suitable additional agent may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparation can be made into an inhalant or a spray. In certain preferred embodiments, the A, B, C, D, E, F crystalline forms of the invention are present in a pharmaceutical composition or medicament in a therapeutically and / or prophylactically effective amount. In certain preferred embodiments, the A, B, C, D, E, F crystalline forms of the present invention are present in a pharmaceutical composition or medicament in the form of a unit dose.

The A, B, C, D, E, F crystalline forms of the compound of formula (I) of the present invention may be administered alone or in combination with one or more second therapeutic agents. Therefore, in certain preferred embodiments, the pharmaceutical composition further contains one or more second therapeutic agents. In certain preferred embodiments, the second therapeutic agent is selected from the group consisting of: an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anticancer agent, and an anti-disease Poison, growth factor regulator, immunomodulator or anti-vascular hyperproliferative compound.

The components to be combined (for example, the A, B, C, D, E, F crystalline forms of the present invention and the second therapeutic agent) can be administered simultaneously or separately and sequentially. For example, the second therapeutic agent may be administered before, at the same time or after administration of the A, B, C, D, E, F crystalline forms of the invention or stereoisomers thereof. In addition, the ingredients to be combined can also be administered in the same formulation or in the form of separate, different formulations.

The A, B, C, D, E, and F crystalline forms of the compound of formula (I) of the present invention can be used for the preparation and treatment of diseases in which tryptophan metabolism is mediated by IDO. Therefore, the present application also relates to the use of the A, B, C, D, E, F crystalline form of the compound of formula (I) of the present invention for the preparation of a medicament for treating and / or preventing IDO in a subject. Diseases Mediated by Tryptophan Metabolism In addition, the present application also relates to a method for inhibiting diseases related to tryptophan metabolism mediated by IDO, which comprises administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of a compound of formula (I) of the present invention A, B, C, D, E, F crystal forms, or the pharmaceutical composition of the present invention.

In certain preferred embodiments, the disease is a disease related to tryptophan metabolism mediated by IDO, and is selected from the group consisting of: cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, Psychological disorder or AIDS; the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 nephroma, head and neck tumor, leukemia, lymphoma, myeloma or Non-small cell lung cancer.

The beneficial effects of the invention

Compared with the prior art, the technical solution of the present invention has the following advantages:

(1) The crystalline forms of the compounds A, B, C, D, E, and F represented by the formula (I) of the present invention do not contain or only contain relatively low levels of residual solvents, and are in accordance with the limit of residual solvents for pharmaceutical products prescribed by the National Pharmacopoeia. Therefore, the crystal of the present invention can be suitably used as a pharmaceutically active ingredient.

(2) The research shows that the crystal form A, B, C, D, E, and F of the compound of formula (I) of the present invention has high purity, and the crystal form does not change under the conditions of light, high temperature, and high humidity. The crystal form stability is good; the HPLC purity change is small and the chemical stability is high; the crystal form A, B, C, D, E, F of the compound represented by the formula (I) obtained by the technical scheme of the present invention can meet the production, transportation and storage of drugs Application requirements, the production process is stable, repeatable and controllable, and can be adapted to industrial production.

Fig. 1 is an XRPD pattern of the crystal form of the compound A represented by formula (I); Fig. 2 is an XRPD pattern of the crystal form of the compound B represented by formula (I); and Fig. 3 is a crystal form of the compound C represented by formula (I). Figure 4 shows the XRPD pattern of the crystal form D of the compound represented by formula (I); Figure 5 shows the XRPD pattern of the crystal form E of the compound represented by formula (I); Figure 6 shows the formula (I) XRPD pattern of compound F crystal form; FIG. 7 is a DSC pattern of compound A crystal form represented by formula (I); FIG. 8 is a DSC pattern of compound B crystal form represented by formula (I); and FIG. 9 is a formula ( I) DSC pattern of the crystal form of compound C shown in FIG. 10; FIG. 10 is a DSC pattern of the crystal form of compound D shown in formula (I); FIG. 11 is DSC pattern of the crystal form of compound E shown in formula (I); The figure shows the DSC spectrum of the Form F of the compound of formula (I); Figure 13 shows the DVS first cycle diagram of the compound B of the formula (I); Figure 14 shows the compound of the formula (I) The DVS second cycle chart spectrum of Form B; Figure 15 is the XRPD chart of Form B on day 0; and Figure 16 is the XRPD chart of Form B after being left for 15 days at 40 ° C and RH 75% relative humidity; Figure 17 shows the XRPD pattern of Form C for 0 days; Figure 18 shows the Form C at 40 ° C and 75% relative humidity RH XRPD pattern 15 days.

The present invention will be explained in more detail with reference to the following embodiments. The embodiments of the present invention are only used to explain the technical solution of the present invention, and do not limit the essence and scope of the present invention.

Test conditions of the instrument used in the experiment:

1.Differential Scanning Calorimeter (DSC)

Instrument model: Mettler Toledo DSC 3 ⁺ STAR ^e System

Purge gas: nitrogen

Heating rate: 10.0 ℃ / min

Temperature range: 20-250

2.X-ray powder diffraction (XRPD)

(1) Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer

Ray: Monochromatic Cu-K α -ray (λ = 1.5406)

Scanning mode: θ / 2 θ, scanning range: 10-48 °

Voltage: 40KV, current: 40mA

(2) Instrument model: Rigaku UltimalV X-ray powder diffractometer

Ray: Monochromatic Cu-K α -ray (λ = 1.5418)

Scanning mode: θ / 2 θ, scanning range: 3-45 °

Voltage: 40KV, current: 40mA

3.Dynamic Vapour Sorption (DVS)

Instrument model: DVS advantage

Temperature: 25 ℃

Solvent: water

Humidity change: 0-95-0-95-0% RH, dm / dt = 0.002

Comparative Example, (S) -2- (4- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a] isoindol-5-yl) piperidin-1-yl) benzene Group) -1H-pyrazol-1-yl) ethanol (for the preparation of the compound represented by formula (I), refer to Example 40 in the patent application PCT / CN2016 / 079054 (WO2016169421A1 (publication date 2016-10-27)). (41, 41)

(1) 6-fluoro-5- (piperidin-4-yl) -5 H -imidazo [5,1- a ] isoindole ditrifluoroacetate (compound 1g ) (see patent application PCT / CN2016 / 079054 (WO2016169421A1 (publication date 2016-10-27)), the preparation method in Example 1)

    First step     4-((2-Bromo-6-fluorobenzene) (hydroxy) methyl) piperidine-1-carboxylic acid third butyl ester 1c

Diisopropylamino lithium (32.5 mL, 65.0 mmol) was added to tetrahydrofuran (50 mL), and the preformed 1-bromo-3-fluorobenzene 1a (8.75 g, 50.0 mmol, 25 mL) was added dropwise at -78 ° C. The solution was stirred at -78 ° C for 1 hour. Then, a tetrahydrofuran solution of the preformed tetramethylpiperidine-1-carboxylic acid third butyl ester 1b (8.75 g, 50.0 mmol, 25 mL) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. After the reaction was completed, methanol (25 mL) was added dropwise to quench the reaction at -78 ° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using an eluent system (n-hexane and ethyl acetate) to obtain Compound 1c (16.3 g, yellow syrup solid, yield 84.0%).

MS m / z (LC-MS): 332.0 [M-56]

    Second step     4-((2-Bromo-6-fluorophenyl) (p-toluenesulfonyloxy) methyl) piperidine-1-carboxylic acid third butyl ester 1d

Compound 1c (15 g, 38.63 mmol) was dissolved in tetrahydrofuran (350 mL), sodium hydride (3.09 g, 77.26 mmol) was added in portions, and stirred until no gas was evolved. A pre-prepared solution of p-toluenesulfonyl chloride (8.10 g, 42.49 mmol, 250 mL) in tetrahydrofuran was added dropwise, stirred at room temperature for 30 minutes, refluxed for 4 hours, and stirred at 70 ° C for 48 hours. After the reaction was completed, the reaction solution was cooled to 0 ° C, and the reaction was quenched by adding water (50 mL) dropwise. A saturated sodium chloride solution (50 mL) was added to separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography using an eluent system (n-hexane and ethyl acetate) to obtain compound 1d (6.6 g, pale yellow viscous solid, yield: 31.80%).

MS m / z (LC-MS): 314.0 / 316.0 [M-56-TsO]

    third step     4-((2-Bromo-6-fluorobenzene) ( 1H -imidazol-1-yl) methyl) piperidine-1-carboxylic acid third butyl ester 1e

Dissolve imidazole (12.5 g, 184.3 mmol) in N , N -dimethylformamide (50 mL), add sodium hydride (7.40 g, 184.3 mmol) in portions, and stir at room temperature for 1 hour. A solution of Compound 1d (10.0 g, 18.43 mmol, 20 mL) in N , N -dimethylformamide was stirred at 100 ° C for 12 hours. After the reaction was completed, ethyl acetate (300 mL) was added, and the organic phase was washed with saturated sodium chloride solution (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by the system (dichloromethane and methanol) to obtain compound 1e (1.90 g, brown viscous solid, yield: 23.5%).

MS m / z (LC-MS): 438.1 / 440.1 [M + 1]

    the fourth step     4- (6-fluoro-5 H -imidazo [5,1-a] isoindol-5-yl) piperidine-1-carboxylic acid third butyl ester 1f

Compound 1e (1.90 g, 4.33 mmol), N, N-dicyclohexylmethylamine (1.35 g, 6.93 mmol), and triphenylphosphorus (908 mg, 3.46 mmol) were added to N , N -dimethylformamide In a solution (10 mL), palladium acetate (390 mg, 1.74 mmol) was added under an argon atmosphere, and the mixture was stirred at 100 ° C for 4.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using an eluent system (n-hexane and ethyl acetate) to obtain compound 1f (1.30 g, yellow viscous solid, yield: 83.8%).

MS m / z (LC-MS): 358.1 [M + 1]

    the fifth step     6-fluoro-5- (piperidin-4-yl) -5 H -imidazo [5,1- a ] isoindole ditrifluoroacetate 1g

Compound 1f (1.30 g, 3.64 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 1 g of a crude compound (1.77 g, brown sticky solid). The product was directly subjected to the next reaction without purification.

MS m / z (LC-MS): 258.3 [M + 1]

(2) 4- (4-bromophenyl) -1- (2-((tetrahydro-2 H -pyran-2-yl) oxy) ethyl) -1 H -pyrazole (compound 40a ) ( (See CN104755477A (Publication date 2015.07.01) Specification on page 44)

(3) ( S ) -2- (4- (4- (4- (4- (6-fluoro- 5H -imidazo [5,1- a ] isoindole-5-yl) piperidin-1-yl) Phenyl) -1 H -pyrazol-1-yl) ethanol (Compound 41 , PCT / CN2016 / 079054 (WO2016169421A1 (publication date 2016-10-27) Preparation methods in Examples 40, 41)

    First step    

4- (4-Bromophenyl) -1- (2-((tetrahydro-2 H -pyran-2-yl) oxy) ethyl) -1 H -pyrazole 40a (14.8 g, 42 mmol) , 6-fluoro-5- (piperidin-4-yl) -5 H -imidazo [5,1- a ] isoindole 17a (13.9 g, 42 mmol) was added N , N -dimethylformamide ( 300 mL), tritributylphosphine tetrafluoroborate (1.863 g, 64.5 mmol) and potassium phosphate (35 g, 168 mmol) were added and replaced with argon for three times. Tris (dibenzylideneacetone) dipalladium (2.92g, 3.19mmol) was added, and the argon gas was substituted once. The reaction solution was heated to 110 ° C and stirred for 2 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove N , N -dimethylformamide, and the resulting residue was purified by silica gel column chromatography using an eluent system (dichloromethane and methanol) to obtain a compound. 40b (6.38 g, grey oil, yield: 29%).

    Second step    

Compound 40b (9 g, 17.1 mmol) was dissolved in methanol (100 mL), concentrated hydrochloric acid (12 M , 5.7 mL) was added, the reaction solution was raised to 45 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and saturated sodium carbonate was added to adjust the pH of the reaction solution to 8, and the filtrate was concentrated under reduced pressure. The obtained product was purified by silica gel column chromatography with an eluent system (dichloromethane and methanol). The residue gave compound 40c (5.2 g, yellow solid, yield: 65%).

    third step    

Compound 40c (1.4g, 3.16mmol) was prepared chiral (Separation conditions: Chiral preparation column Superchiral S-AS (Chiralway), 2cm ID × 25cm Length, 5μm; Mobile phase: CO ₂ / MeOH / DEA = 60 /40/0.05 (v / v / v), flow rate: 50 mL / min), the corresponding components were collected, and concentrated under reduced pressure to obtain compound 40 (630 mg, yellow solid) and compound 41 (652 mg, yellow solid), of which compound 41 is determined by XRPD as a crystal form, the crystal form is 4.1, 6.0, 6.3, 6.5, 7.6, 8.4, 8.7), 9.0, 10.1, 10.7, 12.1, 12.5, 14.2, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4 There are characteristic peaks at 19.9, 20.5, 21.3, 22.1,22.6, 23.4, 24.2, 25.6, 26.4, 27.0, 27.3, 28.3, 28.8, 30.0, and 31.6, and the crystal form is the C form.

Example 1

50 mg of the crude compound of formula (I) was added to the reaction flask, methanol (50-100 μL) was added, and the mixture was stirred at a constant temperature of 50 ° C. for 5 days, filtered, and dried under vacuum to obtain a white to pale yellow powder. The XRPD spectrum of this crystalline sample is shown in Figure 1, and the DSC spectrum is shown in Figure 7. The endothermic peak is around 217.9 ° C, and the initial melting temperature is 216.8 ° C. This crystal form is defined as Form A. The characteristic peak positions are shown in the following table. Shown as 1:     

Example 2

50 mg of the crude compound of formula (I) was added to the reaction flask, acetonitrile (50-100 μL) was added, and the mixture was stirred at a constant temperature of 25 ° C. for 5 days, filtered, and then vacuum dried at 25 ° C. to obtain a white to pale yellow powder. The XRPD of this crystalline sample is shown in Figure 2 and its DSC spectrum is shown in Figure 8. The endothermic peak is around 210.5 ° C and the initial melting temperature is 210.3 ° C. This crystal form is defined as Form B. From Figures 13 and The DVS spectrum of Figure 14 can be used to determine that the B crystal form does not contain crystal water, and its characteristic peak positions are shown in Table 2 below:     

The B-form sample obtained in an ethyl acetate solvent at 50 ° C was measured by XRPD to determine the diffraction angle 2 θ at 6.27, 7.61, 8.67, 9.88, 10.20, 11.01, 11.40, 11.93, 12.44, 14.49, 15.40, 16.31, 16.88, 17.61 There are characteristic peaks at 18.35, 18.78, 19.19, 19.71, 20.77, 21.40, 22.38, 24.26, 25.39, 26.09, 27.36, 28.84 and 31.73.

The B-form sample obtained in a tetrahydrofuran solvent at 50 ° C was measured by XRPD to determine the diffraction angle 2 θ at 6.27, 7.62, 8.68, 9.88, 10.18, 11.18, 11.95, 12.15, 14.46, 15.16, 16.34, 17.58, 18.33, 18.75, 19.13 There are characteristic peaks at 19.83, 20.78, 21.42, 22.33, 24.25, 25.14, 26.51, 27.38, 28.86 and 31.66.

Example 3

50 mg of the crude compound represented by formula (I) was added to a reaction flask, acetone (1.5 mL) was added, the temperature was raised to 80 ° C, the temperature was maintained for 10 minutes, and then reduced to 20 ° C, filtered, and dried to obtain a solid. The diffraction angle 2 θ of this crystal sample by XRPD was 6.27, 7.60, 8.67, 9.88, 10.20, 11.01, 11.40, 11.92, 12.45, 14.49, 15.40, 16.31, 16.88, 17.61, 18.35, 18.78, 19.19, 19.71, 20.77, 21.40 There are characteristic peaks at 22.38, 25.40, 26.10, 27.38, 28.85 and 31.72, and the product is determined to be the B crystal form.

Example 4

Add 50 mg of the crude compound of formula (I) to the reaction flask, add acetone (50-100 μL), stir at a constant temperature of 25 ° C for 5 days, filter, and then vacuum-dry at 25 ° C to obtain a white to pale yellow powder. XRPD is shown in Figure 3, and its DSC spectrum is shown in Figure 9. The endothermic peak is around 210.1 ° C, and the initial melting temperature is 209.5 ° C. This crystal form is defined as the C form, and its characteristic peak positions are shown in Table 3 below:     

The crystal form C sample obtained in an acetone solvent at 25 ° C was detected by XRPD and the diffraction angle 2 θ was 5.99, 6.24, 7.53, 8.30, 8.95, 9.94, 10.64, 12.00, 12.42, 15.92, 16.56, 17.81, 18.17, 18.71, 19.30 There are characteristic peaks at 19.76, 20.48, 21.26, 21.54, 22.04, 22.47, 24.17, 25.00, 26.29, 26.61,27.32, 28.74 and 31.47.

Example 5

50 mg of the crude compound of formula (I) was added to the reaction flask, cumene (50-100 μL) was added, and the mixture was stirred at a constant temperature of 50 ° C. for 5 days, filtered, and dried under vacuum to obtain a white to pale yellow powder. The XRPD of this crystal sample is shown in Figure 4, and its DSC spectrum is shown in Figure 10. The endothermic peak is around 212.9 ° C, and the initial melting temperature is 211.1 ° C. This crystal form is defined as the D crystal form, and its characteristic peak positions are shown in Table 4 below. As shown:     

Example 6

50 mg of the crude compound of formula (I) was added to the reaction flask, ethanol (50-100 μL) was added, and the mixture was stirred at a constant temperature of 50 ° C. for 5 days, filtered, and dried under vacuum to obtain a white to pale yellow powder. The XRPD of this solid sample is shown in Figure 5, and its DSC spectrum is shown in Figure 11. The endothermic peak is around 211.5 ° C, and the initial melting temperature is 210.2 ° C. This crystal form is defined as the E crystal form, and its characteristic peak positions are shown in Table 5 below. As shown:     

Example 7

50 mg of the crude compound of formula (I) was added to the reaction flask, 2-propanol (50-100 μL) was added, and the mixture was stirred at a constant temperature of 50 ° C. for 5 days, filtered, and dried under vacuum to obtain a white to pale yellow powder. The XRPD of this solid sample is shown in Figure 6, and its DSC spectrum is shown in Figure 12. The endothermic peak is around 208.6 ℃, and the initial melting temperature is 206.9 ℃. This crystal form is defined as the F crystal form, and its characteristic peak positions are shown in Table 6 below. As shown:     

Experimental program

The following provides an exemplary test scheme of the crystalline product of the present invention to show the advantageous activity or beneficial technical effect of the crystalline product of the present invention. However, it should be understood that the following test schemes are merely examples of the content of the present invention, rather than limitations on the scope of the present invention. Those skilled in the art can make appropriate modifications or changes to the technical solution of the present invention without departing from the spirit and scope of the present invention under the teachings of this specification.

Experimental Example 1. Stability Investigation of Form B and Form C

Form B and Form C samples were placed flat and open, and the stability of the samples was examined at 40 ° C and relative humidity RH75%. The sampling time was 15 days.

Experimental results : Figure 15 of the instruction manual is the XRPD chart of Form B for 0 days; Figure 16 of the manual design is the XRPD chart of Form B for 15 days at 40 ° C and 75% relative humidity; Figure 17 shows the XRPD pattern of Form C for 0 days; Figure 18 of the description of the specification shows Figure 18 of the XRPD pattern of Form C after 15 days at 40 ° C and 75% relative humidity.

Experimental conclusions : The stability investigation results of the figures 15, 16, 17, and 18 in the description of the specification show that the B-form of the compound represented by formula (I) is placed at 40 ° C and 75% relative humidity RH. Under the condition, the XRPD peak shape has basically not changed, and the crystal form is stable. Under the condition that the C crystal form is placed at 40 ° C and relative humidity RH75%, the XRPD peak shape has changed, some of the peak shape characteristics have disappeared, and the crystallinity has decreased. Under the condition of 40 ℃ RH75%, the physical stability of Form B is better than Form C.

Claims (26)

A crystal form of a compound represented by formula (I), characterized in that Cu-K α radiation is used to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is at 6.3,7.7,9.0,10.4, There are characteristic peaks at 11.0, 12.2, 14.8, 15.2, 16.3, 16.7, 17.3, 17.9, 18.4, 19.5, 19.7, 20.9, 21.2, 21.5, 21.7, 22.1,24.3, 25.6 and 28.9. The error range of this 2 θ is ± 0.2,     The A-form according to item 1 of the scope of the patent application, wherein the A-form is in 6.3, 7.4, 8.99, 10.4, 11.0, 12.2, 14.8, 15.2, 16.3, 16.7, 17.3, 17.9, 18.1, 19.2, 19.7 There are characteristic peaks at 20.1,20.9, 21.2, 21.5, 21.7, 22.1,22.8, 24.3, 24.6, 25.6, 26.4, 27.3, 28.9, 30.1, 31.5, 32.2, 32.5, 34.6, 36.1, 37.3 and 39.0. The 2 θ The error range is ± 0.2.         A method for preparing form A according to item 1 or 2 of the scope of patent application, wherein the method is: adding the compound represented by formula (I) to an organic solvent, performing beating, filtering and crystallization, washing, and drying. The target A crystal form is obtained, and the organic solvent is selected from alcohol solvents.         The preparation method according to item 3 of the patent application scope, wherein the organic solvent is methanol.     A form B of the compound of formula (I), characterized in that: Cu-K α radiation is used to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is at 6.2,7.6,8.7,10.011. There are characteristic peaks at 1,12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, 21.121.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9, and 31.7. The error range of this 2 θ is ± 0.2,     The B-form according to item 5 of the scope of the patent application, wherein the B-form is in 6.2, 6.7, 7.6, 8.7, 10., 11.1, 12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, There are characteristic peaks at 21.1,21.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9, and 31.7. The error range of this 2 θ is ± 0.2.         A method for preparing Form B according to item 5 or 6 of the scope of patent application, which is selected from: Method 1, dissolving a compound represented by formula (I) in a solvent, crystallizing, filtering, and drying to obtain the target. Form B, the solvent is selected from halogenated hydrocarbon solvents; method two, adding the compound represented by formula (I) to an organic solvent, performing beating, filtering, crystallization and washing, and drying to obtain the target form B, the organic The solvent is selected from the group consisting of nitriles, esters, halogenated hydrocarbons, ethers, alcohols, nitroalkanes, or a mixed solvent of alcohols and water. The nitrile solvent is selected from acetonitrile, and the ester solvent is selected from ethyl acetate. Ester, the halogenated hydrocarbon solvent is selected from methylene chloride, the ether solvent is selected from tetrahydrofuran, the alcohol solvent is selected from n-propanol, the nitroalkane solvent is selected from nitromethane, and the alcohol and water The mixed solvent is selected from a mixed solvent of isopropyl alcohol and water.         The preparation method according to item 7 in the scope of the patent application, wherein the halogenated hydrocarbon solvent in the method 1 is dichloromethane.     A crystal form C of a compound represented by formula (I), characterized in that Cu-K α radiation is used to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is 6.0, 6.3, 7.6, 8.4, 8.7, 9.0, 10.1, 10.7, 12.1, 12.5, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1,22.6, 23.4, 24.2, 25.6, 26.4, 27.3 and 28.3 have characteristic peaks, The error range of this 2 θ is ± 0.2,     The crystal form C according to item 9 of the scope of application for a patent, wherein the crystal form C is in 4.1, 6.0, 6.3, 6.5, 7.6, 8.4, 8.7), 9.0, 10.1, 10.7, 12.1, 12.5, 14.2, 15.2, There are characteristic peaks at 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1,22.6, 23.4, 24.2, 25.6, 26.4, 27.0, 27.3, 28.3, 28.8, 30.0, and 31.6, and the error range of 2 θ It is ± 0.2.         A method for preparing the crystal form C according to item 9 or 10 of the scope of patent application, characterized in that the method is: adding the compound represented by formula (I) to an organic solvent, performing beating, filtering and crystallization, washing, and drying The target crystal form C is obtained, and the organic solvent is a ketone solvent.         The preparation method according to item 11 of the scope of patent application, wherein the organic solvent is acetone.     A D crystal form of a compound represented by formula (I), characterized in that Cu-K α radiation is used to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is 15.1, 16.6, 17.6, 18.2, There are characteristic peaks at 19.5, 20.1.20.4, 21.6, 21.9, 22.1,24.6, 26.7, 27.6, and 29.2. The error range of this 2 θ is ± 0.2,     The D crystal form according to item 13 of the scope of patent application, wherein the D crystal form is 15.1, 16.6, 17.6, 18.2, 19.5, 20.1,20.4, 21.6, 21.9, 22.1,24.6, 26.7, 27.6, 29.2, 30.4 There are characteristic peaks at 31.9 and the error range of this 2 θ is ± 0.2.         The method for preparing the D crystal form according to item 13 or 14 of the scope of the patent application, characterized in that the method is: adding the compound represented by the formula (I) to an organic solvent, performing beating, filtering and crystallization, washing, and drying The target D crystal form is obtained, and the organic solvent is selected from aromatic hydrocarbon solvents.         The preparation method according to item 15 of the scope of patent application, wherein the organic solvent is cumene or xylene.     An E crystal form of a compound represented by formula (I), characterized in that: Cu-K α radiation is used to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is 18.2, 18.7, 19.2, 20.1, There are characteristic peaks at 21.7, 22.8, 24.6, 26.7, 27.7, and 29.2. The error range of this 2 θ is ± 0.2.     A method for preparing the E crystal form according to item 17 of the scope of patent application, characterized in that the method is: adding the compound represented by the formula (I) into an organic solvent, performing beating, filtering and crystallization, washing, and drying. The target E-form is obtained, and the organic solvent is selected from alcohol solvents.         The preparation method according to item 18 of the scope of patent application, wherein the organic solvent is ethanol.     An F-form of a compound represented by formula (I), characterized by: using Cu-K α radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 θ, which is 18.7, 19.5, 20.2, 21.5, There are characteristic peaks at 22.0, 22.6, 24.4, 25.6, 26.6, 27.6, 29.2, and 32.0. The error range of this 2 θ is ± 0.2,     A method for preparing the F crystal form according to item 20 of the scope of patent application, characterized in that the method is: adding the compound represented by formula (I) into an organic solvent, performing beating, filtering and crystallization, washing, and drying. The target F crystal form is obtained, and the organic solvent is selected from alcohol solvents.         The preparation method according to item 21 of the scope of patent application, wherein the organic solvent is 2-propanol.         A medicinal composition, the medicinal composition comprises the A crystal form described in item 1 or 2 of the patent application scope, the B crystal form described in item 5 or 6 of the patent application scope, or the 9 or 10 application patent scope Form C, Form D in the scope of patent application No. 13 or 14, Form E in the scope of patent application, Form E in the scope of patent application, and Form F of the scope of patent application, and pharmaceutically acceptable Consisting of a carrier, diluent or excipient.         The pharmaceutical composition according to item 23 of the scope of application for a patent, wherein the pharmaceutical composition further comprises one or more second therapeutically active agents selected from the group consisting of anti-inflammatory agents, matrix metalloproteinase inhibitors, Lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antivirals, growth factor regulators, immunomodulators or anti-vascular hyperproliferative compounds.         A method for preparing a pharmaceutical composition according to item 23 or 24 of the scope of application for a patent, characterized in that the method includes the A-form described in item 1 or 2 of the scope of application for a patent, or item 5 or 6 for a scope of application for a patent The B-form, the C-form described in the 9th or 10th patent application scope, the D-form described in the 13- or 14-application patent scope, the E-form described in the 17-application patent scope, The step of mixing the F crystal form described in item 20 of the patent application with a pharmaceutically acceptable carrier, diluent or excipient.         A Form A described in the scope of patent application 1 or 2, Form B in the scope of patent application 5 or 6, Form C in the scope of patent application 9 or 10, Form D in 13 or 14, Form E in patent application 17, Form F in patent application 20, and pharmaceutical composition in patent application 23 or 24 Of the substance in the treatment of a disease having pathological characteristics of the tryptophan metabolism pathway mediated by IDO, the disease is selected from cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder And AIDS, the cancer is selected from 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 nephroma, head and neck tumor, leukemia, lymphoma, myeloma or non-small Cell lung cancer.