CN108884099B

CN108884099B - Crystal form of free base of imidazo isoindole derivative and preparation method thereof

Info

Publication number: CN108884099B
Application number: CN201780017401.XA
Authority: CN
Inventors: 曹笑立; 尤凌峰; 肖昌琴; 杜振兴; 王立坤
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd; Chengdu Suncadia Pharmaceuticals Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd; Chengdu Suncadia Pharmaceuticals Co Ltd
Priority date: 2016-10-21
Filing date: 2017-10-20
Publication date: 2021-10-08
Anticipated expiration: 2037-10-20
Also published as: TW201815793A; WO2018072742A1; CN108884099A

Abstract

The present invention relates to a crystalline form of the free base of an imidazoisoindole derivative and to a process for its preparation. Specifically, the invention relates to crystal forms A, B, C, D, E and F of a compound shown as a formula (I), and the chemical name of the crystal forms is (S) -2- (4- (4- (6-fluoro-5H-imidazo [5, 1-a)]Isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol. The invention also relates to a preparation method for preparing the crystal forms A, B, C, D, E and F, application of the crystal forms A, B, C, D, E and F in a pharmaceutical composition, and application of the crystal forms A, B, C, D, E and F and the pharmaceutical composition in preparation of medicines for treating diseases with IDO mediated tryptophan metabolic pathway pathological characteristics.

Description

Crystal form of free base of imidazo isoindole derivative and preparation method thereof

Technical Field

The invention relates to crystal forms A, B, C, D, E and F of (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidine-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol, a preparation method thereof, application thereof in a pharmaceutical composition, and application of the crystal forms A, B, C, D, E and F and the pharmaceutical composition thereof in preparation of medicines for treating diseases with IDO mediated tryptophan metabolic pathway pathological characteristics.

Background

The biological treatment of tumor is a new treatment method for preventing and treating tumor by applying modern biotechnology and related products, and is a fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy due to the characteristics of safety, effectiveness, low adverse reaction and the like, and the anti-tumor effect is obtained by mobilizing the natural defense mechanism of host (such as IDO-mediated tumor immune escape mechanism) or giving naturally-generated substances with strong targeting property.

Indoleamine-pyrrole-2, 3-dioxygenase (IDO) is a monomeric iron-containing heme protein consisting of 403 amino acid residues and including two folded alpha-helical domains, a large domain containing a catalytic pocket, and a substrate capable of interacting with IDO in the catalytic pocket in a hydrophobic manner. IDO is an enzyme catalyzing the conversion of tryptophan into formylkynurenine, is widely distributed in tissues of human and other mammals (rabbits and mice) except liver, is the only rate-limiting enzyme capable of catalyzing the catabolism of tryptophan except liver, and tryptophan is an amino acid necessary for cell maintenance, activation and proliferation and is also an essential component for constituting proteins. IDO is closely related to various cytokines such as Interferon (IFN), Interleukin (IL), tumor necrosis factor and the like, and can activate IDO under certain conditions. On one hand, IDO causes local tryptophan depletion, so that T-cells are arrested in the middle stage of G1, and the proliferation of the T-cells is inhibited; on the other hand, the main product of canine urea produced by IDO catalysis of tryptophan metabolism induces T-cell apoptosis by oxygen free radical mediated changes in intracellular oxidants and antioxidants, which is an inherent immunosuppressive mechanism present in the body. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. It has been found that most human tumors constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.

Disclosed inhibitor patent applications for selective inhibition of IDO include WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958, and WO2014066834, among others.

The IDO inhibitor has good application prospect in the pharmaceutical industry as a medicine, and the applicant provides a high-efficiency low-toxicity selective IDO inhibitor compound with a novel structure in the patent application PCT/CN2016/079054(WO2016169421A1, published Japanese 2016-10-27), has excellent effects and effects, particularly excellent drug absorption activity, has the chemical name of (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol and the structure shown as the following

The chemical stability of the medicine is often influenced by the crystal form structure of the medicinal active ingredient, and the crystal form structure of the compound may be changed due to the difference of the crystal form, the preparation method and the storage condition, and other forms of crystal forms are generated sometimes. Generally, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy caking, poor flowability and the like, and these differences often lead to difficulty in production scale-up. The stability of the existing crystal forms needs to be improved. Therefore, it is necessary to improve various properties of the compound, and intensive research is needed to find a new crystal form with high purity and good chemical stability.

Disclosure of Invention

The invention aims to provide crystal forms A, B, C, D, E and F of free base (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidine-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol of an imidazoisoindole derivative, wherein the crystal forms have good crystal form stability and chemical stability, and a used crystallization solvent has low toxicity and low residue, so that the crystal can be better applied to clinic.

The technical scheme of the invention is as follows:

the invention provides a crystal form A of a compound shown as a formula (I), which is characterized in that: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks 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, the error range of the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, the present invention provides a crystalline form a of a compound of formula (I) characterized in that: the form A has characteristic peaks at 6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5,32.2,32.5,34.6,36.1,37.3 and 39.0, and the error range of 2 theta is +/-0.2.

In a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form of compound a of formula (I) comprising:

adding a compound shown as a formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target crystal form A, wherein the organic solvent is selected from alcohol solvents, preferably methanol; the beating temperature is selected from 30 ℃ to the boiling point temperature of the solvent, preferably 50 ℃.

In a preferred embodiment of the present invention, there is provided a crystalline form B of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks 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, the error range of the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, there is provided a crystalline form B of a compound of formula (I) characterized by: the B crystal form has characteristic peaks at 6.2,6.7,7.6,8.7,10, 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3,26.4,27.3,28.9 and 31.7, and the error range of 2 theta is +/-0.2.

In a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form B of compound of formula (I) comprising:

dissolving a compound shown as a formula (I) in a solvent, crystallizing, filtering and drying to obtain a target crystal form B, wherein the solvent is selected from halogenated hydrocarbon solvents, preferably dichloromethane;

adding the compound shown in the formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target crystal form B, wherein the organic solvent is selected from the following components:

the solvent comprises nitrile, ester, halogenated hydrocarbon, ether, alcohol, nitroalkane and a mixed solvent of alcohol and water, wherein 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 nitroalkane solvent is selected from nitromethane, the mixed solvent of alcohol and water is selected from a mixed solvent of isopropanol and water, and preferably 5% -95% of isopropanol; the beating temperature is selected from room temperature to the boiling point temperature of the solvent, preferably 50 ℃, and the room temperature is preferably 15-25 ℃, and more preferably 25 ℃.

In a preferred embodiment of the present invention, the present invention provides a crystalline form C of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks at 6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.3 and 28.3, the error range of the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, the present invention provides a crystalline form C of a compound of formula (I) characterized by: the form C has characteristic peaks at 4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0 and 31.6, and the error range of 2 theta is +/-0.2.

In a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form of compound C represented by formula (I) which comprises:

adding a compound shown as a formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target C crystal form, wherein the organic solvent is a ketone solvent selected from acetone; the beating temperature is selected from room temperature to the boiling point temperature of the solvent, preferably 50 ℃, and the room temperature is preferably 15-25 ℃, and more preferably 25 ℃.

In a preferred embodiment of the present invention, the present invention provides a crystalline form D of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has 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 the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, the present invention provides a crystalline form D of a compound of formula (I) characterized by: the D crystal form has characteristic peaks at 15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6,29.2,30.4 and 31.9, and the error range of 2 theta is +/-0.2.

In a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form of compound D represented by formula (I) which comprises:

adding a compound shown in a formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target D crystal form, wherein the organic solvent is selected from aromatic hydrocarbon solvents, preferably cumene or xylene; the pulping temperature is selected from 30 ℃ to the boiling point temperature of the solvent, and preferably 50 ℃.

In a preferred embodiment of the present invention, the present invention provides a crystalline form E of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has 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 the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form of compound E of formula (I) comprising:

adding a compound shown as a formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target E crystal form, wherein the organic solvent is selected from an alcohol solvent, preferably ethanol; the pulping temperature is selected from 30 ℃ to the boiling point temperature of the solvent, and preferably 50 ℃.

In a preferred embodiment of the present invention, there is provided a crystalline form F of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-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, the error range of the 2 theta is +/-0.2,

in a preferred embodiment of the present invention, there is provided a process for preparing a crystalline form of compound F of formula (I) comprising:

adding a compound shown as a formula (I) into an organic solvent, pulping, filtering, crystallizing, washing and drying to obtain a target F crystal form, wherein the organic solvent is selected from an alcohol solvent, preferably 2-propanol; the pulping temperature is selected from 30 ℃ to the boiling point temperature of the solvent, and preferably 50 ℃.

The invention further relates to a pharmaceutical composition, which consists of the crystal forms A, B, C, D, E and F of the compound shown in the formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a pharmaceutical composition of a compound shown in formula (I) in crystal forms A, B, C, D, E and F, which is characterized by further comprising one or more second therapeutic active agents selected from: anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, anticancer agents, antiviral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.

The invention further relates to a method for preparing the pharmaceutical composition, which is characterized by comprising the step of mixing the crystal forms A, B, C, D, E and F of the compound shown in the formula (I) with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to application of a pharmaceutical composition of a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form F or a crystal form A, B, C, D, E and F of a compound shown in a formula (I) in preparation of a medicine for treating diseases with IDO mediated tryptophan metabolic pathway pathological characteristics, wherein the diseases are selected from cancers, Alzheimer diseases, autoimmune diseases, depression, anxiety, cataracts, psychological disorders and AIDS, and the cancers are 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, papillary renal tumor, head and neck tumor, leukemia, Lymphoma, myeloma, or non-small cell lung cancer.

The crystal forms A, B, C, D, E and F of the obtained compound shown in the formula (I) are subjected to structure determination, crystal form research and the like by an X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), thermogravimetric analyzer (TGA) or dynamic water adsorption instrument (DVS) and the like.

The crystallization method comprises the steps of room temperature crystallization, cooling crystallization, solvent volatilization crystallization, crystal seed addition induction crystallization and the like, wherein the cooling temperature is selected from the temperature below 40 ℃, preferably from-10 ℃ to 40 ℃, and stirring can be further carried out in the crystallization process.

Detailed Description

The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.

In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.

The 'pulping' of the invention refers to a method for purifying by utilizing the characteristic that a substance has poor solubility in a solvent but impurities have good solubility in the solvent, and the pulping purification can remove color, change crystal forms or remove a small amount of impurities.

The term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.

The invention relates to a hydroxyl radicalThe radicals, cyano, nitro, etc. "mean-OH, -CN, -NO₂And the like.

Said "C" of the present invention_1-6Alkyl "denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.

The "ester solvent" according to 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, and specific examples include, but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.

The "ether solvent" according to 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 term "alcoholic solvent" as used herein means a compound in which one or more "hydroxyl groups" are substituted for "C_1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "hydroxy" and "C_1-6Alkyl "is as defined above, 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 conjugated system having a closed ring in the molecule, and a generic term of carbocyclic compounds and derivatives thereof having pi-electron number conforming to houckel rule, and specific examples include, but are not limited to: cumene or xylene.

The term "halogenated hydrocarbon solvent" as used herein means a solvent in which one or more "halogen atoms" are substituted for "C_1-6A group derived from one or more hydrogen atoms on an alkyl group, said "halogen atom" and "C_1-6Alkyl "is as defined above, in particularExamples include, but are not limited to: methyl chloride, dichloromethane, chloroform or carbon tetrachloride.

The "nitrile solvent" in the invention means that one or more "cyano groups" are substituted for "C_1-6Groups derived from one or more hydrogen atoms of alkyl groups, said "cyano" and "C_1-6Alkyl "is as defined above, specific examples include, but are not limited to: acetonitrile or propionitrile.

The "nitroalkane solvent" of the invention refers to one or more "nitro" substituted "C_1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "nitro" and "C_1-6Alkyl "is as defined above, specific examples include, but are not limited to: nitromethane.

The mixed solvent is a solvent formed by mixing one or more different organic solvents according to a certain proportion, or a solvent formed by mixing an organic solvent and water according to a certain proportion, wherein the certain proportion is 0.05: 1-1: 0.05, and is 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 isopropyl alcohol and water, the alcohol solvent being as defined above.

The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,

the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.

The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.

The term "2 theta or 2 theta angle" as used herein refers to the diffraction angle, theta is the Bragg angle and is expressed in degrees or degrees.

The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of

Or angstroms.

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

Furthermore, the pharmaceutical compositions of the present invention may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, for example, oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, oral solid preparations such as tablets, capsules, pills, granules and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. When formulated into oral preparations, the pharmaceutical preparations may further contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be manufactured by a conventional method in the existing pharmaceutical field. When preparing injection, the pharmaceutical preparation can be added with no additive, or added with proper additive according to the nature of the medicine. When used for rectal administration, the pharmaceutical preparation may be formulated into suppositories and the like. For pulmonary administration, the pharmaceutical formulation may be formulated as an inhalant or a spray. In certain preferred embodiments, the crystalline forms a, B, C, D, E, F of the present invention are present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline forms a, B, C, D, E, F of the present invention are present in a pharmaceutical composition or medicament in unit dosage form.

The crystalline forms A, B, C, D, E, F of the compounds of formula (I) of the present invention may be administered alone or in combination with one or more second therapeutic agents. Thus, in certain preferred embodiments, the pharmaceutical composition further comprises one or more second therapeutic agents. In certain preferred embodiments, the second therapeutic agent is selected from: anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, anticancer agents, antiviral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.

The ingredients to be combined (e.g., the crystalline forms a, B, C, D, E, F of the invention and the second therapeutic agent) may be administered simultaneously or separately in sequential order. For example, the second therapeutic agent may be administered prior to, concurrently with, or subsequent to the administration of the crystalline forms a, B, C, D, E, F or stereoisomers thereof of the invention. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate and distinct formulations.

The crystal forms A, B, C, D, E and F of the compound of the formula (I) can be used for preparing medicines for treating and/or preventing diseases of tryptophan metabolism mediated by IDO. The present application therefore also relates to the use of the crystalline forms a, B, C, D, E, F of the compounds of formula (I) according to the invention for the preparation of a medicament for the treatment and/or prevention of diseases which are associated with IDO-mediated tryptophan metabolism in a subject. Furthermore, the present application relates to a method of inhibiting diseases associated with tryptophan metabolism mediated by IDO, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the crystalline forms a, B, C, D, E, F of the compound of formula (I) of the present invention, or the pharmaceutical composition of the present invention.

In certain preferred embodiments, the disease is a disorder associated with tryptophan metabolism mediated by IDO, selected from the group consisting of: cancer, alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders or 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, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, or non-small cell lung cancer.

Advantageous effects of the invention

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

(1) the crystal forms of the compounds A, B, C, D, E and F shown in the formula (I) do not contain or only contain low-content residual solvents, and meet the limit requirements of related medicinal product residual solvents specified by national formulary, so that the crystal can be better used as a medicinal active ingredient.

(2) Researches show that the A, B, C, D, E and F crystal forms of the compound shown in the formula (I) have high purity, the crystal forms are not changed under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good; the HPLC purity change is small, and the chemical stability is high; the crystal forms of the compounds A, B, C, D, E and F shown in the formula (I) obtained by the technical scheme of the invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.

Drawings

FIG. 1 is an XRPD pattern for crystalline form A of compound represented by formula (I);

FIG. 2 is an XRPD pattern for crystalline form B of compound represented by formula (I);

FIG. 3 is an XRPD pattern for crystalline form C of compound represented by formula (I);

FIG. 4 is an XRPD pattern for form D of compound represented by formula (I);

FIG. 5 is an XRPD pattern for crystalline form E of compound represented by formula (I);

FIG. 6 is an XRPD pattern for crystalline form F of compound represented by formula (I);

FIG. 7 is a DSC of crystalline form A of compound represented by formula (I);

FIG. 8 is a DSC of crystalline form B of compound represented by formula (I);

FIG. 9 is a DSC of crystalline form C of compound represented by formula (I);

FIG. 10 is a DSC of crystalline form D of compound represented by formula (I);

FIG. 11 is a DSC of crystalline form E of compound represented by formula (I);

FIG. 12 is a DSC spectrum of crystalline form F of compound represented by formula (I);

FIG. 13 is a DVS first cycle plot of a crystalline form B of compound represented by formula (I);

FIG. 14 is a DVS second cycle plot of crystalline form B of compound represented by formula (I);

figure 15 is an XRPD pattern of form B for day 0;

figure 16 is an XRPD pattern of form B after 15 days at 40 ℃ and RH 75%;

figure 17 is an XRPD pattern of form C for day 0;

figure 18 is an XRPD pattern of form C after 15 days at 40 ℃ and RH 75%.

Detailed Description

The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.

Test conditions of the apparatus used for the experiment:

1. differential Scanning Calorimeter (DSC)

The instrument model is as follows: mettler Toledo DSC 3⁺STAR^eSystem

And (3) purging gas: nitrogen gas

The heating rate is as follows: 10.0 ℃/min

Temperature range: 20-250

2. X-ray Powder Diffraction Spectroscopy (XRPD)

(1) The instrument model is as follows: bruker D8 Discover A25X-ray powder diffractometer

Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)

The scanning mode is as follows: θ/2 θ, scan range: 10-48 degree

Voltage: 40KV, current: 40mA

(2) The instrument model is as follows: rigaku Ultimal V-ray powder diffractometer

Ray: monochromatic Cu-ka radiation (λ ═ 1.5418)

The scanning mode is as follows: θ/2 θ, scan range: 3-45 °

Voltage: 40KV, current: 40mA

3. Dynamic water adsorption instrument (Dynamic vapor absorption, DVS)

The instrument model is as follows: DVS advantage

Temperature: 25 deg.C

Solvent: water (W)

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

Comparative example preparation of (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol (compound of formula (I), see preparation methods in examples 40, 41 in patent application PCT/CN2016/079054(WO2016169421A1 (published as 2016-10-27))

(1) 6-fluoro-5- (piperidin-4-yl) -5H-imidazo [5,1-a ] isoindolditrifluoroacetate (Compound 1g) (see preparation of example 1 in patent application PCT/CN2016/079054(WO2016169421A1 (published Japanese 2016-10-27)))

First step of

4- ((2-bromo-6-fluorobenzene) (hydroxy) methyl) piperidine-1-carboxylic acid tert-butyl ester 1c

Lithium diisopropylamide (32.5mL, 65.0mmol) was added to tetrahydrofuran (50mL), and a solution of the preformed 1-bromo-3-fluorobenzene 1a (8.75g, 50.0mmol, 25mL) in tetrahydrofuran was added dropwise at-78 deg.C and stirred at-78 deg.C for 1 hour. A solution of the prepared tert-butyl 4-formylpiperidine-1-carboxylate 1b (8.75g, 50.0mmol, 25mL) in tetrahydrofuran was added dropwise at-78 ℃ and the mixture was stirred at-78 ℃ for 1 hour. After completion of the reaction, the reaction was quenched by dropwise addition of methanol (25mL) at-78 ℃, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (n-hexane and ethyl acetate) to obtain compound 1c (16.3g, yellow syrup solid, yield 84.0%).

MS m/z(LC-MS)：332.0[M-56]

Second step of

4- ((2-bromo-6-fluorophenyl) (p-toluenesulfonyloxy) methyl) piperidine-1-carboxylic acid tert-butyl ester 1d

Compound 1c (15g, 38.63mmol) was dissolved in tetrahydrofuran (350mL), and sodium hydride (3.09g, 77.26mmol) was added in portions and stirred until no gas evolution occurred. A solution of the preformed p-toluenesulfonyl chloride (8.10g, 42.49mmol, 250mL) in tetrahydrofuran was added dropwise, stirred at room temperature for 30 minutes, refluxed for 4 hours, and stirred at 70 ℃ for 48 hours. After completion of the reaction, it was cooled to 0 ℃ and quenched by dropwise addition of water (50mL), a saturated sodium chloride solution (50mL) was added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (n-hexane and ethyl acetate) to obtain compound 1d (6.6g, pale yellow viscous solid, yield: 31.80%).

MS m/z(LC-MS)：314.0/316.0[M-56-TsO]

The third step

4- ((2-bromo-6-fluorobenzene) (1H-imidazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester 1e

Imidazole (12.5g, 184.3mmol) was dissolved in N, N-dimethylformamide (50mL), sodium hydride (7.40g, 184.3mmol) was added in portions, stirred at room temperature for 1 hour, a solution of the preformed compound 1d (10.0g, 18.43mmol, 20mL) in N, N-dimethylformamide was added dropwise, and stirred at 100 ℃ for 12 hours. After the reaction was completed, ethyl acetate (300mL) was added, the mixture was washed with a saturated sodium chloride solution (150 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (dichloromethane and methanol) to obtain compound 1e (1.90g, brown viscous solid, yield: 23.5%).

MS m/z(LC-MS)：438.1/440.1[M+1]

The fourth step

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

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

MS m/z(LC-MS)：358.1[M+1]

The fifth step

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

Compound 1f (1.30g, 3.64mmol) was dissolved in dichloromethane (5mL), and trifluoroacetic acid (5mL) was added dropwise and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 1g (1.77g, brown viscous solid) of the crude compound, which 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-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazole (Compound 40a) (see CN104755477A (published Japanese 2015.07.01) for preparation on page 44 of the Specification)

(3) (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol (Compound 41, PCT/CN2016/079054(WO2016169421A1 (Kokai No. 2016-10-27) preparation methods in examples 40 and 41)

First step of

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

Second step of

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

The third step

Chiral preparation of compound 40c (1.4g, 3.16mmol) was carried out (separation conditions: chiral preparation column Superchiral S-AS (Chiralway), 2cm I.D.. times.25 cm Length, 5 μm; mobile phase: CO₂/MeOH/DEA＝60/40/0.05(v/v/v), flow rate: 50mL/min) to yield compound 40(630mg, yellow solid) and compound 41(652mg, yellow solid), wherein compound 41 is crystalline by XRPD assay, characterized by peaks at 4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0 and 31.6, which is form C.

Example 1

Adding 50mg of crude compound shown in formula (I) into a reaction bottle, adding methanol (50-100 μ L), stirring at constant temperature of 50 ℃ for 5 days, filtering, and vacuum drying to obtain white to light yellow powder. The XRPD pattern of this crystalline sample is shown in fig. 1, its DSC pattern is shown in fig. 7, its endothermic peak is around 217.9 ℃, its onset melting temperature is 216.8 ℃, this crystalline form is defined as form a, its characteristic peak positions are shown in table 1 below:

TABLE 1 characteristic peaks of form A

Example 2

50mg of the crude compound of formula (I) was added to a reaction flask, acetonitrile (50-100. mu.L) was added, and the mixture was stirred at a constant temperature of 25 ℃ for 5 days, filtered, and then vacuum-dried at 25 ℃ to obtain a white to pale yellow powder. The XRPD of the crystalline sample is shown in fig. 2, the DSC diagram is shown in fig. 8, the endothermic peak is around 210.5 ℃, the initial melting temperature is 210.3 ℃, this form is defined as form B, which can be judged as free of water of crystallization from the DVS diagrams of fig. 13 and 14, and the characteristic peak positions are shown in table 2 below:

TABLE 2 characteristic peaks of form B

Diffraction angles 2 theta of a sample of the crystal form B obtained in an ethyl acetate solvent at 50 ℃ have characteristic peaks 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, 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 through XRPD detection.

The diffraction angle 2 theta of a sample of the crystal form B obtained in a tetrahydrofuran solvent at 50 ℃ has characteristic peaks 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, 19.83, 20.78, 21.42, 22.33, 24.25, 25.14, 26.51, 27.38, 28.86 and 31.66 when detected by XRPD.

Example 3

Adding 50mg of the crude compound shown in the formula (I) into a reaction bottle, adding acetone (1.5mL), heating to 80 ℃, preserving heat for 10 minutes, cooling to 20 ℃, filtering, and drying to obtain a solid. The crystal sample has characteristic peaks at diffraction angles 2 theta of 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, 22.38, 25.40, 26.10, 27.38, 28.85 and 31.72 by XRPD detection, and the product is determined to be B crystal form.

Example 4

Adding 50mg of crude compound shown in the formula (I) into a reaction bottle, adding acetone (50-100 mu L), stirring for 5 days at a constant temperature of 25 ℃, filtering, and then drying in vacuum at 25 ℃ to obtain white to light yellow powder, wherein the XRPD of a crystal sample is shown in figure 3, the DSC spectrum thereof is shown in figure 9, the endothermic peak value is about 210.1 ℃, the initial melting temperature is 209.5 ℃, the crystal form is defined as a C crystal form, and the characteristic peak positions are shown in the following table 3:

TABLE 3C Crystal form characteristic peaks

The diffraction angle 2 theta of a crystal form C sample obtained in an acetone solvent at 25 ℃ has characteristic peaks at 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, 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 through XRPD detection.

Example 5

50mg of the crude compound of formula (I) was added to a reaction flask, cumene (50-100. mu.L) was added, stirred at a constant temperature of 50 ℃ for 5 days, filtered and dried under vacuum to give a white to pale yellow powder. The XRPD pattern of this crystalline sample is shown in fig. 4, the DSC pattern is shown in fig. 10, the endothermic peak is around 212.9 ℃, the onset melting temperature is 211.1 ℃, this crystalline form is defined as form D, and the characteristic peak positions are shown in table 4 below:

TABLE 4 characteristic peaks of the D crystal form

Example 6

Adding 50mg of crude compound shown in formula (I) into a reaction bottle, adding ethanol (50-100 μ L), stirring at constant temperature of 50 ℃ for 5 days, filtering, and vacuum drying to obtain white to light yellow powder. The XRPD pattern of the solid sample is shown in fig. 5, the DSC pattern is shown in fig. 11, the endothermic peak is around 211.5 ℃, the initial melting temperature is 210.2 ℃, this crystal form is defined as form E, and the characteristic peak positions are shown in table 5 below:

TABLE 5 characteristic peaks of the E crystal form

Example 7

Adding 50mg of crude compound shown in formula (I) into a reaction bottle, adding 2-propanol (50-100 μ L), stirring at constant temperature of 50 ℃ for 5 days, filtering, and vacuum drying to obtain white to light yellow powder. The XRPD pattern of the solid sample is shown in fig. 6, the DSC pattern is shown in fig. 12, the endothermic peak is around 208.6 ℃, the onset melting temperature is 206.9 ℃, the form is defined as form F, and the characteristic peak positions are shown in table 6 below:

TABLE 6 characteristic peaks of the F crystal form

Experimental protocol

An exemplary experimental protocol for the crystalline product of the invention is provided below to show the advantageous activity or beneficial technical effects of the crystalline product of the invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure. Those skilled in the art, having the benefit of the teachings of this specification, will be able to make appropriate modifications or alterations to the teachings of this invention without departing from the spirit or scope thereof.

Experimental example 1, stability examination of form B and form C

And (3) placing the samples of the crystal form B and the crystal form C open and flatly, and observing the stability of the samples under the conditions of 40 ℃ and relative humidity RH 75% and the sampling time of 15 days.

The experimental results are as follows:

figure 15 of the accompanying drawings is an XRPD pattern of form B for day 0;

figure 16 of the accompanying drawings is an XRPD pattern of form B after being placed for 15 days at 40 ℃ and 75% relative humidity;

figure 17 of the accompanying drawings is an XRPD pattern of form C for day 0;

figure 18 is an XRPD pattern of form C after 15 days at 40 ℃ and 75% relative humidity.

And (4) experimental conclusion:

the stability examination results of figures 15, 16, 17 and 18 in the attached drawings indicate that the XRPD peak pattern of the B crystal form of the compound shown in the formula (I) is basically unchanged and the crystal form is stable under the condition of being placed at 40 ℃ and relative humidity RH 75%; the XRPD peak pattern of the C crystal form is changed under the condition of being placed at 40 ℃ and relative humidity RH 75%, partial peak pattern characteristics disappear, and the crystallinity is reduced; it can be seen that form B is more physically stable than form C when left at 40 ℃ RH 75%.

Claims

1. A crystalline form a of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks 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, the error range of the 2 theta is +/-0.2,

2. the crystalline form a of claim 1, characterized in that: the form A has characteristic peaks at 6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5,32.2,32.5,34.6,36.1,37.3 and 39.0, and the error range of 2 theta is +/-0.2.

3. A process for preparing form a according to any one of claims 1 to 2, characterized in that it is:

adding the compound shown in the formula (I) into methanol, pulping at 50 ℃, filtering, crystallizing, washing and drying to obtain the target crystal form A.

4. A crystalline form B of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks 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, the error range of the 2 theta is +/-0.2,

5. the form B of claim 4, characterized in that: the B crystal form has characteristic peaks at 6.2,6.7,7.6,8.7,10, 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3,26.4,27.3,28.9 and 31.7, and the error range of 2 theta is +/-0.2.

6. A process for preparing form B according to any one of claims 4 to 5, selected from:

dissolving a compound shown as a formula (I) in dichloromethane, crystallizing, filtering and drying to obtain a target crystal form B;

adding the compound shown in the formula (I) into an acetonitrile solvent, pulping at 25 ℃, filtering, crystallizing, washing and drying to obtain a target crystal form B;

adding the compound shown in the formula (I) into an ethyl acetate solvent or a tetrahydrofuran solvent, pulping at 50 ℃, filtering, crystallizing, washing and drying to obtain the target crystal form B.

7. A crystalline form C of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has characteristic peaks at 6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.3 and 28.3, the error range of the 2 theta is +/-0.2,

8. the crystalline form C of claim 7, characterized in that: the form C has characteristic peaks at 4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0 and 31.6, and the error range of 2 theta is +/-0.2.

9. A process for preparing form C according to any one of claims 7 to 8, wherein the process is:

adding the compound shown in the formula (I) into acetone, pulping at 25 ℃, filtering, crystallizing, washing and drying to obtain the target C crystal form.

10. A crystalline form D of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has 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 the 2 theta is +/-0.2,

11. the crystalline form D of claim 10, characterized in that: the D crystal form has characteristic peaks of the D crystal forms at 15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6,29.2,30.4 and 31.9, and the error range of 2 theta is +/-0.2.

12. A process for preparing form D according to any one of claims 10 to 11, wherein the process is:

adding the compound shown in the formula (I) into isopropyl benzene or xylene, pulping at 50 ℃, filtering, crystallizing, washing and drying to obtain the target D crystal form.

13. A crystalline form E of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern has 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 the 2 theta is +/-0.2,

14. a process for preparing form E according to claim 13, wherein the process is:

adding the compound shown in the formula (I) into ethanol, pulping at 50 ℃, filtering, crystallizing, washing and drying to obtain the target E crystal form.

15. A crystalline form F of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-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, the error range of the 2 theta is +/-0.2,

16. a process for preparing the crystalline form F according to claim 15, characterized in that it is:

adding the compound shown in the formula (I) into 2-propanol, pulping at 50 ℃, filtering, crystallizing, washing and drying to obtain the target F crystal form.

17. A pharmaceutical composition consisting of the crystalline form a according to any one of claims 1-2, the crystalline form B according to any one of claims 4-5, the crystalline form C according to any one of claims 7-8, the crystalline form D according to any one of claims 10-11, the crystalline form E according to claim 13, the crystalline form F according to claim 15 and a pharmaceutically acceptable carrier, diluent or excipient.

18. The pharmaceutical composition of claim 17, further comprising one or more second therapeutically active agents selected from the group consisting of: anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, anti-cancer agents, anti-viral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.

19. A process for preparing a pharmaceutical composition according to any one of claims 17 to 18, comprising the step of admixing the form a according to any one of claims 1 to 2, the form B according to any one of claims 4 to 5, the form C according to any one of claims 7 to 8, the form D according to any one of claims 10 to 11, the form E according to claim 13, the form F according to claim 15 with a pharmaceutically acceptable carrier, diluent or excipient.

20. Use of the crystalline form a according to any one of claims 1 to 2, the crystalline form B according to any one of claims 4 to 5, the crystalline form C according to any one of claims 7 to 8, the crystalline form D according to any one of claims 10 to 11, the crystalline form E according to claim 13, the crystalline form F according to claim 15, the pharmaceutical composition according to any one of claims 17 to 18 for the preparation of a medicament for the treatment of a disease characterized by IDO-mediated tryptophan metabolic pathway pathology, selected from the group consisting of cancer, alzheimer's disease, autoimmune disease, cataracts, psychological disorders and aids, selected from the group consisting of 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, papillary renal tumor, head and neck tumor, leukemia, lymphoma, and myeloma.