ACID ADDITION SALT OF RORy REGULATOR

Information

  • Patent Application
  • 20220411380
  • Publication Number
    20220411380
  • Date Filed
    October 30, 2020
    3 years ago
  • Date Published
    December 29, 2022
    a year ago
Abstract
An acid addition salt of a RORγ regulator. Specifically relating to the acid addition salt of the compound of formula II. More specifically relating to benzoate, oxalate, methanesulfonate, maleate, hydrobromate, hydrochloride salt, and acetate of the compound of formula II and the benzoate crystal form, benzoate amorphous form, oxalate crystal form, oxalate amorphous form, methanesulfonate amorphous form, maleate B crystal form, maleate C crystal form, maleate D crystal form, hydrobromate I crystal form, hydrochloride salt α crystal form, hydrochloride salt β crystal form, hydrochloride salt γ crystal form, and acetate crystal form of the compound of formula II.
Description

The present application claims priority to Chinese Patent Application No. CN201911049930.5 filed on Oct. 31, 2019, which is incorporated herein by reference in its entirety.


TECHNICAL FIELD

The present disclosure relates to the field of pharmaceutical chemistry, and in particular, to an acid addition salt of a compound of formula II as an RORγ regulator.


BACKGROUND

Nuclear receptors are ligand-regulated transcription factors that regulate development, immunity, and cellular metabolism, and are one of the major therapeutic target classes for human diseases. Retinoid-related orphan receptor gamma (RORγ) is a member of the nuclear receptor NR1 subfamily and has a typical nuclear receptor domain structure consisting of a DNA-binding domain, a ligand-binding domain, a hinge domain and an activation function 2 domain (Benoit G, et al., Pharmacological Reviews, 58(4):798-836, 2006; Zhang, Y, et al., Acta Pharmacogica Sinica, 36:71-87, 2015). In contrast to most other nuclear receptors that function as dimers, RORγ works as a monomer. It binds to specific DNA sequences usually consisting of TAAA/TNTAGGTCA, which are called ROR response elements (ROREs).


There are two RORγ subtypes, RORγ1 and RORγ2 (also known as RORγt) that arise from the same RORC gene, and possibly differ in selection of promoters (Villey I et al, Eur. J. Immunol., 29(12):4072-80, 1999). Since the two RORγ subtypes (RORγ1 and RORγt) are derived from the same mRNA, they have identical ligand-binding domains, and are distinguished by N terminus only (Jetten, A. M., 2009; Ivanov, I. I. et al., 2006). Small molecule inhibitors generally bind to the ligand-binding domain to inhibit the function of the receptor. As such, they have no selectivity for the two RORγ subtypes, and are all referred to as RORγ small molecule inhibitors (or modulators) without subtyping.


The two RORγ subtypes have very different tissue distributions. RORγt is mainly expressed in thymus and several immune cells, while RORγ1 is expressed in many tissues, such as thymus, liver, muscle, testis, pancreas, prostate and heart. (Jetten, A. M., 2009; Zhang, Y. et al., 2015). It has been reported that one of the functions of RORγ1 is to regulate the human biochronometer, and particularly, to regulate the circadian rhythm (Jetten, A. M., 2009). T helper 17 (Th17) cells are the major source of autoimmune disease (Ivanov, I. I. et al., 2006). Both RORγ subtypes are expressed in Th17 cells, regulating T cell differentiation and inducing gene transcription in Th17 cells (Ruan, Q., et al., 2011). Cytokines IL-6 and TGF-β induce differentiation of undifferentiated CD4 T helper cells into Th17 cells. RORγt highly expressed in Th17 cells induces transcription of IL-23 receptor gene in undifferentiated CD4 T helper cells, IL23 receptors in turn promote and stabilize production of Th17 cells, forming part of a positive feedback loop (Ivanov, I. I. et al., 2006; Jetten, A. M., 2009). Meanwhile, RORγt can induce the gene transcription of proinflammatory cytokines such as IL-17A, IL-17F, IL-21 and IL-22, and enhance the inflammation process. Like RORγt, RORγ1 is also expressed in Th17 cells, and can also regulate differentiation and induce gene transcription in Th17 cells (Ruan, Q., et al., 2011). Pharmacological antagonism against RORγ has therapeutic potential for autoimmune diseases, making it an attractive target for small molecule inhibitors.


RORγ has been identified as a key mediator in the pathogenesis of several diseases, such as rheumatoid arthritis, psoriasis vulgaris, multiple sclerosis, inflammatory bowel disease, Crohn's disease, sicca syndrome and asthma. (Louten et al., J. Allergy Clin. Immunol., 123:1004-1011, 2009; Annuziato, F., et al., Nat. Rev. Rheumatol., 5(6):325-331, 2009; Lizuka, M., et al., J. Immunol., 194:56-67, 2014). Some other diseases, such as chronic xerophthalmia, Kawasaki's disease, mucosal leishmaniasis and Hashimoto's thyroiditis, are characterized by increased Th17 proportion and/or increased levels of Th17 marker cytokines, such as IL-17, IL-22 and IL-23. (Chen, Y et al., Mucosal. Immunol., 7(1):38-45, 2014; Jia, S., et al., Clin. Exp. Immunol., 162:131-137, 2010; Boaventura, V S et al., Eur. J. Immunol., 40:2830-2836, 2010; Figueroa-Vega, N. et al., J. Clin. Endocrinol. Metab., 95:953-62, 2010). In each of the above examples, the inhibitory effect can be enhanced by inhibiting RORα. RORγt inhibitors are currently being developed for the treatment of autoimmune diseases such as psoriasis vulgaris and rheumatoid arthritis. See Jun R. Huh and Dan R. Littman, Eur. J. Immunol., 42(9):2232-2237 (2012), WO2012/027965, WO2013/029338 and US2015/291607.


Patent Application No. PCT/US19/30526 provides an RORγ regulator having a structure of formula II:




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which is incorporated herein in its entirety.


BRIEF SUMMARY

The present disclosure provides an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, wherein the acid addition salt is an organic acid addition salt or an inorganic acid addition salt.


The present disclosure further relates to a method for preparing an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, wherein the acid addition salt is an organic acid addition salt or an inorganic acid addition salt, and the method comprises mixing a certain amount of the compound of formula II with a proper amount of a solvent and the organic acid or the inorganic acid, and reacting for a period of time to obtain the salt of the compound of formula II with the corresponding acid, wherein the solvent is selected from the group consisting of one or more of a hydrocarbon solvent, an ether solvent, an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a nitrogenous solvent, water and dimethyl sulfoxide.


In some embodiments, the organic acid addition salt is at least one selected from the group consisting of formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, β-naphthalenesulfonate, malate, propiolate, 2-butynoate, 2-hydroxy-ethanesulfonate, 3-butenoate, tartrate, fumarate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1,2-ethanedisulfonate, oxalate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, glycolate, alginate, ascorbate, aspartate, glutamate, 2-phenoxybenzoate, 2-(4-hydroxybenzoyl)benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, dodecylsulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, pivalate, glucuronate, laurate, phthalate, phenylacetate, laurylsulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, p-phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, neopentanoate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salt, alginate, 4-acetamidobenzenesulfonate, caprate, cholate, caprylate, nonanoate, cyclamate, phthalate, cysteine hydrochloride salt, sorbate, glycine hydrochloride salt, 1,5-naphthalenedisulfonate, xylenesulfonate, cystine dihydrochloride salt, undecanoate, polyvinyl sulfonate salt, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinyl sulfate salt, naphthalene-1-sulphonate and valerate.


In some embodiments, the inorganic acid addition salt is at least one selected from the group consisting of hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, bisulfate, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, disulfate, thiocyanate, phosphate, pyrophosphate and metaphosphate.


In some embodiments, the organic acid addition salt may be at least one selected from the group consisting of benzoate, oxalate, methanesulfonate, maleate and acetate, and the inorganic acid addition salt may be selected from the group consisting of hydrochloride and hydrobromide. The present disclosure provides a crystalline form of benzoate, an amorphous form of benzoate, a crystalline form of oxalate, an amorphous form of oxalate, an amorphous form of methanesulfonate, a crystalline form B of maleate, a crystalline form C of maleate, a crystalline form D of maleate, a crystalline form I of hydrobromide, a crystalline form α of hydrochloride, a crystalline form β of hydrochloride, a crystalline form γ of hydrochloride and a crystalline form of acetate of a compound of formula II, and methods for preparing the same.


The present disclosure provides an amorphous form of a compound of formula II, having an XRPD pattern with no distinct sharp diffraction peaks; preferably, the amorphous form has an XRPD pattern as shown in FIG. 1.


The present disclosure provides a benzoate of a compound of formula II.


In some embodiments, the benzoate is an amorphous form having an XRPD pattern with no distinct sharp diffraction peaks; preferably, the amorphous form has an XRPD pattern as shown in FIG. 2.


In some embodiments, the benzoate is a crystalline form having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.305 and 7.411.


Furthermore, the crystalline form of the benzoate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.305, 7.411 and 22.031.


Furthermore, the crystalline form of the benzoate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.305, 7.411, 19.140 and 22.0314.


The present disclosure provides an oxalate of a compound of formula II.


In some embodiments, the oxalate is an amorphous form having an XRPD pattern with no distinct sharp diffraction peaks; preferably, the amorphous form has an XRPD pattern as shown in FIG. 5.


In some embodiments, the oxalate is a crystalline form having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 14.378, 18.463 and 21.670.


Furthermore, the crystalline form of the oxalate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 14.378, 18.463, 21.670 and 23.075.


Furthermore, the crystalline form of the oxalate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 14.378, 18.463, 21.670, 23.075 and 28.127.


The present disclosure provides a methanesulfonate of a compound of formula II.


In some embodiments, the methanesulfonate is an amorphous form having an XRPD pattern with no distinct sharp diffraction peaks; preferably, the amorphous form has an XRPD pattern as shown in FIG. 7.


The present disclosure provides a maleate of a compound of formula II.


In some embodiments, the maleate is a crystalline form B having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.624, 9.659, 13.815, 15.844 and 17.391.


Furthermore, the crystalline form B of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.624, 9.659, 13.815, 15.844, 17.391 and 21.802.


Furthermore, the crystalline form B of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.624, 9.659, 13.815, 15.844, 17.391, 18.619 and 21.802.


Furthermore, the crystalline form B of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.624, 9.659, 13.815, 15.844, 17.391, 18.619, 21.802, 23.667 and 26.441.


In some embodiments, the maleate is a crystalline form C having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.325, 8.635, 9.809, 13.649, 16.133, 16.765 and 18.346.


Furthermore, the crystalline form C of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.325, 8.635, 9.809, 13.649, 16.133, 16.765, 18.346, 21.689 and 23.586.


Furthermore, the crystalline form C of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.325, 8.635, 9.809, 11.661, 13.649, 16.133, 16.765, 18.346, 21.689, 23.586 and 25.303.


In some embodiments, the maleate is a crystalline form D having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 4.486, 7.288, 9.067, 10.001, 13.914, 18.229 and 18.940.


Furthermore, the crystalline form D of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 4.486, 5.998, 7.288, 9.067, 10.001, 13.914, 15.026, 16.227, 18.229 and 18.940.


Furthermore, the crystalline form D of the maleate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 4.486, 5.998, 7.288, 9.067, 10.001, 13.914, 15.026, 16.227, 18.229, 18.940, 23.076, 25.612 and 28.102.


The present disclosure provides a hydrobromide of a compound of formula II.


In some embodiments, the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780 and 20.733.


Furthermore, the crystalline form I of the hydrobromide has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930 and 29.547.


Furthermore, the crystalline form I of the hydrobromide has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 11.918, 12.579, 16.414, 17.075, 17.780, 18.750, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930, 29.547, 30.958, 32.236, 33.382, 38.670, 39.640, 40.830, 42.064, 43.342, 46.824, 48.190, 48.983 and 50.746.


The present disclosure provides a hydrochloride of a compound of formula II.


In some embodiments, the hydrochloride is a crystalline form α having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 13.920, 15.224, 17.425 and 18.309.


Furthermore, the crystalline form α of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 12.166, 13.920, 15.224, 16.041, 16.315, 16.748, 17.425, 18.309, 22.340, 23.359 and 24.570.


Furthermore, the crystalline form α of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 12.166, 13.920, 15.224, 16.041, 16.315, 16.748, 17.425, 18.309, 19.624, 20.235, 21.491, 22.340, 23.359, 23.905 and 24.570. Furthermore, the crystalline form α of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 12.166, 13.920, 15.224, 16.041, 16.315, 16.748, 17.425, 18.309, 19.624, 20.235, 21.491, 22.340, 23.359, 23.905, 24.570, 25.320, 25.811, 26.096, 27.624, 28.213, 29.190, 29.760, 31.266, 31.795, 32.324, 35.906 and 37.291.


In some embodiments, the hydrochloride is a crystalline form β having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.386, 8.191, 12.688, 16.607 and 20.036.


Furthermore, the crystalline form β of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.386, 8.191, 10.818, 12.688, 13.980, 14.915, 16.607, 20.036 and 21.372.


Furthermore, the crystalline form β of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.386, 8.191, 10.818, 12.688, 13.980, 14.915, 16.607, 18.076, 19.056, 20.036, 21.372, 22.040, 23.465, 24.355, 25.869, 26.582, 27.383, 29.253, 29.832, 30.946, 31.480, 32.504 and 33.439.


In some embodiments, the hydrochloride is a crystalline form γ having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.114, 11.997, 12.640, 13.772, 16.478, 17.897 and 20.337.


Furthermore, the crystalline form γ of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.114, 11.997, 12.640, 13.772, 16.478, 17.897, 20.337, 21.422, 23.228 and 24.472.


Furthermore, the crystalline form γ of the hydrochloride has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.114, 11.997, 12.640, 13.772, 16.478, 17.897, 19.671, 20.337, 21.422, 22.156, 23.228, 24.472, 25.882, 27.567, 28.277, 29.830, 31.160, 32.269 and 33.334.


The present disclosure provides an acetate of a compound of formula II.


In some embodiments, the acetate is a crystalline form having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 11.651, 12.495, 15.636, 15.965, 18.075 and 20.935.


Furthermore, the crystalline form of the acetate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 11.651, 12.495, 14.323, 15.121, 15.636, 15.965, 18.075, 19.247, 19.903 and 20.935.


Furthermore, the crystalline form of the acetate has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 11.651, 12.495, 14.323, 15.121, 15.636, 15.965, 18.075, 19.247, 19.903, 20.935, 22.107, 22.998, 23.842, 24.733, 25.530, 26.843, 28.719, 29.750, 30.829, 32.142, 35.143 and 39.973.


The present disclosure further relates to a method for preparing benzoate, oxalate, methanesulfonate, maleate, hydrobromide, hydrochloride or acetate of a compound of formula II, comprising: mixing a certain amount of the compound of formula II with a proper amount of a solvent and benzoic acid, oxalic acid, methanesulfonic acid, maleic acid, hydrobromic acid, hydrochloric acid or acetic acid for reaction to obtain the salt of the compound of formula II with the corresponding acid, wherein the solvent is selected from the group consisting of one or more of a hydrocarbon solvent, an ether solvent, an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a nitrogenous solvent, water and dimethyl sulfoxide,


the hydrocarbon solvent includes, but is not limited to, n-butane, n-pentane, n-hexane or n-heptane;


the ether solvent includes, but is not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane;


the alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol;


the ester solvent includes, but is not limited to, ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent includes, but is not limited to, acetone, acetophenone or 4-methyl-2-pentanone;


the nitrile solvent includes, but is not limited to, acetonitrile or propionitrile; the halogenated hydrocarbon solvent includes, but is not limited to, chloromethane, dichloromethane, chloroform or carbon tetrachloride;


the nitrogenous solvent includes, but is not limited to, nitromethane, N,N-dimethylformamide or N,N-dimethylacetamide.


In some embodiments, a method for preparing an amorphous form of a compound of formula II, comprises: taking a certain amount of the compound of formula II, adding a proper amount of a solvent, precipitating a solid, filtering and drying to obtain the amorphous form of the compound of formula II. In certain embodiments, the solvent may be selected from the group consisting of isopropyl ether, toluene and isopropyl acetate/n-hexane (v:v=1:3).


In some embodiments, a method for preparing an amorphous form of a compound of formula II, comprises: purifying a certain amount of the compound of formula II by high performance liquid chromatography with an elution system of ammonium bicarbonate/water/acetonitrile to obtain the amorphous form of the compound of formula II.


In some embodiments, a method for preparing an amorphous form of a compound of formula II, comprises: taking a certain amount of the compound of formula II, adding a proper amount of a solvent, precipitating a solid, filtering and drying to obtain the amorphous form of the compound of formula II, wherein the solvent is selected from the group consisting of isopropyl ether, toluene and a mixed solvent of isopropyl acetate and n-hexane (v:v=1:3), and the method for precipitating the amorphous form is selected from the group consisting of precipitation at room temperature, precipitation by cooling and precipitation by volatilizing the solvent.


In some embodiments, a method for preparing an amorphous form of a compound of formula II, comprises: taking a certain amount of the compound of formula II, adding a proper amount of isopropyl ether, toluene or a mixed solvent of isopropyl acetate and n-hexane (v:v=1:3), heating until complete or incomplete dissolution, cooling to room temperature, stirring to precipitate a solid, filtering and drying to obtain the amorphous form of the compound of formula II.


The present disclosure further relates to a method for preparing an amorphous or crystalline form of a benzoate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and benzoic acid, precipitating a solid, filtering and drying to obtain the amorphous or crystalline form of the benzoate of the compound of formula II. In certain embodiments, the solvent is n-hexane or methyl tert-butyl ether.


The present disclosure further relates to a method for preparing an amorphous or crystalline form of an oxalate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and oxalic acid, precipitating a solid, filtering and drying to obtain the amorphous or crystalline form of the oxalate of the compound of formula II. In certain embodiments, the solvent is n-hexane or methyl tert-butyl ether.


The present disclosure further relates to a method for preparing an amorphous form of a methanesulfonate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and methanesulfonic acid, precipitating a solid, filtering and drying to obtain the amorphous form of the methanesulfonate of the compound of formula II. In certain embodiments, the solvent is methyl tert-butyl ether.


The present disclosure further relates to a method for preparing crystalline forms B, C and D of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and maleic acid, precipitating a solid, filtering and drying to obtain the crystalline forms B, C and D of the maleate of the compound of formula II. In certain embodiments, the solvent is methyl tert-butyl ether.


The present disclosure further relates to a method for preparing a crystalline form I of a hydrobromide of a compound of formula II, comprising: precipitating a crystal by reacting the compound of formula II with hydrobromic acid in a proper amount of a solvent selected from the group consisting of one or more of a hydrocarbon solvent, an ether solvent, an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a nitrogenous solvent, water and dimethyl sulfoxide, wherein the hydrocarbon solvent includes, but is not limited to, n-butane, n-pentane, n-hexane or n-heptane;


the ether solvent includes, but is not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane;


the alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol;


the ester solvent includes, but is not limited to, ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent includes, but is not limited to, acetone, acetophenone or 4-methyl-2-pentanone;


the nitrile solvent includes, but is not limited to, acetonitrile or propionitrile; the halogenated hydrocarbon solvent includes, but is not limited to, chloromethane, dichloromethane, chloroform or carbon tetrachloride;


the nitrogenous solvent includes, but is not limited to, nitromethane, N,N-dimethylformamide or N,N-dimethylacetamide.


In some embodiments, for the method for preparing the crystalline form I of the hydrobromide of the compound of formula II, the solvent is methyl tert-butyl ether and ethanol.


The present disclosure further relates to a method for preparing a crystalline form I of a hydrobromide of a compound of formula II, comprising: mixing a certain amount of the compound of formula II with a proper amount of a solvent and hydrobromic acid, precipitating a solid, filtering and drying to obtain the crystalline form I of the hydrobromide of the compound of formula II. In certain embodiments, the solvent is methyl tert-butyl ether and ethanol.


The present disclosure further relates to a method for preparing crystalline forms α, β and γ of a hydrochloride of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and hydrochloric acid, precipitating a solid, filtering and drying to obtain the crystalline forms α, β and γ of the hydrochloride of the compound of formula II. In certain embodiments, the solvent is methyl tert-butyl ether.


The present disclosure further relates to a method for preparing a crystalline form γ of a hydrochloride of a compound of formula II, comprising: loading a certain amount of the crystalline form β of the compound of formula II to a DVS system and running a process with parameters of dm/dt=0.002, 50-95-0-95-50% RH, Max 360 min, 25° C. to obtain the crystalline form γ of the hydrochloride of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form of an acetate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of a solvent and acetic acid, precipitating a solid, filtering and drying to obtain the crystalline form of the acetate of the compound of formula II. In certain embodiments, the solvent is water and ethanol.


In certain embodiments, for the preparation process of the amorphous form of the compound of formula II, the benzoate, oxalate, methanesulfonate, maleate, hydrobromide, hydrochloride and acetate of the compound of formula II, and the crystalline form of the benzoate, the amorphous form of the benzoate, the crystalline form of the oxalate, the amorphous form of the oxalate, the amorphous form of the methanesulfonate, the crystalline forms B, C and D of the maleate, the crystalline form I of the hydrobromide, the crystalline forms α, β and γ of the hydrochloride and the crystalline form of the acetate, the solvent is selected from the group consisting of one or more of a hydrocarbon solvent, an ether solvent, an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a nitrogenous solvent, water and dimethyl sulfoxide. The hydrocarbon solvent includes, but is not limited to, n-butane, n-pentane, n-hexane or n-heptane; the ether solvent includes, but is not limited to, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane; the alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol; the ester solvent includes, but is not limited to, ethyl acetate, isopropyl acetate or butyl acetate; the ketone solvent includes, but is not limited to, acetone, acetophenone or 4-methyl-2-pentanone; the nitrile solvent includes, but is not limited to, acetonitrile or propionitrile; the halogenated hydrocarbon solvent includes, but is not limited to, chloromethane, dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride; and the nitrogenous solvent includes, but is not limited to, nitromethane, N,N-dimethylformamide or N,N-dimethylacetamide.


The method for precipitating a solid form of the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein is selected from the group consisting of precipitation at room temperature, precipitation by cooling and precipitation by volatilizing the solvent. In certain embodiments, the solid form of the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein refers to the crystalline form of the benzoate, the amorphous form of the benzoate, the crystalline form of the oxalate, the amorphous form of the oxalate, the amorphous form of the methanesulfonate, the crystalline forms B, C and D of the maleate, the crystalline form I of the hydrobromide, the crystalline forms α, β and γ of the hydrochloride and the crystalline form of the acetate of the compound of formula II.


The method for crystallizing the crystalline form of the compound disclosed herein is selected from the group consisting of crystallization at room temperature, crystallization by cooling, crystallization by volatilization or induction crystallization by adding seed crystal, and the crystalline form of the compound is selected from the group consisting of the crystalline form of the benzoate, the crystalline form of the oxalate, the crystalline forms B, C and D of the maleate, the crystalline form I of the hydrobromide, the crystalline forms α, β and γ of the hydrochloride and the crystalline form of the acetate of the compound of formula II.


The present disclosure further relates to a method for preparing an amorphous or crystalline form of a benzoate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of n-hexane or methyl tert-butyl ether and benzoic acid, stirring at 50° C. overnight, filtering and drying to obtain the amorphous or crystalline form of the benzoate of the compound of formula II.


The present disclosure further relates to a method for preparing an amorphous or crystalline form of an oxalate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether or n-hexane and oxalic acid, stirring at 50° C. overnight, filtering and drying to obtain the amorphous or crystalline form of the oxalate of the compound of formula II.


The present disclosure further relates to a method for preparing an amorphous form of a methanesulfonate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and methanesulfonic acid, stirring at 50° C. overnight, filtering and drying to obtain the amorphous form of the methanesulfonate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form B of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 10 min to 10 h, filtering and drying to obtain the crystalline form B of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form B of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 10 min, 20 min, 30 min, 1 h or 2 h, filtering and drying to obtain the crystalline form B of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form C of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 12 h to 36 h, filtering and drying to obtain the crystalline form C of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form C of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 1 d, filtering and drying to obtain the crystalline form C of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form D of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 48 h to 72 h, filtering and drying to obtain the crystalline form D of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form D of a maleate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and maleic acid, stirring at 50° C. at 600 rpm for 3 d, filtering and drying to obtain the crystalline form D of the maleate of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form I of a hydrobromide of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and hydrobromic acid or a mixture of hydrobromic acid and ethanol, stirring at 25° C. at 600 rpm for 12 h to 72 h, filtering and drying to obtain the crystalline form I of the hydrobromide of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form I of a hydrobromide of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and hydrobromic acid, stirring at 25° C. at 600 rpm for 3 d, filtering and drying to obtain the crystalline form I of the hydrobromide of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form I of a hydrobromide of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and a mixture of hydrobromic acid and ethanol (in a volume ratio selected from the group consisting of 1:1, 1:50 and 1:99), stirring at 25° C. at 600 rpm overnight and for 3 d, filtering and drying to obtain the crystalline form I of the hydrobromide of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form α of a hydrochloride of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and concentrated hydrochloric acid, stirring at 50° C. for 12 h to 48 h, filtering and drying to obtain the crystalline form α of the hydrochloride of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form α of a hydrochloride of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and concentrated hydrochloric acid, stirring at 50° C. for 2 d, filtering and drying to obtain the crystalline form α of the hydrochloride of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form β of a hydrochloride of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and a solution of hydrochloric acid in ethanol, precipitating a solid, filtering and drying to obtain the crystalline form β of the hydrochloride of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form β of a hydrochloride of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of methyl tert-butyl ether and a solution of hydrochloric acid in ethanol (concentrated hydrochloric acid:ethanol=1:99, well mixed), stirring at 25° C. for 1 h and at 50° C. for 2 d, filtering and drying to obtain the crystalline form β of the hydrochloride of the compound of formula II.


The present disclosure further relates to a method for preparing a crystalline form of an acetate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of water and a solution of acetic acid in ethanol, precipitating a solid, filtering and drying to obtain the crystalline form of the acetate of the compound of formula II. The present disclosure further relates to a method for preparing a crystalline form of an acetate of a compound of formula II, comprising: taking a certain amount of the compound of formula II, adding a proper amount of water and a solution of acetic acid in ethanol (precisely transferring 0.1 mL of acetic acid, adding 9.9 mL of ethanol, mixing well), stirring at 50° C. overnight, filtering and drying to obtain the crystalline form of the acetate of the compound of formula II. The present disclosure further relates to a pharmaceutical composition comprising an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt or an amorphous form of the compound of formula II, and one or more pharmaceutically acceptable carriers, diluents or excipients.


The present disclosure further relates to a pharmaceutical composition comprising a crystalline form I of a hydrobromide of a compound of formula II, and one or more pharmaceutically acceptable carriers, diluents or excipients.


The present disclosure further relates to a pharmaceutical composition prepared from an amorphous form of a compound of formula II, an acid addition salt of the compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.


The present disclosure further relates to a pharmaceutical composition prepared from a crystalline form I of a hydrobromide of a compound of formula II and one or more pharmaceutically acceptable carriers, diluents or excipients.


The present disclosure further relates to a pharmaceutical composition comprising an amorphous form of a compound of formula II or an acid addition salt of the compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, and optionally one or more pharmaceutically acceptable carriers and/or diluents. The pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form, for example, into tablet, capsule, pill, granule, solution, suspension, syrup, injection (the formulation is prepared from the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein, or the injection itself comprises the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein, including a solution for injection, a sterile powder for injection and a concentrated solution for injection), suppository, inhalant or spray.


The present disclosure further relates to a method for preparing a pharmaceutical composition, comprising: mixing the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein with at least one pharmaceutically acceptable carrier, diluent or excipient. In addition, the pharmaceutical composition disclosed herein can be administered by any suitable route of administration, such as oral, parenteral, rectal, pulmonary or local administration, to a patient or subject in need. For oral administration, the pharmaceutical composition can be formulated into an oral formulation, for example, a solid oral formulation such as tablet, capsule, pill and granule, or a liquid oral formulation such as oral solution, oral suspension and syrup. When formulated into an oral formulation, the pharmaceutical formulation may further comprise a suitable filler, binder, disintegrant, lubricant and the like. For parenteral administration, the pharmaceutical composition can be formulated into an injection, including a solution for injection, a sterile powder for injection and a concentrated solution for injection. When formulated into an injection, the pharmaceutical composition may be manufactured by conventional methods in the prior art. When formulated into an injection, the pharmaceutical formulation may be free of additives, or contain proper additives according to the nature of the medicament. For rectal administration, the pharmaceutical formulation can be formulated into a suppository or the like. For pulmonary administration, the pharmaceutical formulation can be formulated into an inhalant or spray. In certain embodiments, the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein is present in the pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain embodiments, the amorphous form of the compound of formula II or the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt disclosed herein is present in the pharmaceutical composition or medicament in a form of unit dose.


The present disclosure further relates to use of an amorphous form of a compound of formula II or an acid addition salt of the compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, or a pharmaceutical composition comprising or prepared from the same, in preparing a medicament for treating a disease or condition mediated by RORγ. The disease or condition mediated by RORγ includes, but is not limited to, inflammatory and autoimmune diseases and cancers, wherein the inflammatory and autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis vulgaris, psoriatic arthritis, osteoarthritis, regional suppurative, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, autoimmune thyroid disease, type I immune hypersecretion syndrome, type II autoimmune polycyrine syndrome, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Sjögren syndrome, Crohn's disease, asthma, Kawasaki's disease, Hashimoto's thyroiditis, infectious disease, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allograft rejection, polymyositis, GVHD, acne, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis and allergic rhinitis; the cancers include, but are not limited to, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, mouth cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.


SUMMARY

In the specification and claims of the present application, unless otherwise specified, the scientific and technological terms used herein have meanings generally understood by those skilled in the art. However, definitions and explanations for some of the related terms are provided below to better understand the present disclosure. In addition, if the definitions and explanations of the terms provided in the present application are not consistent with the meanings generally understood by those skilled in the art, the definitions and explanations of the terms provided in the present application shall prevail.


The “ether solvent” described herein includes, but is not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.


Specific examples of “alcohol solvent” described herein include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.


The “ester solvent” described herein includes, but is not limited to: ethyl acetate, isopropyl acetate or butyl acetate.


Specific examples of “ketone solvent” described herein include, but are not limited to: acetone, acetophenone or 4-methyl-2-pentanone.


Specific examples of “nitrile solvent” described herein include, but are not limited to: acetonitrile or propionitrile.


Specific examples of “halogenated hydrocarbon solvent” described herein include, but are not limited to: chloromethane, dichloromethane, chloroform or carbon tetrachloride.


Specific examples of “hydrocarbon solvent” described herein include, but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.


The “X-ray powder diffraction pattern or XRPD” described herein is obtained by Cu-Kα ray diffraction.


The “differential scanning calorimetry or DSC” described herein refers to measurement of the temperature difference and heat flow difference between a sample and a reference substance during a process of increasing or holding the temperature of the sample to characterize all the physical changes and chemical changes related to the thermal effect, and to obtain the phase change information of the sample.


The “2θ or angle 2θ” described herein refers to diffraction angle. θ is Bragg angle in unit ° or degree. The error range of 2θ may be ±0.3, ±0.2 or ±0.1.


Beneficial Effects


The amorphous form of the compound of formula II, the benzoate, oxalate, methanesulfonate, maleate, hydrobromide, hydrochloride and acetate of the compound of formula II, and the crystalline form of the benzoate, the amorphous form of the benzoate, the crystalline form of the oxalate, the amorphous form of the oxalate, the amorphous form of the methanesulfonate, the crystalline forms B, C and D of the maleate, the crystalline form I of the hydrobromide, the crystalline forms α, β and γ of the hydrochloride and the crystalline form of the acetate of the compound of formula II provided herein provide alternative solid forms of the compound of formula II that can be used as RORγ regulators in drug development processes.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 is an XRPD pattern of an amorphous form of a compound of formula II.



FIG. 2 is an XRPD pattern of an amorphous form of a benzoate of a compound of formula II.



FIG. 3 is an XRPD pattern of a crystalline form of a benzoate of a compound of formula II.



FIG. 4 is a DSC pattern of a crystalline form of a benzoate of a compound of formula II.



FIG. 5 is an XRPD pattern of an amorphous form of an oxalate of a compound of formula II.



FIG. 6 is an XRPD pattern of a crystalline form of an oxalate of a compound of formula II.



FIG. 7 is an XRPD pattern of an amorphous form of a methanesulfonate of a compound of formula II.



FIG. 8 is an XRPD pattern of a crystalline form B of a maleate of a compound of formula II.



FIG. 9 is a DSC pattern of a crystalline form B of a maleate of a compound of formula II.



FIG. 10 is a TGA pattern of a crystalline form B of a maleate of a compound of formula II.



FIG. 11 is a DVS vapor sorption plot of a crystalline form B of a maleate of a compound of formula II.



FIG. 12 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form B of a maleate of a compound of formula II.



FIG. 13 is an XRPD pattern of a crystalline form C of a maleate of a compound of formula II.



FIG. 14 is a DSC pattern of a crystalline form C of a maleate of a compound of formula II.



FIG. 15 is a TGA pattern of a crystalline form C of a maleate of the compound of formula II.



FIG. 16 is an XRPD pattern of a crystalline form D of a maleate of a compound of formula II.



FIG. 17 is a DSC pattern of a crystalline form D of a maleate of a compound of formula II.



FIG. 18 is a TGA pattern of a crystalline form D of a maleate of a compound of formula II.



FIG. 19 is an XRPD pattern of a crystalline form I of a hydrobromide of a compound of formula II.



FIG. 20 is a DSC pattern of a crystalline form I of a hydrobromide of a compound of formula II.



FIG. 21 is a TGA pattern of a crystalline form I of a hydrobromide of a compound of formula II.



FIG. 22 is a DVS vapor sorption plot of a crystalline form I of a hydrobromide of a compound of formula II.



FIG. 23 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form I of a hydrobromide of a compound of formula II.



FIG. 24 is an XRPD pattern of a crystalline form α of a hydrochloride of a compound of formula II.



FIG. 25 is a DSC pattern of a crystalline form α of a hydrochloride of a compound of formula II.



FIG. 26 is a TGA pattern of a crystalline form α of a hydrochloride of a compound of formula II.



FIG. 27 is a DVS vapor sorption plot of a crystalline form α of a hydrochloride of a compound of formula II.



FIG. 28 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form α of a hydrochloride of a compound of formula II.



FIG. 29 is an XRPD pattern of a crystalline form β of a hydrochloride of a compound of formula II.



FIG. 30 is a DSC pattern of a crystalline form β of a hydrochloride of a compound of formula II.



FIG. 31 is a TGA pattern of a crystalline form β of a hydrochloride of a compound of formula II.



FIG. 32 is a DVS vapor sorption plot of a crystalline form β of a hydrochloride of a compound of formula II.



FIG. 33 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form β of a hydrochloride of a compound of formula II.



FIG. 34 is an XRPD pattern of a crystalline form γ of a hydrochloride of a compound of formula II.



FIG. 35 is an XRPD pattern of a crystalline form of an acetate of a compound of formula II.



FIG. 36 is a DSC pattern of a crystalline form of an acetate of a compound of formula II.





DETAILED DESCRIPTION

Hereinafter, the present disclosure will be explained in more details with reference to the examples. The examples are only used to illustrate the technical solutions of the present disclosure, rather than limit the essence and scope of the present disclosure.


Test Conditions for the Instruments Used in the Experiment:


The structure of the compounds was determined by nuclear magnetic resonance (NMR) analysis or/and mass spectrometry (MS). NMR shifts (δ) are given in a unit of 10−6 (ppm). NMR analysis was conducted with a Bruker AVANCE-400 system using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as internal standard.


MS was conducted with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).


The HPLC was conducted with an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm chromatographic column).


XRPD refers to X-ray powder diffraction detection: The measurement was conducted using a BRUKER D8 X-ray diffractometer with a Cu anode (40 kV, 40 mA) and Cu-Kα radiation (λ=1.5418 Å). Scanning mode: θ/2θ, scanning range: 10-48°.


DSC refers to differential scanning calorimetry: The measurement was conducted using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a temperature ramping rate of 10° C./min, specific temperature ranges shown in corresponding patterns (mostly 25-300 or 25-350° C.) and a nitrogen purging speed of 50 mL/min.


TGA refers to thermogravimetric analysis: The measurement was conducted using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a temperature ramping rate of 10° C./min, specific temperature ranges shown in corresponding patterns (mostly 25-300° C.) and a nitrogen purging speed of 20 mL/min.


DVS refers to dynamic vapor sorption: The measurement was conducted with a Surface Measurement Systems advantage 2 at 25° C., starting from 50% humidity in humidity range of 0%-95% with a step size of 10%. The judging criterion was that the mass change of each gradient dM/dT is less than 0.002 and TMAX is less than 360 min in two circles.


The monitoring of the reaction progress in the examples was conducted by thin layer chromatography (TLC). The developing solvent for reactions, the eluent system for column chromatography purification and the developing solvent system for thin layer chromatography included: A: n-hexane/ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compound, or by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.


Comparative Example 1. Preparation Example of Compound of Formula II (Methods in Examples 152 and 153 of Patent Application No. PCT/US19/30526)
Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide
Preparation of (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide



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Step I. Preparation of 6-chloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-3,4-diamine

A mixture of 4-bromo-5-chlorobenzene-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 8.15 mmol), tris(dibenzylideneacetone)dipalladium (620 mg), tri-tert-butylphosphonium tetrafluoroborate (393 mg), sodium carbonate (1.7 g, 13.7 mmol), 1,4-dioxane (50 mL) and water (10 mL) was deoxygenated, heated to 90° C., and stirred for 3 h. The reaction solution was concentrated at reduced pressure. The residue was directly loaded on an ISCO solid column, and eluted with a mixed solvent of n-hexane/ethyl acetate to give a white solid product (1.0 g, 51.9% yield). MS (+) ES: 285 (M+H)+.


Step II. Preparation of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate
Preparation of ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate

EDCl (560 mg, 2.93 mmol), HOBT (447 mg, 2.93 mmol) and DIPEA (380 mg, 2.94 mmol) were added to a solution of 6-chloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-3,4-diamine (543 mg, 1.9 mmol), 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-ethoxy-4-oxobutanoic acid (500 mg, 1.47 mmol) and DMF (5 mL), and the reaction system was stirred at room temperature for 2 h. The reaction solution was adsorbed on 5 g of silica gel, loaded onto a silica gel column, and eluted with 45% ethyl acetate in n-hexane to obtain a mixture of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate as a white solid (600 mg, 62.3% yield). MS (ESI): 607 (M+H)+.


Step III. Preparation of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate

A solution of the mixture of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate (800 mg) in acetic acid (15 mL) was heated to 80° C. and stirred for 2 h for reaction. The reaction solution was concentrated at reduced pressure, and the obtained residue was purified by column chromatography with an eluent of 60% ethyl acetate in n-hexane to obtain ethyl 3-(6-chloro-5-(2-(dichloromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate as an off-white solid (600 mg, 77.3% yield). MS (ESI): 589 (M+H)+.


Step IV. Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide
Preparation of (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

A 7 N solution of ammonia in methanol (4.8 mL, 33.9 mmol) was added to a solution of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (400 mg, 0.68 mmol) in methanol (5 mL). The reaction system was heated to 60° C. and stirred for 12 h for reaction. The reaction solution was concentrated at reduced pressure, and the resulting crude product was purified by column chromatography with a n-hexane/ethyl acetate eluent system to obtain 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide (177 mg).


The resulting product was subjected to chiral resolution (conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm I.D.×15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL/min). The corresponding fractions were collected and concentrated at reduced pressure to obtain the target compound (67 mg, 60 mg).


Single-Component Compounds (Shorter Retention Time)


MS (+) ES: 560 (M+H)+


Chiral analysis methodology: retention time: 3.919 min, chiral purity: 100% (column: OD Phenomenex Lux Cellulose-1 150×4.6 mm, 5 μm; mobile phase: ethanol/n-hexane=80:20 (v:v)).


1H NMR (400 mHz, CD3OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96-4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).


Single-Component Compound (Longer Retention Time, Compound of Formula II)


MS (+) ES: 560 (M+H)+


Chiral analysis methodology: retention time: 8.942 min, chiral purity: 100% (column: OD Phenomenex Lux Cellulose-1 150×4.6 mm, 5 μm; mobile phase: ethanol/n-hexane=80:20 (v:v)).


1H NMR (400 mHz, CD3OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96-4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).


Test Example 1. Biochemical Assay of LanthaScreen TR-FRET RORγ-LBD and Co-Activation Peptide

Materials and Reagents


1. RORγ LBD-GST tagged (Cat No. RORC-114H, Creative Biomart)


2. Fluorescein-D22 coactivator (Cat No. PV4386, Invitrogen)


3. LanthaScreen™ Tb anti-GST antibody (Cat No. PV3550, Invitrogen)


4. TR-FRET coregulatory buffer D (Cat No. PV4420, Invitrogen)


5. DTT (Cat No. P2325, Fisher)


6. 384 well assay plate (Cat No. 6008280, Perkin Elmer)


7. Tecan Infinite M1000 plate reader (Tecan)


Procedures


Complete TR-FRET Coregulator Buffer D was prepared by diluting 1 M DTT with TR-FRET Coregulator Buffer D to a final concentration of 5 mM DTT. The compounds were diluted in Complete TR-FRET Coregulator Buffer D. The solutions were serially 7-fold diluted from an initial concentration of 3 μM to the 7th concentration. 10 μL of the dilutions was added to each well of the 384-well plate. For negative and positive controls, 10 μL of Complete TR-FRET Coregulator Buffer D was added.


A RORγ LBD solution was prepared using Complete TR-FRET Coregulator Buffer D. The final concentration of the RORγ LBD solution in each reaction was 25 ng. Other than the negative wells receiving 5 μL of Complete TR-FRET Coregulator Buffer D, 5 μL of the RORγ LBD solution was added to the remaining wells of the 384-well assay plate.


Complete TR-FRET Coregulator Buffer D was used to prepare a solution containing 0.6 μM Fluorescein-D22 and 8 nM Tbanti-GST antibody, and 5 μL of the prepared solution was added to all wells of the 384-well assay plate.


The 384-well plate was mixed gently on a plate shaker and let stand at room temperature for 1 h away from light. The 384-well plate was sealed with a plastic film to avoid evaporation.


The plate was measured on a Tecan Infinite M1000 plate reader at wavelengths of 520 nm and 495 nm. IC50 values were calculated using GraphPad Prism by plotting log compound concentration versus percentage inhibition. The IC50 values for the compounds are shown in Table 1.


Test Example 2. Assay for Inhibiting Cytokine IL-17A Production in Human Peripheral Blood Mononuclear Cells

Materials and Instruments


1. Human PBMC (Stemcell, Cat No. 70025.1)


2. Lymphocyte medium (Zenbio, Cat No. LYMPH-1)


3. TexMACS (Miltenyi Biotec, Cat No. 130-097-196)


4. Human Cytostim (Miltenyi Biotec, Cat No. 130-092-173)


5. Human IL-17 ELISA, human IL-17 enzyme-linked immunosorbent assay kit (R&D Systems, D1700)


6. 96-well cell culture plate (Fisher Scientific, Cat No. 07-200-80)


7. Tecan SPARK plate reader (Tecan)


Procedures


Frozen human peripheral blood mononuclear cells (PBMCs) were rapidly thawed in a pre-warmed lymphocyte medium and centrifuged at 1000 rpm for 10 min. The cell culture supernatant was discarded, and the cells were gently suspended in the TexMACS medium and counted. T cell activating reagent cytostim (10 μL/mL) was added to the cell suspension in certain proportions, and then the cells were seeded in a 96-well cell culture plate at a density of 1×105 PBMCs/well. Test compounds were diluted in gradient using TexMACS medium and added to the treatment wells in 2-3 replicates. Negative control wells containing cells only without cytostim were prepared to obtain background readings. The cell culture plate was incubated in a 5% carbon dioxide/37° C. incubator for 3 days. Cell culture supernatant was collected 3 days after treatment and centrifuged to remove the suspended matter. IL-17A in the supernatant was then quantified using an IL-17A enzyme-linked immunosorbent assay kit. The log(inhibitor) vs. response—Variable slope (four parameters) algorithm in GraphPad Prism 6.0 was used to plot the curve for calculating the IC50 values of the compounds. The calculation equation of inhibition is as follows:







Inhibition


%

=



[

100
-




OD



(
Compound
)


-

OD

(
NC
)




OD

(
PC
)

-

OD

(
NC
)



×
100


]

/

-
1





In the calculation equation, inhibition % is inhibition rate; OD(NC) is the reading of cells in negative control groups with no cytostim and no compound; OD(PC) is the reading of cells in positive control groups with cytostim but no compound; OD(compound) is the reading of cells with cytostim and compound.









TABLE 1







Binding of compounds of formula II to RORγ and IL-17 production in


human peripheral blood mononuclear cells










RORγ coactivation
IL-17 production


Compound
assay (IC50, μM)
(IC50, μM)





Those with longer retention
0.013
0.010


time in Examples 152 and 153




(compound of formula II)









Example 1. Preparation of Amorphous Form of Compound of Formula II

The compound of formula II (30 mg, 53.57 μmol) was added to isopropyl ether (1.5 mL). The mixture was heated to 70° C. to obtain an opaque white suspension. The suspension was slowly cooled to room temperature, stirred for 16 h and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form with XRPD pattern shown in FIG. 1.


Example 2. Preparation of Amorphous Form of Compound of Formula II

The compound of formula II (30 mg, 53.57 μmol) was added to toluene (1.5 mL). The mixture was heated to 70° C. and stirred to obtain a clarified solution. The solution was slowly cooled to room temperature and a solid was precipitated on the inner wall of the container. The mixture was stirred for 16 h at room temperature and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form as determined by X-ray powder diffraction.


Example 3. Preparation of Amorphous Form of Compound of Formula II

The compound of formula II (30 mg, 53.57 μmol) was added to a 1.5 mL mixture of isopropyl acetate/n-hexane (v:v=1:3). The mixture was heated to 70° C. and a viscous solid was precipitated. The solution was slowly cooled to room temperature and a solid was precipitated. The mixture was stirred for 16 h at room temperature and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form as determined by X-ray powder diffraction.


Example 4. Preparation of Amorphous Form of Compound of Formula II

The compound of formula II (5 g, 8.93 mmol) was purified by high performance liquid chromatography (Waters-2767, eluent system: ammonium bicarbonate, water and acetonitrile) to obtain a product (2.5 g, 50% yield). The product was in an amorphous form as determined by X-ray powder diffraction.


Example 5. Influencing Factor Study of Amorphous Form of Compound of Formula II

A sample of the amorphous form of the compound of formula II (Example 4) was let stand open to examine the stability of the sample in conditions of heating (40° C. and 60° C.), illumination (4500 Lux) and high humidity (RH 75% and RH 90%) in a period of 30 days.


Results:









TABLE 2







Results of influencing factor study















Amorphous
Weight




Time
Color and
form Purity
gain
Chiral


Conditions
(days)
appearance
(%)
(%)
purity















Initial
0
White solid
99.91
/
99.4


4500 Lux
5
White solid
99.91
/
/



10
White solid
99.91
/
99.3



30
White solid
99.93
/
99.3


40° C.
5
White solid
99.93
/
/



10
White solid
99.90
/
99.4



30
White solid
99.92
/
99.5


60° C.
5
White solid
99.95
/
/



10
White solid
99.95
/
99.4



30
White solid
99.95
/
99.4


RH 75%
5
White solid
99.92
10.42
/



10
White solid
99.90
13.2 
99.3



30
White solid
99.90
23.24
99.4


RH 90%
5
White solid
99.91
21.67
/



10
White solid
99.92
26.49
99.4



30
White solid
99.89
37.24
99.4









Conclusion:


The results of influencing factor study in Table 2 showed that: the amorphous form of the compound of the formula II has good chemical stability after standing for 30 days in conditions of illumination, high temperature of 40° C., high temperature of 60° C., high humidity of 75% and high humidity of 90%.


Example 6. Long-Term/Accelerated Stability Study of Amorphous Form of Compound of Formula II

The amorphous form of the compound of formula II (Example 4) was subjected to a long-term (25° C., 60% RH)/accelerated (40° C., 75% RH) stability study with a period of 3 months.


Results









TABLE 3







Result of long-term/accelerated stability study of amorphous


form of compound of formula II
















Purity
Purity
Purity
Chiral




Purity/chiral
(%)
(%)
(%)
purity (%)



Condition of
purity
Month
Month
Month
Month


Sample
standing
Initial
1
2
3
3
















Amorphous
25° C., 60% RH
99.87/99.2
99.86
99.86
99.85
99.2


form
40° C., 75% RH
99.87/99.2
99.87
99.86
99.88
99.1



5° C.
99.87/99.2
99.86
99.86
99.85
99.1









The results of the long-term/accelerated stability study in Table 3 showed that: the amorphous form of the compound of formula II has good chemical stability in conditions of a long term (25° C., 60% RH) and acceleration (40° C., 75% RH) in a period of 3 months.


Example 7. Preparation of Amorphous Form of Benzoate of Compound of Formula II

0.5 mL of n-hexane was added to 10 mg of the compound of formula II before 2.3 mg of benzoic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the benzoate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 2.


Example 8. Preparation of Crystalline Form of Benzoate of Compound of Formula II

0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 2.3 mg of benzoic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the benzoate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 3. The DSC pattern is shown in FIG. 4, with a first endothermic peak value at 178.46° C. and a second endothermic peak value at 237.42° C.









TABLE 4







Characteristic peaks of crystalline form of benzoate of conpound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
5.305
16.64444
100.0


Peak 2
7.411
11.91828
43.6


Peak 3
19.140
4.63321
1.3


Peak 4
22.031
4.03134
23.9









Example 9. Preparation of Amorphous Form of Oxalate of Compound of Formula II

0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 2 mg of oxalic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the oxalate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 5.


Example 10. Preparation of Crystalline Form of Oxalate of Compound of Formula II

0.5 mL of n-hexane was added to 10 mg of the compound of formula II before 2 mg of oxalic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the oxalate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 6.









TABLE 5







Characteristic peaks of crystalline form of oxalate of comound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
14.378
6.15525
100.0


Peak 2
18.463
4.80158
51.5


Peak 3
21.670
4.09779
70.9


Peak 4
23.075
3.85126
50.6


Peak 5
28.127
3.17003
21.6









Example 11. Preparation of Amorphous Form of Methanesulfonate of Compound of Formula II

0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 1.8 μL of methanesulfonic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the methanesulfonate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 7.


Example 12. Preparation of Crystalline Form B of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 30 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form B of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 8. The DSC pattern is shown in FIG. 9, with a first endothermic peak value at 138.04° C.; the TGA pattern is shown in FIG. 10.


DVS characterization: the vapor sorption of the crystalline form B of the maleate at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 1.731%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 1.438%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 1.809%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 3.077%.


The comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 11, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 12.









TABLE 6







Characteristic peaks of crystalline form B of maleate of compound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
7.624
11.58707
74.9


Peak 2
9.659
9.14922
40.7


Peak 3
13.815
6.40503
41.2


Peak 4
15.844
5.58882
56.9


Peak 5
17.391
5.09522
100.0


Peak 6
18.619
4.76186
31.5


Peak 7
21.802
4.07319
76.4


Peak 8
23.667
3.75633
49.8


Peak 9
26.441
3.36816
13.2









Example 13. Preparation of Crystalline Form B of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 10 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.


Example 14. Preparation of Crystalline Form B of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 20 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.


Example 15. Preparation of Crystalline Form B of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 1 h to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.


Example 16. Preparation of Crystalline Form B of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 2 h to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.


Example 17. Preparation of Crystalline Form C of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 1 d to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form C of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 13. The DSC pattern is shown in FIG. 14, with a first endothermic peak value at 154.58° C.; the TGA pattern is shown in FIG. 15.









TABLE 7







Characteristic peaks of crystalline form C of maleate of compound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
7.325
12.05902
24.9


Peak 2
8.635
10.23231
46.0


Peak 3
9.809
9.00970
38.0


Peak 4
11.661
7.58265
14.6


Peak 5
13.649
6.48261
27.1


Peak 6
16.133
5.48950
23.5


Peak 7
16.765
5.28383
27.8


Peak 8
18.346
4.83192
100.0


Peak 9
21.689
4.09421
37.3


Peak 10
23.586
3.76901
31.9


Peak 11
25.303
3.51708
15.5









Example 18. Preparation of Crystalline Form D of Maleate of Compound of Formula II

100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 3 d to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form D of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 16. The DSC pattern is shown in FIG. 17, with a first endothermic peak value at 159.27° C.; the TGA pattern is shown in FIG. 18.









TABLE 8







Characteristic peaks of crystalline form D of maleate of compound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
4.486
19.68368
65.1


Peak 2
5.998
14.72391
35.9


Peak 3
7.288
12.12061
48.6


Peak 4
9.067
9.74591
49.9


Peak 5
10.001
8.83770
50.9


Peak 6
13.914
6.35938
59.0


Peak 7
15.026
5.89121
34.9


Peak 8
16.227
5.45786
27.0


Peak 9
18.229
4.86287
100.0


Peak 10
18.940
4.68174
84.8


Peak 11
23.076
3.85108
58.0


Peak 12
25.612
3.47535
60.6


Peak 13
28.102
3.17274
12.9









Example 19. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before 20 μL of hydrobromic acid was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form I of the hydrobromide of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 19. The DSC pattern is shown in FIG. 20, with a first endothermic peak value at 201.73° C.; the TGA pattern is shown in FIG. 21. DVS characterization: the vapor sorption of the crystalline form I of the hydrobromide at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 0.636%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 0.589%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 0.702%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 1.094%.


The desorption process and the sorption process of the sample basically overlapped in the process of 0-95% humidity change; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 22, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 23.









TABLE 9







Characteristic peaks of crystalline form I of hydrobromide


of compound of formula II












No.
2-Theta
d (A)
I %
















Peak 1
8.128
10.86905
68.5



Peak 2
11.918
7.41964
7.5



Peak 3
12.579
7.03116
19.0



Peak 4
16.414
5.39626
54.1



Peak 5
17.075
5.18879
15.6



Peak 6
17.780
4.98456
39.3



Peak 7
18.750
4.72892
7.8



Peak 8
19.675
4.50851
9.9



Peak 9
20.733
4.28082
27.1



Peak 10
21.262
4.17552
100.0



Peak 11
23.113
3.84512
36.8



Peak 12
23.906
3.71929
15.0



Peak 13
24.391
3.64645
67.5



Peak 14
26.550
3.35455
14.5



Peak 15
28.445
3.13522
29.4



Peak 16
28.930
3.08378
26.0



Peak 17
29.547
3.02077
55.8



Peak 18
30.958
2.88630
27.7



Peak 19
32.236
2.77471
19.3



Peak 20
33.382
2.68204
1.4



Peak 21
38.670
2.32653
2.4



Peak 22
39.640
2.27183
3.3



Peak 23
40.830
2.20832
12.6



Peak 24
42.064
2.14635
5.4



Peak 25
43.342
2.08597
5.2



Peak 26
46.824
1.93865
4.0



Peak 27
48.190
1.88683
6.2



Peak 28
48.983
1.85811
4.1



Peak 29
50.746
1.79762
9.3










Example 20. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 500 μL mixture of hydrobromic acid/ethanol (v:v=1:50) was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.


Example 21. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 40 μL mixture of hydrobromic acid/ethanol (v:v=1:1) was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.


Example 22. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

15 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 1000 μL mixture of hydrobromic acid/ethanol (v:v=1:99) was added. The mixture was stirred at 600 rpm at 25° C. overnight and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.


Example 23. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 1000 μL mixture of hydrobromic acid/ethanol (v:v=1:99) was added. The mixture was stirred at 600 rpm at 25° C. overnight and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.


Example 24. Preparation of Crystalline Form α of Hydrochloride of Compound of Formula II

5 mL of methyl tert-butyl ether and 15.6 μL of concentrated hydrochloric acid were added to 100 mg of the compound of formula II. The mixture was stirred at 50° C. for 2 d and dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form α of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 24. The DSC pattern is shown in FIG. 25, with a first endothermic peak value at 192.13° C.; the TGA pattern is shown in FIG. 26.


DVS characterization: the vapor sorption of the sample at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 0.549%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 0.463%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 0.574%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 1.040%.


The desorption process and the sorption process of the sample basically overlapped in the process of 0-95% humidity change; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 27, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 28.









TABLE 10







Characteristic peaks of crystalline form α of hydrochloride of


compound of formula II










No.
2-Theta
d (A)
I %













Peak 1
7.931
11.13829
53.4


Peak 2
10.115
8.73832
19.9


Peak 3
12.166
7.26910
15.4


Peak 4
13.920
6.35673
24.2


Peak 5
15.224
5.81523
33.9


Peak 6
16.041
5.52078
13.9


Peak 7
16.315
5.42854
12.6


Peak 8
16.748
5.28930
12.2


Peak 9
17.425
5.08526
21.3


Peak 10
18.309
4.84177
64.7


Peak 11
19.624
4.52003
15.9


Peak 12
20.235
4.38496
19.6


Peak 13
21.491
4.13138
36.6


Peak 14
22.340
3.97642
67.3


Peak 15
23.359
3.80507
65.0


Peak 16
23.905
3.71950
48.0


Peak 17
24.570
3.62032
100.0


Peak 18
25.320
3.51464
20.1


Peak 19
25.811
3.44896
13.9


Peak 20
26.096
3.41194
10.5


Peak 21
27.624
3.22652
24.8


Peak 22
28.213
3.16057
24.6


Peak 23
29.190
3.05697
5.1


Peak 24
29.760
2.99971
2.4


Peak 25
31.266
2.85855
10.1


Peak 26
31.795
2.81217
5.5


Peak 27
32.324
2.76732
8.1


Peak 28
35.906
2.49902
3.7


Peak 29
37.291
2.40939
8.3









Example 25. Preparation of Crystalline Form β of Hydrochloride of Compound of Formula II

5 mL of methyl tert-butyl ether and a 0.6 mL solution of concentrated hydrochloric acid in ethanol (0.1 mL of concentrated hydrochloric acid was added to 9.9 mL of ethanol and the mixture was well mixed) were added to 100 mg of the compound of formula II. The mixture was stirred at 25° C. for 1 h and at 50° C. for 2 d, and filtered in vacuo. The residue was dried for 2 h at 40° C. to obtain a product. The product was identified as a crystalline form β of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 29. The DSC pattern is shown in FIG. 30, with a first endothermic peak value at 194.04° C.; the TGA pattern is shown in FIG. 31.


DVS characterization: the vapor sorption of the sample at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 1.235%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 1.755%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 1.954%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 2.534%.


The desorption process and the sorption process of the sample basically overlapped in individual processes of 0-95% humidity change, but the desorption process and the sorption process of the first and second cycles could not overlap; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form changed during DVS. The DVS pattern is shown in FIG. 32, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 33.









TABLE 11







Characteristic peaks of crystalline form β of hydrochloride of


compound of formula II










No.
2-Theta
d (A)
I %













Peak 1
5.386
16.39621
39.0


Peak 2
8.191
10.78576
77.6


Peak 3
10.818
8.17156
29.1


Peak 4
12.688
6.97098
42.8


Peak 5
13.980
6.32982
20.9


Peak 6
14.915
5.93499
26.6


Peak 7
16.607
5.33388
19.7


Peak 8
18.076
4.90345
12.8


Peak 9
19.056
4.65352
12.9


Peak 10
20.036
4.42814
20.8


Peak 11
21.372
4.15427
100.0


Peak 12
22.040
4.02986
35.2


Peak 13
23.465
3.78826
25.0


Peak 14
24.355
3.65171
28.5


Peak 15
25.869
3.44132
36.7


Peak 16
26.582
3.35068
21.8


Peak 17
27.383
3.25440
12.0


Peak 18
29.253
3.05045
29.5


Peak 19
29.832
2.99256
39.9


Peak 20
30.946
2.88740
22.9


Peak 21
31.480
2.83959
41.4


Peak 22
32.504
2.75242
7.6


Peak 23
33.439
2.67755
8.5









Example 26. Preparation of Crystalline Form γ of Hydrochloride of Compound of Formula II

A small amount of the crystalline form β of the hydrochloride of the compound of formula II was loaded on a DVS system and subjected to a detection with parameters of dm/dt=0.002, 50-95-0-95-50% RH, Max 360 min, 25° C. The product was identified as a crystalline form β of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 34.









TABLE 12







Characteristic peaks of crystalline form γ of hydrochloride of


compound of formula II










No.
2-Theta
d (A)
I %













Peak 1
8.114
10.88737
89.0


Peak 2
11.997
7.37097
42.5


Peak 3
12.640
6.99748
77.7


Peak 4
13.772
6.42501
45.7


Peak 5
16.478
5.37549
25.8


Peak 6
17.897
4.95221
45.6


Peak 7
19.671
4.50933
9.7


Peak 8
20.337
4.36327
52.8


Peak 9
21.422
4.14464
79.1


Peak 10
22.156
4.00903
62.3


Peak 11
23.228
3.82632
79.1


Peak 12
24.472
3.63450
100.0


Peak 13
25.882
3.43968
26.9


Peak 14
27.567
3.23307
27.4


Peak 15
28.277
3.15351
14.1


Peak 16
29.830
2.99281
38.1


Peak 17
31.160
2.86797
15.9


Peak 18
32.269
2.77189
17.0


Peak 19
33.334
2.68576
13.6









Example 27. Preparation of Crystalline Form of Acetate of Compound of Formula II

1 mL of water was added to 20 mg of the compound of formula II before a solution of acetic acid in ethanol (0.1 mL of acetic acid was added to 9.9 mL of ethanol and the mixture was well mixed) was added in a molar ratio of 1:1. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the acetate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 35. The DSC pattern is shown in FIG. 36, with a first endothermic peak value at 206.96° C., a first exothermic peak value at 213.49° C. and a second endothermic peak value at 246.30° C.









TABLE 13







Characteristic peaks of crystalline form of acetate of compound


of formula II










No.
2-Theta
d (A)
I %













Peak 1
11.651
7.58948
96.9


Peak 2
12.495
7.07863
38.2


Peak 3
14.323
6.17872
29.8


Peak 4
15.121
5.85472
28.9


Peak 5
15.636
5.66274
100.0


Peak 6
15.965
5.54704
66.5


Peak 7
18.075
4.90394
58.9


Peak 8
19.247
4.60782
20.4


Peak 9
19.903
4.45730
25.1


Peak 10
20.935
4.23993
38.5


Peak 11
22.107
4.01768
29.1


Peak 12
22.998
3.86402
47.4


Peak 13
23.842
3.72910
52.3


Peak 14
24.733
3.59676
59.9


Peak 15
25.530
3.48623
35.2


Peak 16
26.843
3.31862
11.7


Peak 17
28.719
3.10600
12.9


Peak 18
29.750
3.00061
6.1


Peak 19
30.829
2.89805
18.2


Peak 20
32.142
2.78260
14.6


Peak 21
35.143
2.55155
3.6


Peak 22
39.973
2.25369
2.6









Example 28. Influencing Factor Study of Crystalline Form α of Hydrochloride and Crystalline Form I of Hydrobromide of Compound of Formula II

Sample of the crystalline form α of the hydrochloride and the crystalline form I of the hydrobromide of the compound of formula II were let stand open to examine the stability of the samples in conditions of illumination (4500 Lux), high temperature (40° C. and 60° C.) and high humidity (RH 75% and RH 92.5%) in a period of 30 days.









TABLE 14







Stability data of the influencing factor study











Crystalline form α of hydrochloride of compound of formula II
















Main








peak
Chiral
Chloride





Color and
purity
purity
ion content
Crystalline


Conditions
Time (days)
appearance
(%)
(%)
(%)
form





Initial
0
White solid
96.925
99.14
5.75
Crystalline








form α


40° C.
7
White solid
96.915
99.131
/
Not changed



14
White solid
96.921
99.115
/
Not changed



30
White solid
96.824
99.207
5.75
Not changed


60° C.
7
White solid
96.884
99.136
/
Not changed



14
White solid
96.907
99.106
/
Not changed



30
White solid
96.814
99.232
5.65
Not changed


75% RH
7
White solid
96.916
99.138
/
Not changed



14
White solid
96.908
99.130
/
Not changed



30
White solid
96.903
99.220
5.68
Not changed


92.5% RH
7
White solid
96.912
99.132
/
Not changed



14
White solid
96.908
99.111
/
Not changed



30
White solid
96.880
99.211
5.67
Not changed


4500 Lux
7
White solid
96.911
99.137
/
Not changed



14
White solid
96.911
99.139
/
Not changed



30
White solid
96.810
99.216
5.71
Not changed














Crystalline form I of hydrobromide of compound of formula II
















Main








peak
Chiral
Bromide





Color and
purity
purity
ion content
Crystalline


Conditions
Time (days)
appearance
(%)
(%)
(%)
form





Initial
0
White solid
97.689
99.298
11.75
Crystalline








form I


40° C.
7
White solid
97.716
99.293
/
Not changed



14
White solid
97.727
99.165
/
Not changed



30
White solid
97.644
99.251
11.73
Not changed


60° C.
7
White solid
97.645
99.299
/
Not changed



14
White solid
97.671
99.187
/
Not changed



30
White solid
97.630
99.263
11.50
Not changed


75% RH
7
White solid
97.687
99.293
/
Not changed



14
White solid
97.705
99.179
/
Not changed



30
White solid
97.676
99.274
11.73
Not changed


92.5% RH
7
White solid
97.706
99.294
/
Not changed



14
White solid
97.701
99.175
/
Not changed



30
White solid
97.653
99.268
11.55
Not changed


4500 Lux
7
White solid
97.683
99.297
/
Not changed



14
White solid
97.660
99.152
/
Not changed



30
White solid
97.626
99.243
11.18
Not changed









Conclusions: the influencing factor study showed that: the crystalline form α of the hydrochloride and the crystalline form I of the hydrobromide of the compound of formula II have good physical and chemical stabilities in conditions of illumination, high temperatures of 40° C. and 60° C. and high humidities of 75% and 92.5%.


Example 29. Long-Term/Accelerated Stability Study of Crystalline Form α of Hydrochloride and Crystalline Form I of Hydrobromide of Compound of Formula II

The crystalline form α of the hydrochloride of the compound of formula II was let stand in conditions of 25° C./60% RH and 40° C./75% RH to examine its stability.









TABLE 15







Long term/accelerated stability study data for the crystalline form α of the


hydrochloride of the compound of formula II











Crystalline form α of hydrochloride of compound of formula II

















Chiral






Color and
Main peak
purity
Chloride ion
Crystalline


Conditions
Time
appearance
purity (%)
(%)
content (%)
form
















Initial
0
White solid
96.925
99.14
5.75
Crystalline








form α


25° C.,
Day 7
White solid
96.915
99.131
/
Not changed


60% RH
Day 14
White solid
96.831
99.111
/
Not changed



Month 1
White solid
96.906
99.225
5.75
Not changed



Month 2
White solid
96.883
99.332
5.74
Not changed



Month 3
White solid
96.749
99.239
/
Not changed



Month 6
White solid
96.170
99.187
5.85
Not changed


40° C.,
Day 7
White solid
96.906
99.137
/
Not changed


75% RH
Day 14
White solid
96.902
99.104
/
Not changed



Month 1
White solid
96.846
99.206
5.44
Not changed



Month 2
White solid
96.780
99.292
5.86
Not changed



Month 3
White solid
96.664
99.149
/
Not changed



Month 6
White solid
95.990
98.972
5.98
Not changed









The long-term/accelerated stability study showed that: the crystalline form α of the hydrochloride of the compound of formula II has good physical and chemical stability in conditions of a long term and acceleration in a period of 6 months.


The crystalline form I of the hydrobromide of the compound of formula II was let stand in conditions of 25° C./60% RH and 40° C./75% RH to examine its stability.









TABLE 16







Long term/accelerated stability study data for the crystalline form I of the


hydrobromide of the compound of formula II











Crystalline form I of hydrobromide of compound of formula II

















Chiral






Color and
Main peak
purity
Bromide ion
Crystalline


Conditions
Time
appearance
purity (%)
(%)
content (%)
form
















Initial
0
White solid
97.689
99.298
11.75
Crystalline








form I


25° C.,
Day 7
White solid
97.689
99.297
/
Not changed


60% RH
Day 14
White solid
97.697
99.198
/
Not changed



Month 1
White solid
97.649
99.255
11.20
Not changed



Month 2
White solid
97.661
99.363
11.05
Not changed



Month 3
White solid
97.552
99.283
/
Not changed



Month 6
White solid
96.981
99.228
11.82
Not changed


40° C.,
Day 7
White solid
97.661
99.295
/
Not changed


75% RH
Day 14
White solid
97.660
99.174
/
Not changed



Month 1
White solid
97.558
99.262
11.49
Not changed



Month 2
White solid
97.561
99.328
10.93
Not changed



Month 3
White solid
97.259
99.275
/
Not changed



Month 6
White solid
96.412
99.199
11.91
Not changed









The long-term/accelerated stability study showed that: the crystalline form I of the hydrobromide of the compound of formula II has good physical and chemical stability in conditions of a long term and acceleration in a period of 6 months.

Claims
  • 1. An acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, wherein the acid addition salt is an organic acid addition salt or an inorganic acid addition salt,
  • 2. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1, wherein the organic acid addition salt is selected from the group consisting of benzoate, oxalate, methanesulfonate, maleate and acetate, and the inorganic acid addition salt is selected from the group consisting of hydrobromide and hydrochloride.
  • 3.-8. (canceled)
  • 9. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780 and 20.733.
  • 10. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930 and 29.547.
  • 11. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 11.918, 12.579, 16.414, 17.075, 17.780, 18.750, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930, 29.547, 30.958, 32.236, 33.382, 38.670, 39.640, 40.830, 42.064, 43.342, 46.824, 48.190, 48.983 and 50.746.
  • 12. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrochloride is a crystalline form α having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 13.920, 15.224, 17.425 and 18.309.
  • 13.-15. (canceled)
  • 16. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 9, wherein the 2θ values of the crystalline forms have an error range of ±0.2.
  • 17.-18. (canceled)
  • 19. A pharmaceutical composition comprising the acid addition salt or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • 20.-24. (canceled)
  • 25. A method for preparing a pharmaceutical composition, comprising: mixing the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1 with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • 26. (canceled)
  • 27. A method for treating a disease or disorder mediated by RORγ in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pharmaceutical composition according to claim 19.
  • 28. The pharmaceutical composition according to claim 19, wherein the pharmaceutically acceptable solvate of the acid addition salt is hydrobromide.
  • 29. The pharmaceutical composition according to claim 28, wherein the hydrobromide is a crystalline form I.
  • 30. The method according to claim 25, wherein the acid addition salt is hydrobromide.
  • 31. The method according to claim 30, wherein the hydrobromide is a crystalline form I.
  • 32. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 10, wherein the 2θ values of the crystalline forms have an error range of ±0.2.
  • 33. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 11, wherein the 2θ values of the crystalline forms have an error range of ±0.2.
  • 34. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 12, wherein the 2θ values of the crystalline forms have an error range of ±0.2.
Priority Claims (1)
Number Date Country Kind
201911049930.5 Oct 2019 CN national
PCT Information
Filing Document Filing Date Country Kind
PCT/CN2020/125125 10/30/2020 WO