WO2021083311A1 - 一种RORγ调节剂的酸加成盐 - Google Patents

一种RORγ调节剂的酸加成盐 Download PDF

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WO2021083311A1
WO2021083311A1 PCT/CN2020/125125 CN2020125125W WO2021083311A1 WO 2021083311 A1 WO2021083311 A1 WO 2021083311A1 CN 2020125125 W CN2020125125 W CN 2020125125W WO 2021083311 A1 WO2021083311 A1 WO 2021083311A1
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compound
formula
acid addition
addition salt
crystal form
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PCT/CN2020/125125
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English (en)
French (fr)
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周先强
杜振兴
王捷
王林
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to BR112022008293A priority Critical patent/BR112022008293A2/pt
Priority to EP20881503.5A priority patent/EP4053109A4/en
Priority to KR1020227018288A priority patent/KR20220093340A/ko
Priority to CA3156332A priority patent/CA3156332A1/en
Priority to JP2022525442A priority patent/JP2023500291A/ja
Priority to US17/755,292 priority patent/US20220411380A1/en
Priority to AU2020377114A priority patent/AU2020377114A1/en
Priority to MX2022005260A priority patent/MX2022005260A/es
Priority to CN202080069974.9A priority patent/CN114502535B/zh
Publication of WO2021083311A1 publication Critical patent/WO2021083311A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure belongs to the field of medicinal chemistry, and relates to an acid addition salt of a compound of formula II as a regulator of ROR ⁇ .
  • Nuclear receptors are transcription factors regulated by ligands, which regulate development, immunity and cell metabolism, and are one of the main drug target categories for human diseases.
  • the retinoid-related orphan receptor ⁇ (ROR ⁇ ) protein is a member of the NR1 subfamily of nuclear receptors, and has a typical nuclear receptor domain structure, consisting of a DNA binding domain, a ligand binding domain, and a hinge domain. And activation function 2 domain composition (Benoit G, et al., Pharmacological Reviews, 58(4): 798-836, 2006; Zhang, Y., et al., Acta Pharmacogica Sinica, 36: 71-87, 2015).
  • ROR ⁇ In contrast to most other nuclear receptors that bind as dimers, ROR ⁇ recognizes and binds as a monomer. It combines with a specific DNA sequence, usually composed of TAAA/TNTAGGTCA, and is called the ROR response element (RORE).
  • ROR ⁇ There are two subtypes of ROR ⁇ , ROR ⁇ 1 and ROR ⁇ 2 (also known as ROR ⁇ t), which are produced by the same RORC gene and may be produced by selecting other promoters (Villey I et al., Eur.J.Immunol. , 29(12): 4072-80, 1999). Because the two subtypes of ROR ⁇ (ROR ⁇ 1 and ROR ⁇ t) are produced by the same mRNA and have the same ligand binding domain, only their protein N-terminals are different (Jetten, A.M., 2009; Ivanov, I.I.et al., 2006). Small molecule inhibitors bind to the ligand binding domain and inhibit the function of the receptor. Therefore, they cannot be selective for the two subtypes of ROR ⁇ . Both are called ROR ⁇ small molecule inhibitors (or regulators), regardless of subtype.
  • ROR ⁇ t is mainly expressed in the thymus and several immune cells
  • ROR ⁇ 1 is expressed in many tissues, such as thymus, liver, muscle, testis, pancreas, prostate, heart, etc.
  • TH17 Type 17 helper immune regulatory T cells
  • Th17 cells Both subtypes of ROR ⁇ are expressed in Th17 cells and regulate type 17 helper immune regulatory T cells. Cell differentiation and induction of gene transcription (Ruan, Q., et al., 2011). Cytokines IL-6 and TGF- ⁇ induce undifferentiated CD4T helper cells to differentiate into Th17 cells, Th17 cells express high levels of ROR ⁇ t, induce IL-23 receptor gene transcription in undifferentiated CD4T helper cells, and IL23 receptor promotes and stabilizes The generation of TH17 cells forms part of a positive feedback loop (Ivanov, IIet al., 2006; Jetten, AM, 2009).
  • ROR ⁇ t can induce gene transcription of cytokines IL-17A, IL-17F, IL-21, IL-22 and other pro-inflammatory effector cytokines to enhance the inflammatory process. Similar to ROR ⁇ t, ROR ⁇ 1 is also expressed in Th17 cells, and can also regulate the differentiation of type 17 helper immune regulatory T cells (TH17) and induce gene transcription (Ruan, Q., et al., 2011). The pharmacological antagonism of ROR ⁇ has therapeutic potential for autoimmune diseases, making it an attractive target for small molecule inhibitors.
  • ROR ⁇ has been identified as a key mediator in the pathogenesis of several diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, Sjogren’s syndrome and asthma.
  • diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, Sjogren’s syndrome and asthma.
  • Some other diseases such as chronic dry eye, Kawasaki disease, mucosal leishmaniasis, and Hashimoto’s thyroiditis, are characterized by an increased proportion of Th17 and/or increased levels of Th17 marker cytokines, such as IL-17, IL-22 And IL-23.
  • Th17 marker cytokines such as IL-17, IL-22 And IL-23.
  • ROR ⁇ t inhibitors are currently being developed for the treatment of autoimmune diseases such as psoriasis 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.
  • the present disclosure provides an acid addition salt or a pharmaceutically acceptable solvate of the acid addition salt of the compound of formula II, the acid addition salt being an organic acid addition salt or an inorganic acid addition salt.
  • the present disclosure also relates to a method for preparing an acid addition salt or a pharmaceutically acceptable solvate of an acid addition salt of the compound of formula II, the acid addition salt being an organic acid addition salt or an inorganic acid addition salt, including
  • a certain amount of the compound of formula II is mixed with an appropriate amount of solvent and organic acid or inorganic acid, and reacted for a period of time to obtain the corresponding acid salt of the compound of formula II.
  • the solvent is selected from hydrocarbon solvents, ether solvents, alcohol solvents, and esters.
  • the organic acid addition salt is selected from formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, Methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, ⁇ -Naphthalene sulfonate, malate, propiolate, 2-butynoate, 2-hydroxy-ethane sulfonate, vinyl acetate, tartrate, fumarate, hydroxyethyl sulfonate Acid salt, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1,2-ethane Disulfonate, oxalate, trifluoroacetate, trifluoromethanes
  • the inorganic acid addition salt is selected from hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite , Bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate or meta At least one of phosphates.
  • the organic acid addition salt may be selected from at least one of benzoate, oxalate, methanesulfonate, maleate, or acetate, and the organic acid addition salt
  • the salt can be selected from hydrochloride or hydrobromide.
  • the present disclosure provides benzoate crystal form, benzoate amorphous form, oxalate crystal form, oxalate amorphous, mesylate amorphous, maleate B crystal form, maleate Crystalline form C, maleate form D, hydrobromide form I, hydrochloride alpha form, hydrochloride beta form, hydrochloride gamma form, acetate crystal form, And its preparation method.
  • the present disclosure provides an amorphous substance of the compound of formula II, the XRPD pattern of the amorphous substance does not have obvious sharp diffraction peaks; preferably, the amorphous substance has the XRPD pattern as shown in FIG. 1.
  • the present disclosure provides the benzoate salt of the compound of formula II.
  • the benzoate is an amorphous substance, and the XRPD pattern of the amorphous substance does not have obvious sharp diffraction peaks; preferably, the amorphous substance has an XRPD pattern as shown in FIG. 2.
  • the benzoate is in a crystalline form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 5.305 and 7.411.
  • the X-ray powder diffraction pattern of the benzoate crystal form has characteristic peaks at diffraction angles 2 ⁇ of 5.305, 7.411, and 22.031.
  • the X-ray powder diffraction pattern of the benzoate crystal form has characteristic peaks at diffraction angles 2 ⁇ of 5.305, 7.411, 19.140, and 22.0314.
  • the present disclosure provides the oxalate salt of the compound of formula II.
  • the oxalate salt is an amorphous substance, and the XRPD pattern of the amorphous substance does not have obvious sharp diffraction peaks; preferably, the amorphous substance has an XRPD pattern as shown in FIG. 5.
  • the oxalate is in a crystalline form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 14.378, 18.463, and 21.670.
  • the X-ray powder diffraction pattern of the oxalate crystal form has characteristic peaks at diffraction angles 2 ⁇ of 14.378, 18.463, 21.670, and 23.075.
  • the X-ray powder diffraction pattern of the oxalate crystal form has characteristic peaks at diffraction angles 2 ⁇ of 14.378, 18.463, 21.670, 23.075, and 28.127.
  • the present disclosure provides mesylate salts of compounds of formula II.
  • the mesylate salt is an amorphous substance, and the XRPD pattern of the amorphous substance does not have obvious sharp diffraction peaks; preferably, the amorphous substance has an XRPD pattern as shown in FIG. 7.
  • the present disclosure provides the maleate salt of the compound of formula II.
  • the maleate is crystal form B, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 7.624, 9.659, 13.815, 15.844, and 17.391.
  • the X-ray powder diffraction pattern of the maleate salt B crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.624, 9.659, 13.815, 15.844, 17.391, and 21.802.
  • the X-ray powder diffraction pattern of the maleate B crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.624, 9.659, 13.815, 15.844, 17.391, 18.619, and 21.802.
  • the X-ray powder diffraction pattern of the maleate B crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.624, 9.659, 13.815, 15.844, 17.391, 18.619, 21.802, 23.667, and 26.441.
  • the maleate is crystal form C, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 7.325, 8.635, 9.809, 13.649, 16.133, 16.765, and 18.346.
  • the X-ray powder diffraction pattern of the maleate salt C crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.325, 8.635, 9.809, 13.649, 16.133, 16.765, 18.346, 21.689, and 23.586.
  • the X-ray powder diffraction pattern of the maleate salt C crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.325, 8.635, 9.809, 11.661, 13.649, 16.133, 16.765, 18.346, 21.689, 23.586, and 25.303. .
  • the maleate is crystal form D, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 4.486, 7.288, 9.067, 10.001, 13.914, 18.229, and 18.940.
  • the X-ray powder diffraction pattern of the maleate salt form D has characteristic peaks at diffraction angles 2 ⁇ of 4.486, 5.998, 7.288, 9.067, 10.001, 13.914, 15.026, 16.227, 18.229, and 18.940.
  • the X-ray powder diffraction pattern of the maleate salt form D has diffraction angles 2 ⁇ 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, 28.102 There are characteristic peaks everywhere.
  • the present disclosure provides hydrobromide salts of compounds of formula II.
  • the hydrobromide salt is in crystalline form I, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 8.128, 12.579, 16.414, 17.075, 17.780, and 20.733.
  • the X-ray powder diffraction pattern of the hydrobromide salt I crystal form has diffraction angles 2 ⁇ 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 There are characteristic peaks at 28.930 and 29.547.
  • the X-ray powder diffraction pattern of the hydrobromide salt I crystal form at diffraction angle 2 ⁇ is 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
  • the present disclosure provides the hydrochloride salt of the compound of formula II.
  • the hydrochloride salt is in ⁇ crystal form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 7.931, 10.115, 13.920, 15.224, 17.425, and 18.309.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has diffraction angles 2 ⁇ 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, 24.570. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has diffraction angles 2 ⁇ 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, There are characteristic peaks at 22.340, 23.359, 23.905, and 24.570.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has diffraction angles 2 ⁇ 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, There are characteristic peaks at 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, 37.291.
  • the hydrochloride salt is in ⁇ crystal form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 5.386, 8.191, 12.688, 16.607, and 20.036.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has characteristic peaks at diffraction angles 2 ⁇ of 5.386, 8.191, 10.818, 12.688, 13.980, 14.915, 16.607, 20.036, and 21.372.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has a diffraction angle 2 ⁇ 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, There are characteristic peaks at 24.355, 25.869, 26.582, 27.383, 29.253, 29.832, 30.946, 31.480, 32.504, 33.439.
  • the hydrochloride salt is in the ⁇ crystal form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 8.114, 11.997, 12.640, 13.772, 16.478, 17.897, and 20.337.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has characteristic peaks at diffraction angles 2 ⁇ of 8.114, 11.997, 12.640, 13.772, 16.478, 17.897, 20.337, 21.422, 23.228, and 24.472.
  • the X-ray powder diffraction pattern of the hydrochloride ⁇ crystal form has a diffraction angle 2 ⁇ 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, There are characteristic peaks at 27.567, 28.277, 29.830, 31.160, 32.269, and 33.334.
  • the present disclosure provides acetate salts of compounds of formula II.
  • the acetate salt is in crystalline form, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of 11.651, 12.495, 15.636, 15.965, 18.075, and 20.935.
  • the X-ray powder diffraction pattern of the acetate crystal form has characteristic peaks at diffraction angles 2 ⁇ of 11.651, 12.495, 14.323, 15.121, 15.636, 15.965, 18.075, 19.247, 19.903, and 20.935.
  • the X-ray powder diffraction pattern of the acetate crystal form has a diffraction angle 2 ⁇ 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
  • the present disclosure also relates to the preparation method of the benzoate, oxalate, methanesulfonate, maleate, hydrobromide, hydrochloride or acetate of the compound of formula II, including taking a certain amount of formula II
  • the compound is mixed and reacted with an appropriate amount of solvent and benzoic acid, oxalic acid, methanesulfonic acid, maleic acid, hydrobromic acid, hydrochloric acid or acetic acid to obtain the corresponding acid salt of the compound of formula II.
  • the solvent is selected from hydrocarbon solvents and ethers.
  • solvents One or more of solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water or dimethyl sulfoxide,
  • the hydrocarbon solvent includes but is not limited to n-butane, n-pentane, n-hexane or n-heptane;
  • the ether solvents include but are 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, 4-methyl-2-pentanone;
  • the nitrile solvent includes but is not limited to acetonitrile or propionitrile;
  • halogenated hydrocarbon solvents include but are not limited to methyl chloride, methylene chloride, chloroform or carbon tetrachloride;
  • the nitrogen-containing solvent includes, but is not limited to, nitromethane, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • the preparation method of the amorphous compound of the formula II includes: taking a certain amount of the compound of the formula II, adding an appropriate amount of solvent, separating the solid, filtering, and drying to obtain the amorphous compound of the compound of the formula II.
  • the preparation method of the amorphous compound of the formula II includes: taking a certain amount of the compound of the formula II and purifying by high performance liquid chromatography to obtain the amorphous compound of the compound of formula II, and the elution system is ammonium bicarbonate/ Water/acetonitrile.
  • the present disclosure also relates to a preparation method of the benzoate amorphous or crystalline form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and benzoic acid, separating out the solid, filtering and drying to obtain the compound of formula II
  • the benzoate amorphous or crystal form including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and benzoic acid, separating out the solid, filtering and drying to obtain the compound of formula II
  • the solvent is n-hexane or methyl tert-butyl ether.
  • the present disclosure also relates to a preparation method of the oxalate amorphous or crystalline form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and oxalic acid, separating out the solid, filtering and drying to obtain the oxalate of the compound of formula II Amorphous or crystal form of acid salt.
  • the solvent is n-hexane or methyl tert-butyl ether.
  • the present disclosure also relates to a preparation method of the amorphous methanesulfonate of the compound of formula II, which comprises: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and methanesulfonic acid, separating out the solid, filtering and drying to obtain the methane of the compound of formula II Amorphous sulfonate.
  • the solvent is methyl tert-butyl ether.
  • the present disclosure also relates to the preparation methods of the maleate salt form B, C and D of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and maleic acid, separating out the solid, filtering, After drying, the maleate salt of the formula II is obtained in crystal form B, crystal form C or crystal form D.
  • the solvent is methyl tert-butyl ether.
  • the present disclosure also relates to a method for preparing the hydrobromide salt I crystal form of the compound of formula II, which includes the step of reacting the compound of formula II with hydrobromic acid in an appropriate amount of solvent to precipitate crystals.
  • the solvent is selected from hydrocarbon solvents and ether solvents. , One or more of alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water or dimethyl sulfoxide,
  • the hydrocarbon solvent includes but is not limited to n-butane, n-pentane, n-hexane or n-heptane;
  • the ether solvents include but are 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, 4-methyl-2-pentanone;
  • the nitrile solvent includes but is not limited to acetonitrile or propionitrile;
  • halogenated hydrocarbon solvents include but are not limited to methyl chloride, methylene chloride, chloroform or carbon tetrachloride;
  • the nitrogen-containing solvent includes, but is not limited to, nitromethane, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • the solvent in the preparation method of the hydrobromide salt form I of the compound of formula II is methyl tert-butyl ether and ethanol.
  • the present disclosure also relates to a preparation method of the hydrobromide salt I crystal form of the compound of formula II, which includes: mixing a certain amount of compound of formula II with an appropriate amount of solvent and hydrobromic acid, separating out the solid, filtering, and drying to obtain the compound of formula II Hydrobromide salt I crystal form.
  • the solvent is methyl tert-butyl ether and ethanol.
  • the present disclosure also relates to a method for preparing the hydrochloride ⁇ crystal form, ⁇ crystal form, and ⁇ crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and hydrochloric acid to precipitate the solid, filtering and drying to obtain
  • the hydrochloride salt of the formula II has a crystal form, a crystal form ⁇ , or a crystal form ⁇ .
  • the solvent is methyl tert-butyl ether.
  • the present disclosure also relates to a preparation method of the acetate crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of solvent and acetic acid, separating out the solid, filtering, and drying to obtain the acetate crystal form of the compound of formula II .
  • the solvent is water and ethanol.
  • the amorphous form of the compound of formula II described in the present disclosure the benzoate, oxalate, methanesulfonate, maleate, hydrobromide, hydrochloride, Acetate, and benzoate crystal form, benzoate amorphous, oxalate crystal form, oxalate amorphous, mesylate amorphous, maleate B crystal form, Maleate crystal form C, maleate crystal form D, hydrobromide crystal form I, hydrochloride alpha crystal form, hydrochloride beta crystal form, hydrochloride gamma crystal form or acetate crystal form
  • the solvent used in the preparation process is selected from hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, dimethyl sulfoxide One or more.
  • the hydrocarbon solvents include but are not limited to n-butane, n-pentane, n-hexane or n-heptane;
  • the ether solvents include but are not limited to diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane;
  • the alcohol solvents include but are not limited to methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol;
  • the ester solvents include but are not limited to ethyl acetate , Isopropyl acetate or butyl acetate;
  • the ketone solvents include but are not limited to acetone, acetophenone, 4-methyl-2-pentanone;
  • the nitrile solvents include but are not limited to acetonitrile, propionitrile;
  • the solid form precipitation method 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 of the present disclosure is selected from the group consisting of solid precipitation at room temperature, solid precipitation on cooling, The solvent volatilized to precipitate a solid.
  • the solid form of the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt of the present disclosure refers to the crystalline form of the benzoate salt of the compound of formula II, Amorphous benzoate, crystal oxalate, amorphous oxalate, amorphous methanesulfonate, maleate B crystal, maleate C crystal, maleate D crystal, Hydrobromide I crystal form, hydrochloride ⁇ crystal form, hydrochloride ⁇ crystal form, hydrochloride ⁇ crystal form, acetate crystal form.
  • the crystallization mode of the crystalline form of the compound of the present disclosure is selected from room temperature crystallization, cooling crystallization, volatilization crystallization, or addition of seed crystals to induce crystallization, and the crystalline form of the compound is selected from the compound of formula II benzoate crystal Form, oxalate crystal form, maleate crystal form B, maleate crystal form C, maleate crystal form D, hydrobromide crystal form I, hydrochloride ⁇ crystal form, hydrochloride ⁇ crystal form, hydrochloride ⁇ crystal form, acetate crystal form.
  • the present disclosure also relates to a method for preparing the amorphous or crystalline form of the benzoate of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of n-hexane or methyl tert-butyl ether, adding benzoic acid at 50°C Stir overnight, filter and dry under the conditions to obtain the amorphous or crystal form of the benzoate of the compound of formula II.
  • the present disclosure also relates to a preparation method of the oxalate amorphous or crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of methyl tert-butyl ether or n-hexane, adding oxalic acid, at 50°C Stir overnight, filter, and dry to obtain the oxalate amorphous or crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the amorphous methanesulfonate of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding methanesulfonic acid, and stirring overnight at 50°C. After filtering and drying, an amorphous form of the mesylate salt of the compound of formula II is obtained.
  • the present disclosure also relates to a method for preparing the maleate salt B crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 10 minutes at 50°C -10h, filter and dry to obtain the maleate B crystal form of the compound of formula II.
  • the present disclosure also relates to a method for preparing the maleate salt B crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 10 minutes at 50°C , 20min, 30min, 1h or 2h, filtered and dried to obtain the maleate B crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the maleate salt C crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 12 hours at 50°C -36h, filter and dry to obtain the maleate C crystal form of the compound of formula II.
  • the present disclosure also relates to a method for preparing the maleate salt C crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 1 d at 50°C , Filtration and drying to obtain the maleate C crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the maleate salt form D of the compound of formula II, which includes: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 48 hours at 50°C -72h, filter and dry to obtain the maleate D crystal form of the compound of formula II.
  • the present disclosure also relates to a method for preparing the maleate salt form D of the compound of formula II, which includes: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding maleic acid, and stirring at 600 rpm for 3 days at 50°C , Filtration and drying to obtain the maleate D crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the hydrobromide salt I crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding hydrobromic acid or a mixture of hydrobromic acid and ethanol The solution was stirred at 600 rpm at 25°C for 12h-72h, filtered, and dried to obtain the hydrobromide salt I crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the hydrobromide salt I crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding hydrobromic acid, and stirring at 600 rpm for 3 days at 25°C , Filtering and drying to obtain the hydrobromide salt I crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the hydrobromide salt I crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of methyl tert-butyl ether, and adding a mixed solution of hydrobromic acid and ethanol (volume ratio It can be selected from 1:1, 1:50, 1:99), stirred at 600 rpm overnight at 25°C or stirred for 3 days, filtered, and dried to obtain the hydrobromide salt I crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the hydrochloride ⁇ crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding concentrated hydrochloric acid, and stirring at 50°C for 12h-48h, Filter and dry to obtain the hydrochloride ⁇ crystal form of the compound of formula II.
  • the present disclosure also relates to a preparation method of the hydrochloride ⁇ crystal form of the compound of formula II, including: taking a certain amount of compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding concentrated hydrochloric acid, stirring at 50°C for 2 days, filtering, After drying, the hydrochloride ⁇ crystal form of the compound of formula II is obtained.
  • the present disclosure also relates to a preparation method of the hydrochloride ⁇ crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of methyl tert-butyl ether, adding ethanolic hydrochloric acid solution, separating the solid, filtering, and drying to obtain The hydrochloride salt of the compound of formula II ⁇ crystal form.
  • the present disclosure also relates to a preparation method of the acetate crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of water, adding ethanol acetic acid solution, separating the solid, filtering, and drying to obtain the acetic acid of the compound of formula II Salt crystal form.
  • the present disclosure also relates to a preparation method of the acetate crystal form of the compound of formula II, including: taking a certain amount of the compound of formula II, adding an appropriate amount of water, and adding ethanol acetic acid solution (precisely pipette 0.1 ml of acetic acid, add 9.9 ml of ethanol, and shake well ), stirred overnight at 50°C, filtered, and dried to obtain the acetate crystal form of the compound of formula II.
  • the present disclosure also relates to a pharmaceutical composition, which contains the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt or the amorphous form of the compound of formula II, and also contains one or more pharmaceutically acceptable compounds.
  • the present disclosure also relates to a pharmaceutical composition containing the hydrobromide salt I crystal form of the compound of formula II, and further comprising one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to a pharmaceutical composition, which is composed of an amorphous form of a compound of formula II or an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of an acid addition salt, and one or more pharmaceutically acceptable solvates.
  • a pharmaceutical composition which is composed of an amorphous form of a compound of formula II or an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of an acid addition salt, and one or more pharmaceutically acceptable solvates.
  • an acceptable carrier, diluent or excipient is a pharmaceutical composition, which is composed of an amorphous form of a compound of formula II or an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of an acid addition salt, and one or more pharmaceutically acceptable solvates.
  • the present disclosure also relates to a pharmaceutical composition, which is prepared from the hydrobromide salt I crystal form of the compound of formula II and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to an amorphous form of a compound of formula II or an acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of an acid addition salt, and optionally one or more pharmaceutically acceptable carriers and/or Pharmaceutical composition of diluent.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (the formulation is an amorphous form of the compound of formula II described in this disclosure or an acid-added compound of formula II).
  • the pharmaceutically acceptable solvate of the salt or acid addition salt is prepared or the injection itself contains the amorphous form of the compound of formula II described in the present disclosure or the acid addition salt of the compound of formula II or the pharmaceutically acceptable salt of the acid addition salt.
  • Accepted solvates include injection, sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays.
  • the present disclosure further relates to a method for preparing a pharmaceutical composition, comprising combining 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 of the present disclosure with at least one A mixture of pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition described in the present disclosure can also be administered to patients or subjects in need of such treatment in any suitable way of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • oral administration the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral mixtures, etc. Suspensions, syrups, etc.
  • the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like.
  • parenteral administration the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When made into an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When formulating injections, additives may not be added to the pharmaceutical preparations, or appropriate additives may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays.
  • 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 of the present disclosure is present in the pharmaceutical combination in a therapeutically and/or prophylactically effective amount In substances or drugs. 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 of the present disclosure is present in the pharmaceutical composition in the form of a unit dose Or in medicine.
  • the present disclosure further relates to an amorphous form of the compound of formula II, or an acid addition salt or a pharmaceutically acceptable solvate of an acid addition salt of the compound of formula II, or a pharmaceutical composition containing the same or a pharmaceutical composition prepared therefrom Use in the preparation of a medicine for treating ROR ⁇ -mediated diseases or disorders.
  • the ROR ⁇ -mediated diseases or conditions include but are not limited to inflammation and autoimmune diseases and cancer, wherein inflammation and autoimmune diseases include but are not limited to arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis , Psoriatic arthritis, osteoarthritis, regional purulent, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune eye disease, autoimmune thyroid disease, type I immunity Polysecretory syndrome, type II autoimmune polyendocrine syndrome, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Syndrome, Crohn’s disease, asthma, Kawasaki disease, Hashimoto’s thyroiditis, infectious disease, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), lung disease, glomerulonephritis, myocarditis, thyroiditis, dry Ophthalmology, uveitis, Behcet disease, asthma, atopic
  • ether solvents include, but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.
  • alcohol solvent examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • ester solvent in the present disclosure includes, but is not limited to, ethyl acetate, isopropyl acetate or butyl acetate.
  • ketone solvent examples include but are not limited to: acetone, acetophenone, and 4-methyl-2-pentanone.
  • nitrile solvent in the present disclosure include, but are not limited to: acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent examples include, but are not limited to: methyl chloride, methylene chloride, chloroform, or carbon tetrachloride.
  • hydrocarbon solvent examples include, but are not limited to: n-butane, n-pentane, n-hexane, or n-heptane.
  • the "X-ray powder diffraction pattern or XRPD" described in the present disclosure is obtained by Cu-K ⁇ ray diffraction.
  • the “differential scanning calorimetry or DSC” mentioned in the present disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference material during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemistry related to the thermal effect. Change, get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, and the unit is ° or degree.
  • the error range of the 2 ⁇ may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • Figure 1 is the XRPD image of the amorphous compound of formula II.
  • Figure 2 is the XRPD image of the benzoate amorphous compound of formula II.
  • Figure 3 is an XRPD diagram of the crystalline form of the benzoate of the compound of formula II.
  • Figure 4 is the DSC spectrum of the crystalline form of the benzoate of the compound of formula II.
  • Figure 5 is the XRPD image of the oxalate amorphous compound of formula II.
  • Figure 6 is the XRPD pattern of the oxalate crystal form of the compound of formula II.
  • Figure 7 is the XRPD image of the amorphous mesylate of the compound of formula II.
  • Figure 8 is the XRPD diagram of the maleate salt B crystal form of the compound of formula II.
  • Fig. 9 is a DSC chart of the maleate salt B crystal form of the compound of formula II.
  • Figure 10 is a TGA spectrum of the maleate B crystal form of the compound of formula II.
  • Figure 11 is the DVS moisture absorption spectrum of the maleate salt B crystal form of the compound of formula II.
  • Fig. 12 is a comparison diagram of XRPD before and after DVS detection of the maleate salt B crystal form of the compound of formula II.
  • Fig. 13 is an XRPD diagram of the maleate salt C crystal form of the compound of formula II.
  • Figure 14 is a DSC spectrum of the maleate salt C crystal form of the compound of formula II.
  • Figure 15 is a TGA spectrum of the maleate salt C crystal form of the compound of formula II.
  • Figure 16 is the XRPD pattern of the maleate salt form D of the compound of formula II.
  • Figure 17 is a DSC spectrum of the maleate salt form D of the compound of formula II.
  • Figure 18 is a TGA spectrum of the maleate salt form D of the compound of formula II.
  • Figure 19 is the XRPD pattern of the crystalline form I of the hydrobromide salt of the compound of formula II.
  • Fig. 20 is a DSC chart of the crystalline form I of hydrobromide salt of the compound of formula II.
  • Figure 21 is a TGA spectrum of the hydrobromide salt form I of the compound of formula II.
  • Figure 22 is a DVS moisture absorption spectrum of the hydrobromide salt form I of the compound of formula II.
  • Fig. 23 is a comparison diagram of XRPD before and after DVS detection of the hydrobromide salt I crystal form of the compound of formula II.
  • Fig. 24 is an XRPD pattern of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 25 is a DSC chart of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 26 is a TGA spectrum of the hydrochloride ⁇ crystal form of the compound of formula II.
  • Figure 27 is a DVS moisture absorption spectrum of the hydrochloride ⁇ crystal form of the compound of formula II.
  • Figure 28 is a comparison diagram of XRPD before and after DVS detection of the ⁇ crystal form of the compound of formula II hydrochloride.
  • Figure 29 is the XRPD pattern of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 30 is a DSC chart of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 31 is a TGA spectrum of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 32 is the DVS moisture absorption spectrum of the ⁇ crystal form of the hydrochloride salt of the compound of formula II.
  • Figure 33 is a comparison diagram of XRPD before and after DVS detection of the ⁇ crystal form of compound hydrochloride of formula II.
  • Figure 34 is the XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula II.
  • Figure 35 is an XRPD pattern of the crystalline form of the acetate salt of the compound of formula II.
  • Figure 36 is a DSC chart of the crystalline form of the acetate salt of the compound of formula II.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • Methylsilane (TMS) Methylsilane
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • XRPD is an X-ray powder diffraction test: the measurement is carried out using a BRUKER D8 X-ray diffractometer. The specific information collected: Cu anode (40kV, 40mA), Cu-K ⁇ rays Scanning mode: ⁇ /2 ⁇ , scanning range: 10-48°.
  • DSC is differential scanning calorimetry: the measurement uses METTLER TOLEDO DSC 3+ differential scanning calorimeter, the heating rate is 10°C/min, and the specific temperature range refers to the corresponding graph (mostly 25-300 or 25-350°C), nitrogen purge Speed 50mL/min.
  • TGA thermogravimetric analysis: METTLER TOLEDO TGA 2 type thermogravimetric analyzer is used for detection, the heating rate is 10°C/min, the specific temperature range refers to the corresponding graph (mostly 25-300°C), and the nitrogen purge speed is 20mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems advantage 2, at 25°C, the humidity starts from 50%, the humidity range is 0%-95%, and the step is 10%.
  • the judgment standard is the mass change of each gradient dM/dT If it is less than 0.002, TMAX is less than 360min, and cycle twice.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: In the n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the first step is the preparation of 6-chloro-2’-(difluoromethoxy)-[1,1’-diphenyl]-3,4-diamine
  • reaction solution was concentrated under reduced pressure, and the residue was directly loaded on an ISCO solid column, and eluted with a mixed solvent of n-hexane/ethyl acetate to obtain a white solid product (1.0g, yield 51.9%), MS(+)ES:285( M+H)+.
  • Test Example 1 Biochemical experiment of LanthaScreen TR-FRET ROR ⁇ -LBD and co-activating peptide
  • TR-FRET coregulatory buffer D (Cat No, PV4420, Invitrogen)
  • IC 50 values were calculated by the relationship between the logarithm of compound concentration plotted percentage inhibition using GraphPad Prism. Table 1 shows the IC 50 values of the compounds.
  • Test Example 2 Assay for inhibiting IL-17A cytokine production in human peripheral blood mononuclear cells
  • Lymphocyte medium (Zenbio, Cat No. LYMPH-1)
  • Human IL-17 ELISA human IL-17 enzyme-linked immunoassay kit (R&D Systems, D1700)
  • the frozen human peripheral blood mononuclear cells were quickly recovered in the pre-warmed lymphocyte culture medium, centrifuged at 1000 rpm for 10 min, the cell culture supernatant was removed, the cells were gently suspended in TexMACS medium, and the cells were counted.
  • the T cell activating reagent cytostim (10 ⁇ L/mL) was added to the cell suspension proportionally, and then the cells were planted in a 96-well cell culture plate at a density of 1 ⁇ 10 5 peripheral blood mononuclear cells/well.
  • Use TexMACS medium to gradually dilute the test compound, and add them to each experimental well, each group of 2-3 parallel wells. Prepare negative control wells containing only cells without cytostim to obtain background readings.
  • the inhibition rate calculation formula is as follows:
  • Inhibition% is the inhibition rate
  • OD(NC) is the reading of the negative control of cells without cytostim and no compound
  • OD(PC) is the reading of the positive control of cells with cytostim but no compound
  • OD(compound ) Is the reading of the cell plus cytostim and compound.
  • the compound of formula II (30mg, 53.57 ⁇ mol) was added to isopropyl ether (1.5mL), heated to 70°C, it was an opaque white suspension, slowly reduced to room temperature, stirred for 16 hours, filtered, collected the filter cake, and vacuumed After drying, the product (20 mg, yield: 66%) was obtained.
  • the product is amorphous, and the XRPD spectrum is shown in Figure 1.
  • the compound of formula II (30mg, 53.57 ⁇ mol) was added to toluene (1.5mL), heated to 70°C, stirred to dissolve, slowly reduced to room temperature, solids precipitated on the wall, stirred at room temperature for 16 hours, filtered, collected the filter cake, and vacuum After drying, the product (20 mg, yield: 66%) was obtained. According to X-ray powder diffraction, the product is amorphous.
  • the compound of formula II (5 g, 8.93 mmol) was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the product (2.5 g, yield: 50%). According to X-ray powder diffraction, the product is amorphous.
  • the amorphous substance of the compound of formula II (Example 4) was placed open and flat, and the samples were examined under heating (40°C, 60°C), light (4500 Lux), and high humidity (RH 75%, RH 90%) conditions
  • the sampling period is 30 days.
  • the amorphous form of the compound of formula II (Example 4) was subjected to long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) stability studies for 3 months.
  • the product is defined as the maleate salt B crystal form of the compound of formula II, and the XRPD spectrum is shown in FIG. 8.
  • the DSC spectrum is shown in Figure 9 with the first endothermic peak at 138.04°C; the TGA spectrum is shown in Figure 10.
  • DVS characterization Under the condition of 25°C, between 20.0%RH and 80.0%RH, the water absorption of maleate B crystal sample increases with the increase of humidity, and the weight change is 1.731%. Less than 2% but not less than 0.2%, the sample is slightly hygroscopic. Under normal storage conditions (ie 25°C, humidity 60%), water absorption is about 1.438%; under accelerated test conditions (ie humidity 70%), water absorption is about 1.809%; under extreme conditions (ie humidity 90%), water absorption is about 3.077 %.
  • the comparison of X-ray powder diffraction before and after DVS shows that the crystal form before and after DVS has not changed.
  • the DVS spectrum is shown in Figure 11, and the X-ray powder diffraction comparison spectrum before and after the DVS detection is shown in Figure 12.
  • 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
  • the product is the maleate B crystal form of the compound of formula II.
  • the product is the maleate B crystal form of the compound of formula II.
  • the product is the maleate B crystal form of the compound of formula II.
  • the product is the maleate B crystal form of the compound of formula II.
  • the product is defined as the maleate C crystal form of the compound of formula II, and the XRPD spectrum is shown in FIG. 13.
  • the DSC spectrum is shown in FIG. 14, the first endothermic peak is 154.58° C.; the TGA spectrum is shown in FIG. 15.
  • the product is defined as the maleate salt D crystal form of the compound of formula II, and the XRPD spectrum is shown in FIG. 16.
  • the DSC spectrum is shown in Figure 17, the first endothermic peak is 159.27°C; the TGA spectrum is shown in Figure 18.
  • 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
  • the product is defined as the hydrobromide I crystal form of the compound of formula II, and the XRPD spectrum is shown in FIG. 19.
  • the DSC spectrum is shown in Figure 20, the first endothermic peak is 201.73°C; the TGA spectrum is shown in Figure 21.
  • DVS characterization Under the condition of 25°C, between 20.0%RH and 80.0%RH, the water absorption of hydrobromide I crystal form samples increases with the increase of humidity, and the weight change is 0.636%. Less than 2% but not less than 0.2%, the sample is slightly hygroscopic. Under normal storage conditions (ie 25°C, humidity 60%), water absorption is about 0.589%; under accelerated test conditions (ie humidity 70%), water absorption is about 0.702%; under extreme conditions (ie humidity 90%), water absorption is about 1.094 %.
  • the desorption process and the adsorption process of the sample basically coincided; the X-ray powder diffraction comparison chart before and after DVS showed that the crystal form did not change before and after DVS.
  • the DVS spectrum is shown in Figure 22, and the X-ray powder diffraction comparison spectrum before and after the DVS detection is shown in Figure 23.
  • 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
  • the product is defined as the ⁇ crystal form of compound hydrochloride of formula II, and the XRPD spectrum is shown in FIG. 24.
  • the DSC spectrum is shown in Figure 25, with the first endothermic peak at 192.13°C; the TGA spectrum is shown in Figure 26.
  • DVS characterization Under the condition of 25°C, between 20.0%RH-80.0%RH, the water absorption of the sample increases with the increase of humidity, the weight change is 0.549%, and the moisture gain is less than 2% but not less than 0.2 %, the sample is slightly hygroscopic. Under normal storage conditions (ie, humidity at 25°C and 60%), the water absorption is about 0.463%; under accelerated test conditions (ie, humidity is 70%), the water absorption is about 0.574%; under extreme conditions (ie, humidity is 90%), the water absorption is about 1.040 %.
  • the desorption process and the adsorption process of the sample basically coincided; the X-ray powder diffraction comparison chart before and after DVS showed that the crystal form did not change before and after DVS.
  • the DVS spectrum is shown in Fig. 27, and the X-ray powder diffraction comparison spectrum before and after the DVS detection is shown in Fig. 28.
  • 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
  • DVS characterization Under the condition of 25°C, between 20.0%RH-80.0%RH, the water absorption of the sample increases with the increase of humidity, the weight change is 1.235%, and the moisture gain is less than 2% but not less than 0.2 %, the sample is slightly hygroscopic. Under normal storage conditions (ie 25°C and humidity 60%), the water absorption is about 1.755%; under accelerated test conditions (ie, humidity is 70%), the water absorption is about 1.954%; under extreme conditions (ie, humidity is 90%), the water absorption is about 2.534 %.
  • the single desorption process and the adsorption process of the sample basically overlap, the first and second cycle desorption process and the adsorption process cannot overlap;
  • X-ray powder diffraction before and after DVS The comparison chart shows that the crystal form changes before and after DVS.
  • the DVS spectrum is shown in Fig. 32, and the X-ray powder diffraction comparison spectrum before and after the DVS detection is shown in Fig. 33.
  • 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
  • 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
  • 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 Study on the stability of factors affecting the hydrochloride ⁇ crystal form and hydrobromide I crystal form of the compound of formula II
  • hydrochloride ⁇ crystal form and the hydrobromide crystal form I of the formula II compound are placed in an open and flat position, and they are tested under light (4500 Lux), high temperature (40°C, 60°C), high humidity (RH 75%, RH 92.5%). ) The stability of the sample under the conditions, the sampling period is 30 days
  • the hydrochloride ⁇ crystal form of the compound of formula II was placed at 25°C, 60% RH and 40°C, 75% RH to investigate its stability.
  • the hydrobromide I crystal form of the compound of formula II was placed at 25° C., 60% RH and 40° C., 75% RH to investigate its stability.

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Abstract

一种RORγ的调节剂的酸加成盐。具体而言，涉及式II化合物的酸加成盐。更具体地，涉及式II化合物的苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐、氢溴酸盐、盐酸盐、乙酸盐，以及式II化合物的苯甲酸盐晶型、苯甲酸盐无定型、草酸盐晶型、草酸盐无定型、甲磺酸盐无定型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型、乙酸盐晶型。

Description

一种RORγ调节剂的酸加成盐
本申请要求申请日为2019年10月31日的中国专利申请CN201911049930.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于药物化学领域，涉及一种RORγ的调节剂式II化合物的酸加成盐。
背景技术
核受体是配体调节的转录因子，其调节发育、免疫和细胞代谢，是人类疾病的主要药物靶标类别之一。类视黄醇相关的孤儿受体γ(RORγ)蛋白是核受体的NR1亚家族的成员，并且具有典型的核受体结构域结构，由DNA结合结构域、配体结合域、铰链结构域和激活功能2结构域组成(Benoit G，等，Pharmacological Reviews，58(4)：798-836,2006；Zhang，Y.，et al.，Acta Pharmacogica Sinica，36：71-87,2015)。与大多数其他作为二聚体结合的核受体相反，RORγ识别并作为单体结合。它与特定的DNA序列结合，通常由TAAA/TNTAGGTCA组成，称为ROR反应元件(RORE)。
有两种亚型的RORγ，RORγ1和RORγ2(也被称为RORγt)，它们是由相同的RORC基因产生的，可能是通过选择其它启动子而产生的(Villey I等，Eur.J.Immunol.，29(12)：4072-80，1999年)。因为RORγ两个亚型(RORγ1和RORγt)由相同的mRNA产生，具有相同的配体结合域，仅仅它们蛋白N-末端不同(Jetten,A.M.,2009；Ivanov,I.I.et al.,2006)。小分子抑制剂结合在配体结合域，抑制受体的功能，因此对RORγ两个亚型无法达到有选择性，均称RORγ小分子抑制剂(或调控剂)，不分亚型。
RORγ这两种亚型组织表达分布十分不同。RORγt主要在胸腺以及几种免疫细胞中表达，而RORγ1则在许多组织表达，比如，胸腺,肝脏，肌肉，睾丸，胰腺、前列腺、心脏等等组织(Jetten,A.M.,2009；Zhang,Y.et al.,2015)。文献报告RORγ1的功能之一是调节人生物钟，参与昼夜节律的调节(Jetten,A.M.,2009)。17型辅助性免疫调节T细胞(TH17)是引起自身免疫疾病的主要根源(Ivanov,I.I.et al.,2006)，RORγ两个亚型均在Th17细胞里表达，调节17型辅助性免疫调节T细胞分化和诱导基因转录(Ruan，Q.,et al.，2011)。细胞因子IL-6和TGF-β诱导未分化CD4T辅助细胞分化成Th17细胞，Th17细胞表达高水平的RORγt，诱导未分化CD4T辅助细胞中IL-23受体基因转录，IL23受体又促进和稳定TH17细胞的生成，形成正反馈回路的一部分(Ivanov,I.I.et al., 2006；Jetten,A.M.,2009)。同时RORγt能够诱导细胞因子IL-17A,IL-17F,IL-21，IL-22等促炎效应细胞因子的基因转录，增强炎症过程。与RORγt相似，RORγ1也在Th17细胞里有一些表达，也可以调节17型辅助性免疫调节T细胞(TH17)分化和诱导基因转录(Ruan，Q.,et al.，2011)。RORγ的药理学拮抗对自身免疫性疾病具有治疗潜力，使其成为一个有吸引力小分子抑制剂的靶点。
RORγ已被确定为几种疾病发病机制中的关键介质，如类风湿性关节炎、牛皮癣、多发性硬化症、炎症性肠病、克罗恩病、干燥综合症和哮喘等。(Louten等，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)。一些其他疾病，例如慢性干眼症、川崎病、粘膜利什曼病和桥本氏甲状腺炎，其特征在于Th17比例增加和/或Th17标志细胞因子水平升高，例如IL-17、IL-22和IL-23。(Chen，Y.等，Mucosal.Immunol.，7(1)：38-45,2014；Jia，S.，et al.，Clin.Exp.Immunol.，162：131-137,2010；Boaventura，VS等，Eur.J.Immunol.，40：2830-2836,2010；Figueroa-Vega，N.等，J.Clin.Endocrinol.Metab.，95：953-62,2010)。在上述每个例子中，均可以通过同时抑制RORα来增强抑制作用。RORγt抑制剂目前正在开发用于治疗自身免疫疾病，例如牛皮癣和类风湿性关节炎。见Jun R.Huh和Dan R.Littman，Eur.J.Immunol.，42(9)：2232-2237(2012)、WO2012/027965、WO2013/029338和US2015/291607。
申请号为PCT/US19/30526的申请中提供了一种RORγ的调节剂，结构如式II化合物：
Figure PCTCN2020125125-appb-000001
该申请的全部内容并入本文。
发明内容
本公开提供式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述酸加成盐为有机酸加成盐或无机酸加成盐。
本公开还涉及式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物的制备方法，所述酸加成盐为有机酸加成盐或无机酸加成盐，包括取一定量的式II化合物，与适量溶剂和有机酸或者无机酸混合，反应一段时间，得到式II化合物的对应酸的盐， 所述溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水或二甲基亚砜的一种或者多种。
在一些实施方案中，所述有机酸加成盐选自甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、1,2-乙二磺酸盐、β-萘磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、苯乙酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、癸酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、盐酸甘氨酸盐、1,5-萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、萘-1-磺酸盐或戊酸盐中的至少一种。
在一些实施方案中，所述无机酸加成盐选自盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐或偏磷酸盐中的至少一种。
在一些实施方案中，所述有机酸加成盐可选自苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐或乙酸盐中的至少一种，所述有机酸加成盐可选自盐酸盐或氢溴酸盐。
本公开提供了式II化合物的苯甲酸盐晶型、苯甲酸盐无定型、草酸盐晶型、草酸盐无定型、甲磺酸盐无定型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型、乙酸盐晶型，及其制备方法。
本公开提供一种式II化合物的无定型物，所述无定型物的XRPD图谱无明显的尖锐衍射峰；优选地，所述无定型物具有如图1所示的XRPD图谱。
本公开提供式II化合物的苯甲酸盐。
在一些实施方案中，所述苯甲酸盐为无定型物，所述无定型物的XRPD图谱无明显的尖锐衍射峰；优选地，所述无定型物具有如图2所示的XRPD图谱。
在一些实施方案中，所述苯甲酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为5.305、7.411处有特征峰。
进一步的，所述苯甲酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为5.305、7.411、22.031处有特征峰。
进一步的，所述苯甲酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为5.305、7.411、19.140、22.0314处有特征峰。
本公开提供式II化合物的草酸盐。
在一些实施方案中，所述草酸盐为无定型物，所述无定型物的XRPD图谱无明显的尖锐衍射峰；优选地，所述无定型物具有如图5所示的XRPD图谱。
在一些实施方案中，所述草酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为14.378、18.463、21.670处有特征峰。
进一步的，所述草酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为14.378、18.463、21.670、23.075处有特征峰。
进一步的，所述草酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为14.378、18.463、21.670、23.075、28.127处有特征峰。
本公开提供式II化合物的甲磺酸盐。
在一些实施方案中，所述甲磺酸盐为无定型物，所述无定型物的XRPD图谱无明显的尖锐衍射峰；优选地，所述无定型物具有如图7所示的XRPD图谱。
本公开提供式II化合物的马来酸盐。
在一些实施方案中，所述马来酸盐为B晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.624、9.659、13.815、15.844、17.391处有特征峰。
进一步的，所述马来酸盐B晶型的X-射线粉末衍射图谱，在衍射角2θ为7.624、9.659、13.815、15.844、17.391、21.802处有特征峰。
进一步的，所述马来酸盐B晶型的X-射线粉末衍射图谱，在衍射角2θ为7.624、9.659、13.815、15.844、17.391、18.619、21.802处有特征峰。
进一步的，所述马来酸盐B晶型的X-射线粉末衍射图谱，在衍射角2θ为7.624、 9.659、13.815、15.844、17.391、18.619、21.802、23.667、26.441处有特征峰。
在一些实施方案中，所述马来酸盐为C晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.325、8.635、9.809、13.649、16.133、16.765、18.346处有特征峰。
进一步的，所述马来酸盐C晶型的X-射线粉末衍射图谱，在衍射角2θ为7.325、8.635、9.809、13.649、16.133、16.765、18.346、21.689、23.586处有特征峰。
进一步的，所述马来酸盐C晶型的X-射线粉末衍射图谱，在衍射角2θ为7.325、8.635、9.809、11.661、13.649、16.133、16.765、18.346、21.689、23.586、25.303处有特征峰。
在一些实施方案中，所述马来酸盐为D晶型，其X-射线粉末衍射图谱，在衍射角2θ为4.486、7.288、9.067、10.001、13.914、18.229、18.940处有特征峰。
进一步的，所述马来酸盐D晶型的X-射线粉末衍射图谱，在衍射角2θ为4.486、5.998、7.288、9.067、10.001、13.914、15.026、16.227、18.229、18.940处有特征峰。
进一步的，所述马来酸盐D晶型的X-射线粉末衍射图谱，在衍射角2θ为4.486、5.998、7.288、9.067、10.001、13.914、15.026、16.227、18.229、18.940、23.076、25.612、28.102处有特征峰。
本公开提供式II化合物的氢溴酸盐。
在一些实施方案中，所述氢溴酸盐为I晶型，其X-射线粉末衍射图谱，在衍射角2θ为8.128、12.579、16.414、17.075、17.780、20.733处有特征峰。
进一步的，所述氢溴酸盐I晶型的X-射线粉末衍射图谱，在衍射角2θ为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、29.547处有特征峰。
进一步的，所述氢溴酸盐I晶型的X-射线粉末衍射图谱，在衍射角2θ为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、50.746处有特征峰。
本公开提供式II化合物的盐酸盐。
在一些实施方案中，所述盐酸盐为α晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.931、10.115、13.920、15.224、17.425、18.309处有特征峰。
进一步的，所述盐酸盐α晶型的X-射线粉末衍射图谱，在衍射角2θ为7.931、10.115、12.166、13.920、15.224、16.041、16.315、16.748、17.425、18.309、22.340、23.359、24.570处有特征峰。
进一步的，所述盐酸盐α晶型的X-射线粉末衍射图谱，在衍射角2θ为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处有特征峰。进一步的，所述盐酸盐α晶型的X-射线粉末衍射图谱，在衍射角2θ为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、37.291处有特征峰。
在一些实施方案中，所述盐酸盐为β晶型，其X-射线粉末衍射图谱，在衍射角2θ为5.386、8.191、12.688、16.607、20.036处有特征峰。
进一步的，所述盐酸盐β晶型的X-射线粉末衍射图谱，在衍射角2θ为5.386、8.191、10.818、12.688、13.980、14.915、16.607、20.036、21.372处有特征峰。
进一步的，所述盐酸盐β晶型的X-射线粉末衍射图谱，在衍射角2θ为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、33.439处有特征峰。
在一些实施方案中，所述盐酸盐为γ晶型，其X-射线粉末衍射图谱，在衍射角2θ为8.114、11.997、12.640、13.772、16.478、17.897、20.337处有特征峰。
进一步的，所述盐酸盐γ晶型的X-射线粉末衍射图谱，在衍射角2θ为8.114、11.997、12.640、13.772、16.478、17.897、20.337、21.422、23.228、24.472处有特征峰。
进一步的，所述盐酸盐γ晶型的X-射线粉末衍射图谱，在衍射角2θ为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、33.334处有特征峰。
本公开提供式II化合物的乙酸盐。
在一些实施方案中，所述乙酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为11.651、12.495、15.636、15.965、18.075、20.935处有特征峰。
进一步的，所述乙酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为11.651、12.495、14.323、15.121、15.636、15.965、18.075、19.247、19.903、20.935处有特征峰。
进一步的，所述乙酸盐晶型的X-射线粉末衍射图谱，在衍射角2θ为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、39.973处有特征峰。
本公开还涉及式II化合物的苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐、氢溴酸盐、 盐酸盐或乙酸盐的制备方法，包括取一定量的式II化合物，与适量溶剂和苯甲酸、草酸、甲磺酸、马来酸、氢溴酸、盐酸或者乙酸混合反应，得到式II化合物的对应酸的盐，所述的溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水或二甲基亚砜的一种或者多种，
所述烃类溶剂包括但不限于正丁烷、正戊烷、正己烷或正庚烷；
所述醚类溶剂包括但不限于四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；
所述醇类溶剂包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；
所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；
所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮；
所述腈类溶剂包括但不限于乙腈或丙腈；
所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、氯仿或四氯化碳；
所述含氮溶剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
在一些实施方案中，式II化合物的无定型物的制备方法，包括：取一定量的式II化合物，加入适量溶剂，析出固体，过滤、干燥，得到式II化合物的无定型物。在某些实施方案中，所述的溶剂可选自异丙醚、甲苯或乙酸异丙酯/正己烷(V:V＝1:3)。
在一些实施方案中，式II化合物的无定型物的制备方法，包括：取一定量的式II化合物，高效液相色谱法纯化得到式II化合物的无定型物，洗脱体系为碳酸氢铵/水/乙腈。
一些实施方案中，式II化合物的无定型物的制备方法，包括：取一定量的式II化合物，加入适量溶剂，析出固体、过滤、干燥，得到式II化合物的无定型物，所述溶剂选自异丙醚、甲苯、乙酸异丙酯和正己烷(V:V＝1:3)混合溶液，所述无定型物的析出方法选自室温析出固体、冷却析出固体、挥发溶剂析出固体。
一些实施方案中，式II化合物的无定型物的制备方法，包括：取一定量的式II化合物，加入适量异丙醚、甲苯或者乙酸异丙酯和正己烷(V:V＝1:3)混合溶液，升温溶解或者不完全溶解，降至室温，搅拌析出固体，过滤，干燥，得到式II化合物的无定型物。
本公开还涉及式II化合物的苯甲酸盐无定型物或者晶型的制备方法，包括：取一定量的式II化合物，加入适量溶剂和苯甲酸，析出固体，过滤、干燥，得到式II化合物的苯甲酸盐无定型物或晶型。在某些实施方案中，所述的溶剂为正己烷或者甲基叔丁基醚。
本公开还涉及式II化合物的草酸盐无定型物或者晶型的制备方法，包括：取一定量的式II化合物，加入适量溶剂和草酸，析出固体，过滤、干燥，得到式II化合物的草酸盐无定型物或晶型。在某些实施方案中，所述的溶剂为正己烷或者甲基叔丁基醚。
本公开还涉及式II化合物的甲磺酸盐无定型物的制备方法，包括：取一定量的式II化合物，加入适量溶剂和甲磺酸，析出固体，过滤、干燥，得到式II化合物的甲磺酸盐无定型物。在某些实施方案中，所述的溶剂为甲基叔丁基醚。
本公开还涉及式II化合物的马来酸盐B晶型、C晶型、D晶型的制备方法，包括：取一定量的式II化合物，加入适量溶剂和马来酸，析出固体，过滤、干燥，得到式II化合物的马来酸盐B晶型、C晶型或D晶型。在某些实施方案中，所述的溶剂为甲基叔丁基醚。
本公开还涉及式II化合物的氢溴酸盐I晶型的制备方法，包括式II化合物在适量溶剂中与氢溴酸反应，析出晶体的步骤，所述溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水或二甲基亚砜的一种或者多种，
所述烃类溶剂包括但不限于正丁烷、正戊烷、正己烷或正庚烷；
所述醚类溶剂包括但不限于四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；
所述醇类溶剂包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；
所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；
所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮；
所述腈类溶剂包括但不限于乙腈或丙腈；
所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、氯仿或四氯化碳；
所述含氮溶剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
在一些实施方案中，式II化合物的氢溴酸盐I晶型的制备方法中所述溶剂为甲基叔丁基醚和乙醇。
本公开还涉及式II化合物的氢溴酸盐I晶型的制备方法，包括：将一定量的式II化合物，与适量溶剂和氢溴酸混合，析出固体，过滤、干燥，得到式II化合物的氢溴酸盐I晶型。在某些实施方案中，所述的溶剂为甲基叔丁基醚和乙醇。
本公开还涉及式II化合物的盐酸盐α晶型、β晶型、γ晶型的制备方法，包括：取一定量的式II化合物，加入适量溶剂和盐酸，析出固体，过滤、干燥，得到式II化合物的盐酸盐α晶型、β晶型或γ晶型。在某些实施方案中，所述的溶剂为甲基叔丁基醚。
本公开还涉及式II化合物的盐酸盐γ晶型的制备方法，包括：取一定量的式II化合物β晶型放置于DVS仪器中，按照DVS参数dm/dt＝0.002，50-95-0-95-50％RH，Max360min，25℃，得到式II化合物的盐酸盐γ晶型。
本公开还涉及式II化合物的乙酸盐晶型的制备方法，包括：取一定量的式II化合物，加入适量溶剂和乙酸，析出固体，过滤、干燥，得到式II化合物的乙酸盐晶型。在某些实施方案中，所述的溶剂为水和乙醇。
在某些实施方案中，本公开所述式II化合物的无定型，式II化合物的苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐、氢溴酸盐、盐酸盐、乙酸盐，以及式II化合物的苯甲酸盐晶型、苯甲酸盐无定型、草酸盐晶型、草酸盐无定型、甲磺酸盐无定型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型或者乙酸盐晶型的制备过程中所用溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水、二甲基亚砜的一种或者多种。所述烃类溶剂包括但不限于正丁烷、正戊烷、正己烷或正庚烷；所述醚类溶剂包括但不限于乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；所述醇类溶包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮；所述腈类溶剂包括但不限于乙腈、丙腈；所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳；所述含氮溶剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
本公开所述式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物的固体形式的析出方法，选自室温析出固体、冷却析出固体、挥发溶剂析出固体。
在某些实施方案中，本公开所述化式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物的固体形式指的是式II化合物的苯甲酸盐晶型、苯甲酸盐无定型、草酸盐晶型、草酸盐无定型、甲磺酸盐无定型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型、乙酸盐晶型。
本公开所述化合物的晶型的析晶方式，选自室温析晶、冷却析晶、挥发析晶或加入晶种诱导析晶，所述化合物的晶型选自式II化合物苯甲酸盐晶型、草酸盐晶型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型、乙酸盐晶型。
本公开还涉及式II化合物的苯甲酸盐无定型物或者晶型的制备方法，包括：取一定量的式II化合物，加入适量正己烷或者甲基叔丁基醚，加入苯甲酸，50℃条件下搅拌过夜、过滤、干燥，得到式II化合物的苯甲酸盐无定型物或者晶型。
本公开还涉及式II化合物的草酸盐无定型物或者晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚或者正己烷，加入草酸，50℃条件下搅拌过夜、过滤、干燥，得到式II化合物的草酸盐无定型物或者晶型。
本公开还涉及式II化合物的甲磺酸盐无定型物的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入甲磺酸，50℃条件下搅拌过夜、过滤、干燥，得到式II化合物的甲磺酸盐无定型物。
本公开还涉及式II化合物的马来酸盐B晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌10min-10h、过滤、干燥，得到式II化合物的马来酸盐B晶型。
本公开还涉及式II化合物的马来酸盐B晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌10min、20min、30min、1h或者2h、过滤、干燥，得到式II化合物的马来酸盐B晶型。
本公开还涉及式II化合物的马来酸盐C晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌12h-36h、过滤、干燥，得到式II化合物的马来酸盐C晶型。
本公开还涉及式II化合物的马来酸盐C晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌1d、过滤、干燥，得到式II化合物的马来酸盐C晶型。
本公开还涉及式II化合物的马来酸盐D晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌48h-72h、过滤、干燥，得到式II化合物的马来酸盐D晶型。
本公开还涉及式II化合物的马来酸盐D晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入马来酸，50℃条件下600rpm搅拌3d、过滤、干燥，得到式II化合物的马来酸盐D晶型。
本公开还涉及式II化合物的氢溴酸盐I晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入氢溴酸或者氢溴酸与乙醇的混合溶液，25℃条件下600rpm搅拌12h-72h、过滤、干燥，得到式II化合物的氢溴酸盐I晶型。
本公开还涉及式II化合物的氢溴酸盐I晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入氢溴酸，25℃条件下600rpm搅拌3d、过滤、干燥，得到式II化合物的氢溴酸盐I晶型。
本公开还涉及式II化合物的氢溴酸盐I晶型的制备方法，包括：取一定量的式II化 合物，加入适量甲基叔丁基醚，加入氢溴酸与乙醇的混合溶液(体积比可选自1:1、1:50、1:99)，25℃条件下600rpm搅拌过夜或者搅拌3d、过滤、干燥，得到式II化合物的氢溴酸盐I晶型。
本公开还涉及式II化合物的盐酸盐α晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入浓盐酸，50℃条件下搅拌12h-48h、过滤、干燥，得到式II化合物的盐酸盐α晶型。
本公开还涉及式II化合物的盐酸盐α晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入浓盐酸，50℃条件下搅拌2d、过滤、干燥，得到式II化合物的盐酸盐α晶型。
本公开还涉及式II化合物的盐酸盐β晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入乙醇盐酸溶液，析出固体、过滤、干燥，得到式II化合物的盐酸盐β晶型。
本公开还涉及式II化合物的盐酸盐β晶型的制备方法，包括：取一定量的式II化合物，加入适量甲基叔丁基醚，加入乙醇盐酸溶液(浓盐酸：乙醇＝1:99，摇匀)，25℃搅拌1h，在50℃条件搅拌2d，过滤，干燥，得到式II化合物的盐酸盐β晶型。
本公开还涉及式II化合物的乙酸盐晶型的制备方法，包括：取一定量的式II化合物，加入适量水，加入乙醇醋酸溶液，析出固体、过滤、干燥，得到式II化合物的乙酸盐晶型。
本公开还涉及式II化合物的乙酸盐晶型的制备方法，包括：取一定量的式II化合物，加入适量水，加入乙醇醋酸溶液(精密移取0.1ml醋酸，加入9.9ml乙醇，摇匀)，在50℃条件搅拌过夜，过滤，干燥，得到式II化合物的乙酸盐晶型。
本公开还涉及一种药物组合物，含有式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物或者式II化合物的无定型物，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开还涉及一种药物组合物，含有式II化合物的氢溴酸盐I晶型，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开还涉及一种药物组合物，其是由式II化合物的无定型物或式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，与一种或多种药学上可接受的载体、稀释剂或赋形剂制备得到的。
本公开还涉及一种药物组合物，其是由式II化合物的氢溴酸盐I晶型与一种或多种药学上可接受的载体、稀释剂或赋形剂制备得到的。
本公开还涉及包括式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，和任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(该制剂为利用本公开所述式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物制备得到或者注射剂本身包含本公开所述的式II化合物的无定型或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本公开进一步涉及一种制备药物组合物的方法，包括使本公开的式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
此外，本公开所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些实施方案中，本公开式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物以治疗和/或预防有效量存在于药物组合物或药物中。在某些实施方案中，本公开所述式II化合物的无定型物或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物以单位剂量的形式存在于药物组合物或药物中。
本公开进一步涉及式II化合物的无定型物、或者式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物、或者包含其的药物组合物或者由其制备的药物组合物在制备用于治疗RORγ介导的疾病或病症的药物中的用途。所述的RORγ介导的疾病或病症包括但不限于炎症和自身免疫疾病和癌症，其中炎症和自身免疫疾病包括但不限于关节炎、类风湿性关节炎、幼年型类风湿性关节炎、牛皮癣、银屑病关节炎、骨关节炎、区域性脓性、溃疡性结肠炎、强直性脊柱炎、自身免疫性糖尿病、I型糖尿病、自身免疫性 眼病、自身免疫性甲状腺疾病、I型免疫性多分泌综合征、II型自身免疫性多内分泌综合征、多发性硬化症、炎症性肠病、炎症性肠综合征、幼年特发性关节炎、
Figure PCTCN2020125125-appb-000002
综合征、克罗恩病、哮喘、川崎病、桥本氏甲状腺炎、传染病、强直性脊柱炎、慢性阻塞性肺病(COPD)、肺部疾病、肾小球肾炎、心肌炎、甲状腺炎、干眼症、葡萄膜炎、Behcet病、哮喘、特应性皮炎、接触性皮炎、等移植物排斥反应、多发性肌炎、GVHD、痤疮、溃疡性结肠炎、系统性红斑狼疮、硬皮病、支气管炎、皮肌炎和过敏性鼻炎；其中癌症包括但不限于非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、滑膜肉瘤、乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢肿瘤、腹膜肿瘤、黑色素瘤、实体瘤、胶质瘤、神经胶质母细胞瘤、肝细胞癌、乳突肾肿瘤、头颈肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本公开所述的“醚类溶剂”包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环。
本公开所述的“醇类溶剂”具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本公开所述的“酯类溶剂”包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本公开所述的“酮类溶剂”具体实例包括但不限于：丙酮、苯乙酮、4-甲基-2-戊酮。
本公开所述的“腈类溶剂”具体实例包括但不限于：乙腈或丙腈。
本公开所述的“卤代烃类溶剂”具体实例包括但不限于：氯甲烷、二氯甲烷、氯仿或四氯化碳。
本公开所述的“烃类溶剂”具体实例包括但不限于：正丁烷、正戊烷、正己烷或正庚烷。
本公开所述的“X-射线粉末衍射图谱或XRPD”是经Cu-Kα射线衍射得到。
本公开所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，所述2θ的 误差范围可以是±0.3、±0.2或±0.1。
发明的有益效果
本公开提供的式II化合物的无定型，式II化合物的苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐、氢溴酸盐、盐酸盐、乙酸盐，以及式II化合物的苯甲酸盐晶型、苯甲酸盐无定型、草酸盐晶型、草酸盐无定型、甲磺酸盐无定型、马来酸盐B晶型、马来酸盐C晶型、马来酸盐D晶型、氢溴酸盐I晶型、盐酸盐α晶型、盐酸盐β晶型、盐酸盐γ晶型和乙酸盐晶型提供了可用作RORγ调节剂的式II化合物在药物开发过程中的可选固体形式。
附图说明
图1为式II化合物无定型物的XRPD图。
图2为式II化合物苯甲酸盐无定型物的XRPD图。
图3为式II化合物苯甲酸盐晶型的XRPD图。
图4为式II化合物苯甲酸盐晶型的DSC谱图。
图5为式II化合物草酸盐无定型物的XRPD图。
图6为式II化合物草酸盐晶型的XRPD图。
图7为式II化合物甲磺酸盐无定型物的XRPD图。
图8为式II化合物马来酸盐B晶型的XRPD图。
图9为式II化合物马来酸盐B晶型的DSC谱图。
图10为式II化合物马来酸盐B晶型的TGA谱图。
图11为式II化合物马来酸盐B晶型的DVS吸湿谱图。
图12为式II化合物马来酸盐B晶型的DVS检测前后XRPD对比图。
图13为式II化合物马来酸盐C晶型的XRPD图。
图14为式II化合物马来酸盐C晶型的DSC谱图。
图15为式II化合物马来酸盐C晶型的TGA谱图。
图16为式II化合物马来酸盐D晶型的XRPD图。
图17为式II化合物马来酸盐D晶型的DSC谱图。
图18为式II化合物马来酸盐D晶型的TGA谱图。
图19为式II化合物氢溴酸盐I晶型的XRPD图。
图20为式II化合物氢溴酸盐I晶型的DSC谱图。
图21为式II化合物氢溴酸盐I晶型的TGA谱图。
图22为式II化合物氢溴酸盐I晶型的DVS吸湿谱图。
图23为式II化合物氢溴酸盐I晶型的DVS检测前后XRPD对比图。
图24为式II化合物盐酸盐α晶型的XRPD图。
图25为式II化合物盐酸盐α晶型的DSC谱图。
图26为式II化合物盐酸盐α晶型的TGA谱图。
图27为式II化合物盐酸盐α晶型的DVS吸湿谱图。
图28为式II化合物盐酸盐α晶型的DVS检测前后XRPD对比图。
图29为式II化合物盐酸盐β晶型的XRPD图。
图30为式II化合物盐酸盐β晶型的DSC谱图。
图31为式II化合物盐酸盐β晶型的TGA谱图。
图32为式II化合物盐酸盐β晶型的DVS吸湿谱图。
图33为式II化合物盐酸盐β晶型的DVS检测前后XRPD对比图。
图34为式II化合物盐酸盐γ晶型的XRPD图。
图35为式II化合物乙酸盐晶型的XRPD图。
图36为式II化合物乙酸盐晶型的DSC谱图。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα射线
Figure PCTCN2020125125-appb-000003
扫描方式：θ/2θ，扫描范围：10-48°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温 速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度20mL/min。
DVS为动态水分吸附：采用Surface Measurement Systems advantage 2，在25℃，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT小于0.002，TMAX小于360min，循环两圈。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
对比例1、式II化合物制备例(申请号为PCT/US19/30526的申请中实施例152,153的制备方法)
(S)-3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酰胺的制备
(R)-3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酰胺的制备
Figure PCTCN2020125125-appb-000004
第一步6-氯-2’-(二氟甲氧基)-[1,1’-二苯基]-3,4-二胺的制备
4-溴-5-氯苯-1,2-二胺(1.5g，6.78mmol)、2-(2-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(2.2g，8.15mmol)、三(二亚苄基丙酮)二钯(620mg)、三叔丁基磷四氟硼酸盐(393mg)、碳酸钠(1.7g，13.7mmol)、1,4-二氧六环(50mL)和水(10mL)混合物去氧，加热到90℃，搅拌反应3小时。反应液减压浓缩，残余物直接加载到ISCO固体柱上，用正己烷/乙酸乙酯混合溶剂洗脱，得到白色固体产物(1.0g，收率51.9％)，MS(+)ES:285(M+H)+。
第二步4-((4-氨基-6-氯-2’-(二氯甲氧基)-[1,1’二苯基]-3-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯的制备
4-((5-氨基-2-氯-2’-(二氯甲氧基)-[1,1’二苯基]-4-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯的制备
6-氯-2’-(二氟甲氧基)-[1,1’-二苯基]-3,4-二胺(543mg，1.9mmol)、2-(4-((环丙基甲基)磺酰基)苯基)-4-乙氧基-4-氧代丁酸(500mg，1.47mmol)和DMF(5mL)溶液中加入EDCl(560mg，2.93mmol)，HOBT(447mg，2.93mmol)和DIPEA(380mg，2.94mmol)，反应液室温搅拌2小时。反应液用5g硅胶吸附，加载到硅胶柱，用45％乙酸乙酯的正己烷溶液洗脱，得到4-((4-氨基-6-氯-2’-(二氯甲氧基)-[1,1’二苯基]-3-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯和4-((5-氨基-2-氯-2’-(二氯甲氧基)-[1,1’二苯基]-4-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯的混合物为白色固体(600mg，收率：62.3％)MS(ESI):607(M+H)+.
第三步3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酸乙酯的制备
4-((4-氨基-6-氯-2’-(二氯甲氧基)-[1,1’二苯基]-3-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯和4-((5-氨基-2-氯-2’-(二氯甲氧基)-[1,1’二苯基]-4-基)氨基)-3-(4-((环丙基甲基)磺酰基)苯基)-4-氧代丁酸乙酯的混合物(800mg)的乙酸(15mL)溶液加热到80℃搅拌反应2小时。反应液减压浓缩，所得残余物柱层析纯化，用60％乙酸乙酯的正己烷溶液洗脱，得到3-(6-氯-5-(2-(二氯甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酸乙酯为灰白色固体(600mg，收率：77.3％)。MS(ESI):589(M+H) +.
第四步(S)-3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酰胺的制备
(R)-3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酰胺的制备
3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酸乙酯(400mg，0.68mmol)的甲醇(5mL)溶液中加入7N氨甲醇溶液(4.8mL，33.9mmol)，反应液升温至60℃搅拌反应12小时。反应液减压浓缩，粗品产物用柱层析纯化，洗脱体系为正己烷和乙酸乙酯，得到3-(6-氯-5-(2-(二氟甲氧基)苯基)-1H-苯并[d]咪唑-2-基)-3-(4-((环丙基甲基)磺酰基)苯基)丙酰胺(177mg)。
手性拆分(分离条件：CHIRALCEL OZ-H(OZH00CD-VC005),0.46cm I.D.×15cm L；流动相：100％甲醇；流速：1.0mL/min)，收集相应组分减压浓缩，得到标题化合物(67mg，60mg)。
单一组分化合物(保留时间较短)
MS(+)ES:560(M+H) +
手性分析方法：保留时间3.919分钟，手性纯度：100％(色谱柱：OD Phenomenex Lux Cellulose-1 150*4.6mm,5μm；流动相：乙醇/正己烷＝80:20(v:v))。
1H NMR(400mHz,CD 3OD):7.92(d,8.0Hz,2H),7.51-7.49(s,1H),7.65(d,8.0Hz,2H),7.56-7.54(m,1H),7.48-7.44(m,1H),7.33-7.32(m,2H),7.28-7.26(d,8.0Hz,1H),6.86(d,8.0Hz,1H),4.96-4.92(t,8.0Hz,1H),3.41-3.35(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3.06(dd,8.0Hz,1H),0.93-0.91(m,1H),0.52-0.50(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).
单一组分化合物(保留时间较长，式II化合物)
MS(+)ES:560(M+H) +
手性分析方法：保留时间8.942分钟，手性纯度：100％(色谱柱：OD Phenomenex Lux Cellulose-1 150*4.6mm,5μm；流动相：乙醇/正己烷＝80:20(v:v))。
1H NMR(400mHz,CD3OD):7.92(d,8.0Hz,2H),7.51-7.49(s,1H),7.65(d,8.0Hz,2H),7.56-7.54(m,1H),7.48-7.44(m,1H),7.33-7.32(m,2H),7.28-7.26(d,8.0Hz,1H),6.86(d,8.0Hz,1H),4.96-4.92(t,8.0Hz,1H),3.41-3.35(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3.06(dd,8.0Hz,1H),0.93-0.91(m,1H),0.52-0.50(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).
测试实施例1.LanthaScreen TR-FRET RORγ-LBD和共激活肽的生化实验
材料和试剂
1.RORγLBD-GST tagged(Cat No.RORC-114H，Creative Biomart)
2.Fluorescein-D22coactivator，(Cat No.PV4386，Invitrogen)
3.LanthaScreen TMTb anti-GST antibody(目录号PV3550，Invitrogen)
4.TR-FRET coregulatory buffer D(Cat No，PV4420，Invitrogen)
5.DTT(Cat No.P2325，Fisher)
6. 384孔测定板(Cat No.6008280，Perkin Elmer)
7.Tecan Infinite M1000读板仪(Tecan)
实验步骤
通过向TR-FRET Coregulator Buffer D中加入1M DTT至终浓度为5mM DTT，制备Complete TR-FRET Coregulator BufferD。在Complete TR-FRET Coregulator BufferD中进行化合物稀释。最高剂量为3μM，7倍稀释，总共7个剂量。向384孔板的每个孔中加入10μL。对于阴性和阳性对照，加入10μL CompleteTR-FRET Coregulator Buffer D.
使用Complete TR-FRET Coregulator BufferD制备RORγLBD溶液。RORγLBD溶液在每个反应的最终浓度为25ng。除了添加5μL Complete TR-FRET Coregulator Buffer D的阴性孔之外，将5μL RORγLBD溶液添加到384孔测定板的所有孔中。
使用Complete TR-FRET Coregulator Buffer D制备含有0.6μM Fluorescein-D22和8nM Tbanti-GST antibody的溶液，然后向384孔测定板的所有孔中各加入5μL所制备的溶液。
将384孔板简单地轻轻混合在平板振荡器上，在室温下避光反应1小时。用塑料膜密封384孔板以使避免蒸发。
在Tecan Infinite M1000读板仪上波长为520nm和495nm读板。使用GraphPad Prism通过绘制化合物浓度的对数与抑制百分比的关系来计算IC 50值。表1中显示了化合物的IC  50值。
测试实施例2.在人外周血单核细胞中抑制IL-17A细胞因子产生的测定
实验材料及仪器
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，人IL-17酶联免疫试剂盒(R&D Systems,D1700)
6. 96孔细胞培养板(Fisher Scientific,Cat No.07-200-80)
7.Tecan SPARK读板仪(Tecan)
实验步骤
将冻存的人外周血单核细胞(PBMC)在预热的淋巴细胞培养基中快速复苏，离心1000rpm，10min，除去细胞培养上清，将细胞轻轻悬浮于TexMACS培养基中，计数细胞。在细胞悬液中按比例加入T细胞激活试剂cytostim(10μL/mL)，然后以1×10 5个外 周血单核细胞/孔的密度将细胞种植于96孔细胞培养板中。使用TexMACS培养基梯度稀释待测化合物，分别加入各实验孔中，每组2-3个平行孔。准备只含细胞不加cytostim的阴性对照孔，以得到背景读数。将细胞培养板放置于5％二氧化碳37℃培养箱孵育3天。药物处理3天后收取细胞培养上清液，离心去除悬浮物。然后使用IL-17A酶联免疫试剂盒定量上清液中IL-17A。使用GraphPad Prism 6.0的log(inhibitor)vs.response--Variable slope(four parameters)算法来计算化合物抑制率的IC 50值。抑制率计算式如下:
Figure PCTCN2020125125-appb-000005
计算式中，Inhibition％为抑制率；OD(NC)为细胞不加cytostim和不加化合物的阴性对照的读数；OD(PC)为细胞加cytostim但不加化合物的阳性对照的读数；OD(compound)为细胞加cytostim和加化合物的读数。
表1.式II化合物对RORγ的结合和在人外周血单核细胞中IL-17产生
Figure PCTCN2020125125-appb-000006
实施例1、式II化合物无定型物的制备
将式II化合物(30mg，53.57μmol)加入到异丙醚(1.5mL)中，加热到70℃，为不澄清白色混悬液，缓慢降至室温，搅拌16小时，过滤，收集滤饼，真空干燥，得到产物(20mg，收率：66％)。将该产物为无定型物，XRPD谱图如图1所示。
实施例2、式II化合物无定型物的制备
将式II化合物(30mg，53.57μmol)加入到甲苯(1.5mL)中，加热到70℃，搅拌溶清，缓慢降至室温，壁上析出固体，室温搅拌16小时，过滤，收集滤饼，真空干燥，得到产物(20mg，收率：66％)。经X-射线粉末衍射检测，该产物为无定型物。
实施例3、式II化合物无定型物的制备
将式II化合物(30mg，53.57μmol)加入到1.5mL乙酸异丙酯和正己烷(V:V＝1:3)混合溶液中，加热到70℃，有粘状固体，缓慢降至室温，析出固体，室温搅拌16小时，过滤，收集滤饼，真空干燥，得到产物(20mg，收率：66％)。经X-射线粉末衍射检测，该产物为无定型物。
实施例4、式II化合物无定型物的制备
将式II化合物(5g，8.93mmol)高效液相色谱法(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到产物(2.5g，收率：50％)。经X-射线粉末衍射检测，该产物为无定型物。
实施例5、式II化合物无定型物影响因素实验
将式II化合物的无定型物(实施例4)样品敞口平摊放置，考察在加热(40℃、60℃)、光照(4500Lux)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
实验结果：
表2.影响因素实验结果
Figure PCTCN2020125125-appb-000007
实验结论：
由表2的影响因素实验结果表明：在光照、高温40℃、高温60℃、高湿75％、高湿90％条件下，放置30天，式II化合物的无定型物的化学稳定性较好。
实施例6、式II化合物无定型物样品长期加速稳定性实验
将式II化合物的无定型物(实施例4)进行3个月的长期(25℃、60％RH)、加速(40℃、 75％RH)稳定性考察。
实验结果
表3.式II化合物无定型物长期加速稳定性实验结果：
Figure PCTCN2020125125-appb-000008
由表3的长期加速稳定性实验结果显示：式II化合物的无定型物长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置3个月的化学稳定性好。
实施例7、式II化合物苯甲酸盐无定型物的制备
称量10mg式II化合物，加入0.5ml正己烷，加入2.3mg苯甲酸，放于50℃条件下搅拌过夜，抽滤，在40℃烘干1h，得到产物。经X-射线粉末衍射检测，将该产物定义为式II化合物苯甲酸盐无定型物，XRPD谱图如图2所示。
实施例8、式II化合物苯甲酸盐晶型的制备
称量10mg式II化合物，加入0.5ml甲基叔丁基醚，加入2.3mg苯甲酸，放于50℃条件下搅拌过夜，抽滤，在40℃烘干1h，得到产物。经X-射线粉末衍射检测，将该产物定义为式II化合物苯甲酸盐晶型，XRPD谱图如图3所示。DSC谱图如图4所示，第一吸热峰峰值178.46℃，第二吸热峰峰值237.42℃。
表4.式II化合物苯甲酸盐晶型的特征峰
序号 2-Theta d(A) I％
峰1 5.305 16.64444 100.0
峰2 7.411 11.91828 43.6
峰3 19.140 4.63321 1.3
峰4 22.031 4.03134 23.9
实施例9、式II化合物草酸盐无定型物的制备
称量10mg式II化合物，加入0.5ml甲基叔丁基醚，加入2mg草酸，放于50℃条件下搅拌过夜，抽滤，样品在40℃烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物草酸盐无定型物，XRPD谱图如图5所示。
实施例10、式II化合物草酸盐晶型的制备
称量10mg式II化合物，加入0.5ml正己烷，加入2mg草酸，放于50℃条件下搅拌过夜，抽滤，样品在40℃烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物草酸盐晶型，XRPD谱图如图6所示。
表5.式II化合物草酸盐晶型的特征峰
序号 2-Theta d(A) I％
峰1 14.378 6.15525 100.0
峰2 18.463 4.80158 51.5
峰3 21.670 4.09779 70.9
峰4 23.075 3.85126 50.6
峰5 28.127 3.17003 21.6
实施例11、式II化合物甲磺酸盐无定型物的制备
称量10mg式II化合物，加入0.5ml甲基叔丁基醚，加入1.8μl甲磺酸，放于50℃条件下搅拌过夜，抽滤，40℃烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物甲磺酸盐无定型物，XRPD谱图如图7所示。
实施例12、式II化合物马来酸盐B晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下30min，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物马来酸盐B晶型，XRPD谱图如图8所示。DSC谱图如图9所示，第一吸热峰峰值138.04℃；TGA谱图如图10所示。
DVS表征：马来酸盐B晶型样品在25℃的条件下，在20.0％RH-80.0％RH之间，随着湿度的增加吸水量也在增加，重量变化为1.731％，引湿增重小于2％但不小于0.2％，该样品略有引湿性。在正常储存条件(即25℃湿度60％)，吸水约为1.438％；在加速试验条件(即湿度70％)，吸水约为1.809％；在极端条件(即湿度90％)，吸水约为3.077％。
DVS前后X-射线粉末衍射对比图显示DVS前后晶型未发生转变。DVS谱图如图11所示，DVS检测前后X-射线粉末衍射对比谱图如图12所示。
表6.式II化合物马来酸盐B晶型的特征峰
序号 2-Theta d(A) I％
峰1 7.624 11.58707 74.9
峰2 9.659 9.14922 40.7
峰3 13.815 6.40503 41.2
峰4 15.844 5.58882 56.9
峰5 17.391 5.09522 100.0
峰6 18.619 4.76186 31.5
峰7 21.802 4.07319 76.4
峰8 23.667 3.75633 49.8
峰9 26.441 3.36816 13.2
实施例13、式II化合物马来酸盐B晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下10min，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物马来酸盐B晶型。
实施例14、式II化合物马来酸盐B晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下20min，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物马来酸盐B晶型。
实施例15、式II化合物马来酸盐B晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下1h，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物马来酸盐B晶型。
实施例16、式II化合物马来酸盐B晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下2h，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物马来酸盐B晶型。
实施例17、式II化合物马来酸盐C晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下1d，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物马来酸盐C晶型，XRPD谱图如图13所示。DSC谱图如图14所示，第一吸热峰峰值154.58℃；TGA谱图如图15所示。
表7.式II化合物马来酸盐C晶型的特征峰
序号 2-Theta d(A) I％
峰1 7.325 12.05902 24.9
峰2 8.635 10.23231 46.0
峰3 9.809 9.00970 38.0
峰4 11.661 7.58265 14.6
峰5 13.649 6.48261 27.1
峰6 16.133 5.48950 23.5
峰7 16.765 5.28383 27.8
峰8 18.346 4.83192 100.0
峰9 21.689 4.09421 37.3
峰10 23.586 3.76901 31.9
峰11 25.303 3.51708 15.5
实施例18、式II化合物马来酸盐D晶型的制备
称量100mg式II化合物与22mg马来酸，加入5ml甲基叔丁基醚，在50℃条件下，600rpm搅拌下3d，溶液呈悬浮状，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物马来酸盐D晶型，XRPD谱图如图16所示。DSC谱图如图17所示，第一吸热峰峰值159.27℃；TGA谱图如图18所示。
表8.式II化合物马来酸盐D晶型的特征峰
序号 2-Theta d(A) I％
峰1 4.486 19.68368 65.1
峰2 5.998 14.72391 35.9
峰3 7.288 12.12061 48.6
峰4 9.067 9.74591 49.9
峰5 10.001 8.83770 50.9
峰6 13.914 6.35938 59.0
峰7 15.026 5.89121 34.9
峰8 16.227 5.45786 27.0
峰9 18.229 4.86287 100.0
峰10 18.940 4.68174 84.8
峰11 23.076 3.85108 58.0
峰12 25.612 3.47535 60.6
峰13 28.102 3.17274 12.9
实施例19：式II化合物氢溴酸盐I晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚、20μl氢溴酸，放置25℃条件下600rpm搅拌3天，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物氢溴酸盐I晶型，XRPD谱图如图19所示。DSC谱图如图20所示，第一吸热峰峰值201.73℃；TGA谱图如图21所示。
DVS表征：氢溴酸盐I晶型样品在25℃的条件下，在20.0％RH-80.0％RH之间，随着湿度的增加吸水量也在增加，重量变化为0.636％，引湿增重小于2％但不小于0.2％，该样品略有引湿性。在正常储存条件(即25℃湿度60％)，吸水约为0.589％；在加速试验条件(即湿度70％)，吸水约为0.702％；在极端条件(即湿度90％)，吸水约为1.094％。
在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合；DVS前后X-射线粉末衍射对比图显示DVS前后晶型未发生转变。DVS谱图如图22所示，DVS检测前后X-射线粉末衍射对比谱图如图23所示。
表9.式II化合物氢溴酸盐I晶型的特征峰
序号 2-Theta d(A) I％
峰1 8.128 10.86905 68.5
峰2 11.918 7.41964 7.5
峰3 12.579 7.03116 19.0
峰4 16.414 5.39626 54.1
峰5 17.075 5.18879 15.6
峰6 17.780 4.98456 39.3
峰7 18.750 4.72892 7.8
峰8 19.675 4.50851 9.9
峰9 20.733 4.28082 27.1
峰10 21.262 4.17552 100.0
峰11 23.113 3.84512 36.8
峰12 23.906 3.71929 15.0
峰13 24.391 3.64645 67.5
峰14 26.550 3.35455 14.5
峰15 28.445 3.13522 29.4
峰16 28.930 3.08378 26.0
峰17 29.547 3.02077 55.8
峰18 30.958 2.88630 27.7
峰19 32.236 2.77471 19.3
峰20 33.382 2.68204 1.4
峰21 38.670 2.32653 2.4
峰22 39.640 2.27183 3.3
峰23 40.830 2.20832 12.6
峰24 42.064 2.14635 5.4
峰25 43.342 2.08597 5.2
峰26 46.824 1.93865 4.0
峰27 48.190 1.88683 6.2
峰28 48.983 1.85811 4.1
峰29 50.746 1.79762 9.3
实施例20：式II化合物氢溴酸盐I晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚，500μl氢溴酸与乙醇混合溶液(体积比1:50)，放置25℃条件下600rpm搅拌3天，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物氢溴酸盐I晶型。
实施例21：式II化合物氢溴酸盐I晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚，40μl氢溴酸与乙醇混合溶液(体积比1:1)，放置25℃条件下600rpm搅拌3天，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物氢溴酸盐I晶型。
实施例22、式II化合物氢溴酸盐I晶型的制备
称量100mg式II化合物，加入15ml甲基叔丁基醚，1000μl氢溴酸与乙醇混合溶液(体积比1:99)，放置25℃条件下600rpm搅拌过夜，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物氢溴酸盐I晶型。
实施例23、式II化合物氢溴酸盐I晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚，1000μl氢溴酸与乙醇混合溶液(体积比1:99)，放置25℃条件下600rpm搅拌过夜，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物为式II化合物氢溴酸盐I晶型。
实施例24、式II化合物盐酸盐α晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚与15.6μl浓盐酸，50℃条件搅拌2d，40℃烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物盐酸盐α晶型，XRPD谱图如图24所示。DSC谱图如图25所示，第一吸热峰峰值192.13℃；TGA谱图如图26所示。
DVS表征：样品在25℃的条件下，在20.0％RH-80.0％RH之间，随着湿度的增加吸水量也在增加，重量变化为0.549％，引湿增重小于2％但不小于0.2％，该样品略有引湿性。在正常储存条件(即25℃湿度60％)，吸水约为0.463％；在加速试验条件(即湿度70％)，吸水约为0.574％；在极端条件(即湿度90％)，吸水约为1.040％。
在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合；DVS前后X-射线粉末衍射对比图显示DVS前后晶型未发生转变。DVS谱图如图27所示，DVS检测前后X-射线粉末衍射对比谱图如图28所示。
表10.式II化合物盐酸盐α晶型的特征峰
序号 2-Theta d(A) I％
峰1 7.931 11.13829 53.4
峰2 10.115 8.73832 19.9
峰3 12.166 7.26910 15.4
峰4 13.920 6.35673 24.2
峰5 15.224 5.81523 33.9
峰6 16.041 5.52078 13.9
峰7 16.315 5.42854 12.6
峰8 16.748 5.28930 12.2
峰9 17.425 5.08526 21.3
峰10 18.309 4.84177 64.7
峰11 19.624 4.52003 15.9
峰12 20.235 4.38496 19.6
峰13 21.491 4.13138 36.6
峰14 22.340 3.97642 67.3
峰15 23.359 3.80507 65.0
峰16 23.905 3.71950 48.0
峰17 24.570 3.62032 100.0
峰18 25.320 3.51464 20.1
峰19 25.811 3.44896 13.9
峰20 26.096 3.41194 10.5
峰21 27.624 3.22652 24.8
峰22 28.213 3.16057 24.6
峰23 29.190 3.05697 5.1
峰24 29.760 2.99971 2.4
峰25 31.266 2.85855 10.1
峰26 31.795 2.81217 5.5
峰27 32.324 2.76732 8.1
峰28 35.906 2.49902 3.7
峰29 37.291 2.40939 8.3
实施例25、式II化合物盐酸盐β晶型的制备
称量100mg式II化合物，加入5ml甲基叔丁基醚与0.6ml乙醇盐酸溶液(0.1ml浓盐酸，加入9.9ml乙醇，摇匀)，25℃搅拌1h，在50℃条件搅拌2d，抽滤，40℃烘干2h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物盐酸盐β晶型，XRPD谱图如图29所示。DSC谱图如图30所示，第一吸热峰峰值194.04℃；TGA谱图如图31所示。
DVS表征：样品在25℃的条件下，在20.0％RH-80.0％RH之间，随着湿度的增加吸水量也在增加，重量变化为1.235％，引湿增重小于2％但不小于0.2％，该样品略有引湿性。在正常储存条件(即25℃湿度60％)，吸水约为1.755％；在加速试验条件(即湿度70％)，吸水约为1.954％；在极端条件(即湿度90％)，吸水约为2.534％。
在0％-95％的湿度变化过程中，该样品的单次解吸附过程与吸附过程基本重合，第一次与第二次循环解吸附过程与吸附过程不能重合；DVS前后X-射线粉末衍射对比图显示DVS前后晶型发生转变。DVS谱图如图32所示，DVS检测前后X-射线粉末衍射对比谱图如图33所示。
表11.式II化合物盐酸盐β晶型的特征峰
序号 2-Theta d(A) I％
峰1 5.386 16.39621 39.0
峰2 8.191 10.78576 77.6
峰3 10.818 8.17156 29.1
峰4 12.688 6.97098 42.8
峰5 13.980 6.32982 20.9
峰6 14.915 5.93499 26.6
峰7 16.607 5.33388 19.7
峰8 18.076 4.90345 12.8
峰9 19.056 4.65352 12.9
峰10 20.036 4.42814 20.8
峰11 21.372 4.15427 100.0
峰12 22.040 4.02986 35.2
峰13 23.465 3.78826 25.0
峰14 24.355 3.65171 28.5
峰15 25.869 3.44132 36.7
峰16 26.582 3.35068 21.8
峰17 27.383 3.25440 12.0
峰18 29.253 3.05045 29.5
峰19 29.832 2.99256 39.9
峰20 30.946 2.88740 22.9
峰21 31.480 2.83959 41.4
峰22 32.504 2.75242 7.6
峰23 33.439 2.67755 8.5
实施例26、式II化合物盐酸盐γ晶型的制备
少量式II化合物盐酸盐β晶型放置于DVS仪器中，按照DVS参数dm/dt＝0.002，50-95-0-95-50％，Max360min，25℃，最终样品经X-射线粉末衍射检测，该产物定义为式II化合物盐酸盐γ晶型，XRPD谱图如图34所示。
表12.式II化合物盐酸盐γ晶型的特征峰
序号 2-Theta d(A) I％
峰1 8.114 10.88737 89.0
峰2 11.997 7.37097 42.5
峰3 12.640 6.99748 77.7
峰4 13.772 6.42501 45.7
峰5 16.478 5.37549 25.8
峰6 17.897 4.95221 45.6
峰7 19.671 4.50933 9.7
峰8 20.337 4.36327 52.8
峰9 21.422 4.14464 79.1
峰10 22.156 4.00903 62.3
峰11 23.228 3.82632 79.1
峰12 24.472 3.63450 100.0
峰13 25.882 3.43968 26.9
峰14 27.567 3.23307 27.4
峰15 28.277 3.15351 14.1
峰16 29.830 2.99281 38.1
峰17 31.160 2.86797 15.9
峰18 32.269 2.77189 17.0
峰19 33.334 2.68576 13.6
实施例27、式II化合物乙酸盐晶型的制备
称量20mg式II化合物，加入1ml水，加入摩尔比1:1乙醇酸溶液(精密移取0.1ml醋酸，加入9.9ml乙醇，摇匀)，放于50℃条件下搅拌过夜，抽滤，40℃条件下烘干1h，得到产物。经X-射线粉末衍射检测，该产物定义为式II化合物乙酸盐晶型，XRPD谱图如图35所示。DSC谱图如图36所示，第一吸热峰峰值206.96℃，第一放热峰峰值213.49℃，第二吸热峰峰值246.30℃。
表13.式II化合物乙酸盐晶型的特征峰
序号 2-Theta d(A) I％
峰1 11.651 7.58948 96.9
峰2 12.495 7.07863 38.2
峰3 14.323 6.17872 29.8
峰4 15.121 5.85472 28.9
峰5 15.636 5.66274 100.0
峰6 15.965 5.54704 66.5
峰7 18.075 4.90394 58.9
峰8 19.247 4.60782 20.4
峰9 19.903 4.45730 25.1
峰10 20.935 4.23993 38.5
峰11 22.107 4.01768 29.1
峰12 22.998 3.86402 47.4
峰13 23.842 3.72910 52.3
峰14 24.733 3.59676 59.9
峰15 25.530 3.48623 35.2
峰16 26.843 3.31862 11.7
峰17 28.719 3.10600 12.9
峰18 29.750 3.00061 6.1
峰19 30.829 2.89805 18.2
峰20 32.142 2.78260 14.6
峰21 35.143 2.55155 3.6
峰22 39.973 2.25369 2.6
实施例28、式II化合物盐酸盐α晶型、氢溴酸盐I晶型影响因素稳定性研究
式II化合物盐酸盐α晶型、氢溴酸盐I晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表14.影响因素稳定性数据
Figure PCTCN2020125125-appb-000009
Figure PCTCN2020125125-appb-000010
结论：影响因素实验表明：在光照、高温40℃和60℃、高湿75％和92.5％条件下，式II化合物盐酸盐α晶型、氢溴酸盐I晶型具有较好的物理、化学稳定性。
实施例29、式II化合物盐酸盐α晶型、氢溴酸盐I晶型长期/加速稳定性研究
将式II化合物盐酸盐α晶型，分别放置25℃、60％RH和40℃、75％RH条件考察其 稳定性。
表15.式II化合物盐酸盐α晶型长期/加速稳定性数据
Figure PCTCN2020125125-appb-000011
长期/加速稳定性实验显示：式II化合物盐酸盐α晶型长期加速稳定性条件下放置6个月的物理、化学稳定性好。
将式II化合物氢溴酸盐I晶型，分别放置25℃、60％RH和40℃、75％RH条件考察其稳定性。
表16.式II化合物氢溴酸盐I晶型长期/加速稳定性数据
Figure PCTCN2020125125-appb-000012
长期/加速稳定性实验显示：式II化合物氢溴酸盐I晶型长期加速稳定性条件下放置6个月的物理、化学稳定性好。

Claims (27)

  1. 式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述酸加成盐为有机酸加成盐或无机酸加成盐，
    Figure PCTCN2020125125-appb-100001
  2. 根据权利要求1所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述有机酸加成盐选自苯甲酸盐、草酸盐、甲磺酸盐、马来酸盐或乙酸盐，所述无机酸加成盐选自氢溴酸盐或盐酸盐。
  3. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，其中所述苯甲酸盐、草酸盐、甲磺酸盐为无定型物。
  4. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述苯甲酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为5.305、7.411处有特征峰。
  5. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述草酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为14.378、18.463、21.670处有特征峰。
  6. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述马来酸盐为B晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.624、9.659、13.815、15.844、17.391处有特征峰。
  7. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述马来酸盐为C晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.325、8.635、9.809、13.649、16.133、16.765、18.346处有特征峰。
  8. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述马来酸盐为D晶型，其X-射线粉末衍射图谱，在衍射角2θ为4.486、7.288、9.067、10.001、13.914、18.229、18.940处有特征峰。
  9. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述氢溴酸盐为I晶型，其X-射线粉末衍射图谱，在衍射角2θ为8.128、12.579、16.414、17.075、17.780、20.733处有特征峰。
  10. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述氢溴酸盐为I晶型，其X-射线粉末衍射图谱，在衍射角2θ为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、29.547处有特征峰。
  11. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述氢溴酸盐为I晶型，其X-射线粉末衍射图谱，在衍射角2θ为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、50.746处有特征峰。
  12. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述盐酸盐为α晶型，其X-射线粉末衍射图谱，在衍射角2θ为7.931、10.115、13.920、15.224、17.425、18.309处有特征峰。
  13. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述盐酸盐为β晶型，其X-射线粉末衍射图谱，在衍射角2θ为5.386、8.191、12.688、16.607、20.036处有特征峰。
  14. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述盐酸盐为γ晶型，其X-射线粉末衍射图谱，在衍射角2θ为8.114、11.997、12.640、13.772、16.478、17.897、20.337处有特征峰。
  15. 根据权利要求2所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，所述乙酸盐为晶型，其X-射线粉末衍射图谱，在衍射角2θ为11.651、12.495、15.636、15.965、18.075、20.935处有特征峰。
  16. 如权利要求4-15任一项所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，其中晶型的2θ值误差范围为±0.2。
  17. 一种如权利要求9-11任一项所述的式II化合物的氢溴酸盐I晶型的制备方法，其包括式II化合物在适量溶剂中与氢溴酸反应，析出晶体的步骤，所述溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水或二甲基亚砜的一种或者多种，
    所述烃类溶剂包括但不限于正丁烷、正戊烷、正己烷或正庚烷；
    所述醚类溶剂包括但不限于四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；
    所述醇类溶剂包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；
    所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；
    所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮；
    所述腈类溶剂包括但不限于乙腈或丙腈；
    所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、氯仿或四氯化碳；
    所述含氮溶剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
  18. 根据权利要求17所述的制备方法，所述溶剂为甲基叔丁基醚和乙醇。
  19. 一种药物组合物，其含有权利要求1-16任一项所述的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 一种药物组合物，其含有式II化合物的无定型物，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂，
    Figure PCTCN2020125125-appb-100002
  21. 一种药物组合物，其含有权利要求9-11任一项所述的氢溴酸盐I晶型，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
  22. 一种药物组合物，其是由权利要求1-16任一项所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，与一种或多种药学上可接受的载体、稀释剂或赋形剂制备得到的。
  23. 一种药物组合物，其是由式II化合物的无定型物与一种或多种药学上可接受的载体、稀释剂或赋形剂制备得到的，
    Figure PCTCN2020125125-appb-100003
  24. 一种药物组合物，其是由权利要求9-11任一项所述的氢溴酸盐I晶型与一种或多种药学上可接受的载体、稀释剂或赋形剂制备得到的。
  25. 一种制备药物组合物的方法，包括使权利要求1-16任一项所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物，与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
  26. 一种制备药物组合物的方法，其包括使式II化合物的无定型物与至少一种药学上可接受的载体、稀释剂或赋形剂混合，
    Figure PCTCN2020125125-appb-100004
  27. 一种如权利要求1-16任一项所述的式II化合物的酸加成盐或者酸加成盐的药学上可接受的溶剂化物或如权利要求19-24任一项所述的药物组合物在制备用于治疗RORγ介导的疾病或病症的药物中的用途。
PCT/CN2020/125125 2019-10-31 2020-10-30 一种RORγ调节剂的酸加成盐 WO2021083311A1 (zh)

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