HK1245775B - Salts as hepatitis c virus inhibitors - Google Patents

Description

Salts as hepatitis C virus inhibitors

Technical Field

The present invention belongs to the field of medicine and relates to base addition salts and acid addition salts of a compound represented by formula (I) and pharmaceutical compositions thereof, and further relates to uses of the compound and the pharmaceutical composition in preparing medicines, in particular, uses in preparing medicines for preventing, treating, curing or alleviating hepatitis C virus (HCV) infection.

Background Art

HCV is a major human pathogen, infecting an estimated 170 million people worldwide—five times the number infected by human immunodeficiency virus type 1. Most individuals infected with HCV develop severe, progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection is the leading cause of premature death from liver disease worldwide.

HCV is a positive-strand RNA virus. Based on comparisons of deduced amino acid sequences and extensive similarity in the 5' untranslated region, HCV is classified as a separate genus within the Flaviviridae family. All members of the Flaviviridae family are enveloped virions containing a positive-strand RNA genome that encodes all known virus-specific proteins through translation of a single, uninterrupted open reading frame (ORF).

There is considerable heterogeneity in the nucleotides and the amino acid sequence encoded of the whole HCV genome. At least 7 major genotypes have been identified, and more than 50 subtypes have been disclosed. In cells infected by HCV, viral RNA is translated into polyproteins and split into 10 kinds of individual proteins. At the amino terminal, it is a structural protein, followed by E1 and E2. In addition, there are also 6 kinds of non-structural proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a very important role in the HCV life cycle (see, for example, Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).

The major HCV genotypes have different distributions around the world. Although a large number of studies have been conducted on the effects of genotypes on pathogenesis and treatment, the clinical significance of HCV genetic heterogeneity remains unclear.

The single-stranded HCV RNA genome is approximately 9,500 nucleotides long, with a single open reading frame, encoding a single, large polyprotein of approximately 3,000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases, producing structural and nonstructural (NS) proteins. In the case of HCV, the formation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is achieved by two viral proteases. The first is generally believed to be a metalloprotease that cleaves at the NS2-NS3 junction; the second is a serine protease contained in the N-terminal region of NS3 (also referred to herein as NS3 protease), which mediates all subsequent cleavages downstream of NS3, acting in cis at the NS3-NS4A cleavage site and in trans at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The formation of the NS3 protein complex with NS4A appears to be a processing event that is necessary to increase the efficiency of proteolysis at all sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.

Currently, the most effective HCV treatment is a combination of α-interferon and ribavirin, which produces sustained efficacy in 40% of patients. Recent clinical results demonstrate that pegylated α-interferon is superior to unmodified α-interferon as a monotherapy. However, even with experimental treatment regimens combining pegylated α-interferon and ribavirin, most patients are unable to achieve sustained reductions in viral load, and many patients often experience side effects that prevent them from continuing treatment. Therefore, new and effective treatments for HCV infection are urgently needed.

Patent application number CN 201610072777.8 records many HCV inhibitor compounds, among which the compound represented by formula (I) has good inhibitory activity against HCV NS3/4A protein, but its exposure amount is not ideal.

Summary of the Invention

Different salts and solid forms of pharmaceutical active ingredients may have different properties. Variations in the properties of different salts and solid forms can provide improved formulations. Therefore, in order to find a solid form with improved drugability, the inventors, through extensive experimental research, unexpectedly obtained pharmaceutically acceptable base addition salts and acid addition salts of the compound represented by formula (I), and pharmaceutical compositions thereof, which have good biological activity and significantly improved pharmacokinetic properties of the compound represented by formula (I), resulting in better drugability.

The purpose of the present invention is to provide a class of salts having HCV viral proteins, such as NS3 protease inhibitory activity, and the salts can be used to prepare drugs for treating or alleviating HCV infection and related diseases.

The present invention relates to base addition salts and acid addition salts of a compound represented by formula (I) and pharmaceutical compositions thereof, and further relates to the use of the compound or pharmaceutical composition in preparing a medicament, particularly in preparing a medicament for preventing, treating, curing, or alleviating hepatitis C virus (HCV) infection. The base addition salt or acid addition salt of the compound represented by formula (I) of the present invention includes a hydrate or solvate form.

In one aspect, the present invention relates to a pharmaceutically acceptable base addition salt of a compound represented by formula (I):

In some embodiments, the base addition salt of the present invention is at least one selected from lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, iron salts, zinc salts, and ammonium salts; or the salt is at least one selected from the group consisting of salts of the compound represented by formula (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol, pyridine, picoline, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole, lysine, arginine, L-arginine, histidine, N-methylglucamine, dimethylglucamine, ethylglucamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, aminopropylene glycol, 1-amino-2,3,4-butanetriol, L-lysine, and ornithine.

In some embodiments, the base addition salt of the present invention is an amorphous N-methylglucamine salt, wherein the amorphous N-methylglucamine salt has an X-ray powder diffraction pattern substantially as shown in FIG1 .

In some embodiments, the base addition salt of the present invention is an amorphous L-arginine salt, wherein the amorphous L-arginine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .

In some embodiments, the base addition salt of the present invention is an amorphous L-lysine salt, wherein the amorphous L-lysine salt has an X-ray powder diffraction pattern substantially as shown in FIG3 .

In some embodiments, the base addition salt of the present invention is an amorphous sodium salt, wherein the amorphous sodium salt has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .

In some embodiments, the base addition salt of the present invention is an amorphous calcium salt, wherein the amorphous calcium salt has an X-ray powder diffraction pattern substantially as shown in FIG5 .

In some embodiments, the base addition salt of the present invention is an amorphous potassium salt, wherein the amorphous potassium salt has an X-ray powder diffraction pattern substantially as shown in FIG6 .

In some embodiments, the base addition salt of the present invention is an amorphous lithium salt, wherein the amorphous lithium salt has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .

In some embodiments, the base addition salt of the present invention is an amorphous diethylamine salt, wherein the amorphous diethylamine salt has an X-ray powder diffraction pattern substantially as shown in FIG8 .

In some embodiments, the base addition salt of the present invention is an amorphous tromethamine salt, wherein the amorphous tromethamine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

In some embodiments, the base addition salt of the present invention is amorphous diethylaminoethanol salt, wherein the amorphous diethylaminoethanol salt has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .

In some embodiments, the base addition salt of the present invention is an amorphous piperazine salt, wherein the amorphous piperazine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .

In some embodiments, the base addition salt of the present invention is an amorphous magnesium salt, wherein the amorphous magnesium salt has an X-ray powder diffraction pattern substantially as shown in FIG12 .

In some embodiments, the base addition salt of the present invention is an amorphous dimethylethanolamine salt, wherein the amorphous dimethylethanolamine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .

In some embodiments, the base addition salt of the present invention is an amorphous ethylenediamine salt, wherein the amorphous ethylenediamine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .

In some embodiments, the base addition salt of the present invention is an amorphous triethanolamine salt, wherein the amorphous triethanolamine salt has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

In some embodiments, the base addition salt of the present invention is an amorphous ethanolamine salt, wherein the amorphous ethanolamine salt has an X-ray powder diffraction pattern substantially as shown in FIG16 .

In some embodiments, the base addition salt of the present invention is an amorphous imidazole salt, wherein the amorphous imidazole salt has an X-ray powder diffraction pattern substantially as shown in FIG. 17 .

In another aspect, the present invention relates to a pharmaceutically acceptable acid addition salt of a compound represented by formula (I):

In some embodiments, the acid addition salt of the present invention is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from at least one of hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate and metaphosphate; the organic acid salt is selected from at least one of formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, 1, 2-Ethanedisulfonate, β-Naphthalenesulfonate, Malate, Propiate, 2-Butynoate, 2-Hydroxy-ethanesulfonate, Vinylacetate, Tartrate, L-Tartrate, Fumarate, Isethionate, Maleate, Lactate, Lactobionate, Pamoate, Salicylate, Galactarate, Gluceptate, Mandelate, 1,2-Ethanedisulfonate, Oxalate, Trifluoroacetate, Trifluoromethanesulfonate, Adipate, Suberate, Sebacate, Butyne-1,4-dioate, Hexyne-1,6-dioate, Hydroxyacetate, Alginate, Ascorbate, Erysoascorbate, Aspartate, L-Aspartate, Glutamate, L-Glutamate, 2-Phenoxyethanol benzoate, 2-(4-hydroxybenzoyl)benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, L-camphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, lactobionate, galactobionate, cyclopentylpropionate, dodecyl sulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, pivalate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, At least one of pectinate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salts, alginate, 4-acetamidobenzenesulfonate, decanoate, cholate, octanoate, nonanoate, cyclamate, phthalate, cysteine hydrochloride, sorbate, glycine hydrochloride, 1,5-naphthalenedisulfonate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyethylenesulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyethylenesulfate, naphthalene-1-sulfonate, and valerate.

In some embodiments, the acid addition salt of the present invention is an amorphous citrate, wherein the amorphous citrate has an X-ray powder diffraction pattern substantially as shown in FIG18 .

In some embodiments, the acid addition salt of the present invention is an amorphous p-toluenesulfonate salt, wherein the amorphous p-toluenesulfonate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .

In some embodiments, the acid addition salt of the present invention is an amorphous benzenesulfonate salt, wherein the amorphous benzenesulfonate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 20 .

In some embodiments, the acid addition salt of the present invention is an amorphous methanesulfonate, wherein the amorphous methanesulfonate has an X-ray powder diffraction pattern substantially as shown in FIG. 21 .

In some embodiments, the acid addition salt of the present invention is an amorphous sulfate salt, wherein the amorphous sulfate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 22 .

In some embodiments, the acid addition salt of the present invention is an amorphous phosphate salt, wherein the amorphous phosphate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 23 .

In some embodiments, the acid addition salt of the present invention is an amorphous nitrate, wherein the amorphous nitrate has an X-ray powder diffraction pattern substantially as shown in FIG. 24 .

In some embodiments, the acid addition salt of the present invention is amorphous 1,5-naphthalene disulfonate, wherein the amorphous 1,5-naphthalene disulfonate has an X-ray powder diffraction pattern substantially as shown in FIG. 25 .

In some embodiments, the acid addition salt of the present invention is an amorphous 1,2-ethanedisulfonate salt, wherein the amorphous 1,2-ethanedisulfonate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 26 .

In some embodiments, the acid addition salt of the present invention is an amorphous β-naphthalenesulfonate salt, wherein the amorphous β-naphthalenesulfonate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 27 .

In some embodiments, the acid addition salt of the present invention is an amorphous cyclaxate salt, wherein the amorphous cyclaxate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 28 .

In some embodiments, the acid addition salt of the present invention is an amorphous isethionate salt, wherein the amorphous isethionate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 29 .

In some embodiments, the acid addition salt of the present invention is an amorphous maleate salt, wherein the amorphous maleate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 30 .

In some embodiments, the acid addition salt of the present invention is an amorphous hydrobromide salt, wherein the amorphous hydrobromide salt has an X-ray powder diffraction pattern substantially as shown in FIG. 31 .

In some embodiments, the acid addition salt of the present invention is an amorphous hydrochloride salt, wherein the amorphous hydrochloride salt has an X-ray powder diffraction pattern substantially as shown in FIG. 32 .

In another aspect, the present invention relates to a pharmaceutical composition comprising an acid addition salt of a compound represented by formula (I) or a base addition salt of a compound represented by formula (I) according to the present invention. Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HCV drugs; wherein the other anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the generation of type 1 helper T cell responses, interfering RNA for silencing or downregulating the HCV positive-strand RNA genome, antisense RNA for silencing or downregulating the HCV positive-strand RNA genome, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, ritonavir, Bavituximab, Civacir ^™ , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172), sovaprevir (ACH-1625), samatasvir r(IDX-719), veruprevir(ABT-450), erlotinib, simeprevir(TMC-435), asunaprevir(BMS-650032), vaniprevir(MK-7009), faldaprevir(BI-2013335), VX-135, CIGB-230, furaprevir(TG-2 349), pibrentasvir(ABT-530), glecaprevir(ABT-493), uprifosbuvir(IDX-21437), radalbuvir( GS-9669), JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride(PPI-668), velpatasvir(GS-5816), MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin(EP-013420), VBY-376, TMC-649128, mericitabine(R-7128), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371), VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof; wherein the interferon is one of interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus α-interferon, and interferon γ or a combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one HCV inhibitor, wherein the HCV inhibitor is used to inhibit the HCV replication process and/or inhibit the function of HCV viral protein; wherein the HCV replication process is selected from at least one of the processes of HCV entry, uncoating, translation, replication, assembly and release; and the HCV viral protein is selected from at least one of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B and the internal ribosome entry site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

On the other hand, the present invention relates to the use of an acid addition salt or a base addition salt of a compound represented by formula (I) or a pharmaceutical composition thereof in the preparation of a drug, wherein the drug is used to inhibit HCV replication and/or inhibit the function of HCV viral proteins, wherein the HCV replication process is selected from at least one of the processes of HCV entry, uncoating, translation, replication, assembly and release; and the HCV viral proteins are selected from at least one of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B and an internal ribosome entry site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

On the other hand, the present invention relates to the use of an acid addition salt or a base addition salt of a compound represented by formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating, curing or alleviating HCV infection or hepatitis C disease in a patient.

Definition of terms

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications to which this invention pertains are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

As used herein, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, and the like.

The term "pharmaceutically acceptable" as used herein refers to substances that are acceptable for pharmaceutical use from a toxicological point of view and do not adversely interact with the active ingredient.

"Pharmaceutically acceptable salts" means salts that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and have a reasonable benefit/risk ratio. They are well known in the art, such as the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66: 1-19, which is incorporated herein by reference.

As used herein, the term "about" has its conventional meaning. In some embodiments, when associated with a numerical value, it can be understood to mean ±10%, or ±5%, or ±2%, or ±1%, or ±0.5%, or ±0.1% of the numerical value. In other embodiments, the word "about" is omitted to indicate an exact value.

The "pharmaceutically acceptable acid addition salt" of the present invention refers to an addition salt formed by the compound represented by formula (I) with an inorganic acid or an organic acid. Suitable inorganic acid salts include, but are not limited to, hydrochlorides, sulfates, bisulfates, nitrates, hydrobromides, hydroiodides, carbonates, bicarbonates, sulfites, bisulfites, pyrosulfates, monohydrogen phosphates, dihydrogen phosphates, perchlorates, persulfates, hemisulfates, bisulfates, thiocyanates, phosphates, pyrophosphates, and metaphosphates; suitable organic acid salts include, but are not limited to, formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propiolate, and 2-butynoate. , 2-Hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, glycolate, alginate, ascorbate, isoascorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 2-(4-hydroxy)benzoate Benzoyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, L-camphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, lauryl sulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, pivalate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectinate, phthalic acid salts, including hydroxybenzoate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salts, alginate, 4-acetamidobenzenesulfonate, caprate, cholate, octanoate, nonanoate, cyclamate, phthalate, cysteine hydrochloride, sorbate, glycine hydrochloride, naphthalene disulfonate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyethylenesulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyethylenesulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and valerate.

The "pharmaceutically acceptable base addition salt" of the present invention refers to an addition salt formed between the compound represented by formula (I) and a base. Suitable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, aluminum, ferric, ferrous, manganic, manganous, copper, zinc, and ammonium salts; or salts of a compound of formula (I) with methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol, pyridine, picoline, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole, lysine, arginine, L-arginine, histidine, N-methylglucamine, dimethylglucamine, ethylglucamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, aminopropylene glycol, 1-amino-2,3,4-butanetriol, L-lysine, and ornithine.

"Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity, characterized by a diffuse, unsharp X-ray powder diffraction pattern. Amorphous is a special physical form of solid matter, and its locally ordered structure suggests that it is inextricably linked to crystalline forms. Amorphous forms of substances can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). The solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, ethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, n-propyl acetate, methyl tert-butyl ether, n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, a mixed solvent of methanol and dichloromethane in a volume ratio of 2:1 to 1:2, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, n-butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, 2-acetone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, mixtures thereof, and the like.

The term "solvate" herein refers to an association formed between one or more solvent molecules and a salt of a compound of the present invention, or solvent molecules adsorbed on the amorphous surface of a salt of a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, dichloromethane, ethyl acetate, acetic acid, aminoethanol, and a mixture of methanol and dichloromethane in a volume ratio of 2:1 to 1:2. The term "hydrate" refers to an association formed between water as the solvent molecule, or water molecules adsorbed on the amorphous surface of a salt of a compound of the present invention.

Amorphous materials can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

In the present invention, the base addition salt or acid addition salt may contain a solvent. Common solvents include water, ethanol, methanol, isopropanol, n-propyl acetate, tetrahydrofuran, acetone, isopropyl ether, ethyl ether, isopropyl acetate, n-heptane, ethyl acetate, and a mixture of methanol and dichloromethane in a volume ratio of 2:1 to 1:2. Base addition salts or acid addition salts containing a certain amount of water or other solvents should be considered to be within the scope of the present invention as long as they have any of the characteristics of the base addition salt or acid addition salt described in the present invention.

In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all given in degrees (°).

The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks of the X-ray powder diffraction pattern are shown therein.

When referring to a spectrum and/or data presented in a graph, a "peak" is a feature that can be identified by one skilled in the art and is not attributable to background noise.

“Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

In the context of the present invention, when or whether the word "about" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N +/- 1%, N +/- 2%, N +/- 3%, N +/- 5%, N +/- 7%, N +/- 8% or N +/- 10% is specifically disclosed, where "+/-" means plus or minus.

Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more different atomic enriched isotopes. Isotopically enriched compounds have the structure provided by the present invention, except that one or more atoms are replaced by atoms with selected atomic weights or mass numbers. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined herein, for example, compounds in which radioactive isotopes such as ³ H, ¹⁴ C, and ¹⁸ F are present, or compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically enriched compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiotherapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein using an appropriate isotopically labeled reagent in place of the unlabeled reagent originally used.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg _D2O , acetone- _d6 , DMSO- _d6 .

The definitions and conventions of stereochemistry used herein are generally those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, (+), and (–) are used to designate the sign by which a compound rotates plane-polarized light. (–) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and a mixture of these isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in a lack of stereoselectivity or stereospecificity in chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

The base addition salt or acid addition salt of the compound of the present invention or the pharmaceutical composition is suitable for a method of treating mammals (especially humans) suffering from HCV infection or HCV infection-related diseases, which comprises administering an amorphous salt of the compound represented by formula (I) to the mammal in need of treatment.

Pharmaceutical compositions, formulations and administration of salts of the compounds of the present invention

As described herein, the pharmaceutical compositions of the present invention comprise any base addition salt or acid addition salt of the compound of formula (I) of the present invention, and further comprise pharmaceutically acceptable excipients, such as carriers, diluents, fillers, binders, flavoring agents, or excipients. These, as used herein, include any solvent, diluent or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, suitable for a specific target dosage form. As described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are combined indicate that various excipients can be used in the formulation of pharmaceutically acceptable pharmaceutical compositions and their known preparation methods. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, for example by producing any adverse biological effects or interacting in a deleterious manner with any other component of the pharmaceutically acceptable pharmaceutical composition, their use is contemplated by the present invention.

Examples of pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coatings; sweeteners; flavoring agents; fragrances; preservatives and antioxidants.

The pharmaceutical composition further comprises an anti-HCV drug. The anti-HCV drug can be any known anti-HCV drug that is different from the compounds of the present invention. For example, it can be interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, a compound that promotes the generation of type 1 helper T cell responses, an interfering RNA for silencing or down-regulating the HCV positive-strand RNA genome, an antisense RNA for silencing or down-regulating the HCV positive-strand RNA genome, imiquimod, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, Bavituximab, Civacir ^™ , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172), sovaprevir (ACH-1625), samatasvir r(IDX-719), veruprevir(ABT-450), erlotinib, simeprevir(TMC-435), asunaprevir(BMS-650032), vaniprevir(MK-7009), faldaprevir(BI-2013335), VX-135, CIGB-230, furaprevir(TG-2 349), pibrentasvir(ABT-530), glecaprevir(ABT-493), uprifosbuvir(IDX-21437), radalbuvir( GS-9669), JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride(PPI-668), velpatasvir(GS-5816), MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-1 36. IDX-316, modithromycin(EP-013420), VBY-376, TMC-649128, mericitabine(R-7128), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, P SI-879, HCV-796, nesbuvir (HCV-371), VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, consensus alpha-interferon, interferon gamma or a combination thereof. Among them, the interfering RNA that silences or downregulates the HCV positive-chain RNA genome is an RNA that specifically targets the HCV positive-chain RNA genome, and degrades the HCV positive-chain RNA (i.e., messenger RNA) through RNA interference, thereby regulating the expression of the HCV positive-chain RNA genome at the transcriptional level; the antisense RNA that silences or downregulates the HCV positive-chain RNA genome is an RNA that specifically binds to the HCV positive-chain RNA through complementary pairing, and on the one hand, it forms a steric hindrance effect by binding to the HCV positive-chain RNA, thereby preventing the ribosome from binding to the HCV positive-chain RNA; on the other hand, after binding to the HCV positive-chain RNA, it activates endogenous RNA enzymes or ribozymes, thereby degrading the HCV positive-chain RNA, thereby achieving silencing or downregulation of the HCV positive-chain RNA genome. The pharmaceutical composition further comprises at least one HCV inhibitor, which is used to inhibit the HCV replication process and/or inhibit the function of HCV viral proteins; the HCV replication process includes at least one of HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV release processes; the HCV viral proteins are selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and at least one of the internal ribosome entry site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.

When used for treatment, a therapeutically effective amount of a salt of a compound of the present invention, particularly a base or acid addition salt of a compound of formula (I), can be administered as a raw chemical or as an active ingredient in a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of a compound of the present invention, particularly a base or acid addition salt of a compound of formula (I), and one or more pharmaceutically acceptable carriers, diluents, or excipients. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a significant patient benefit (e.g., a reduction in viral load). When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that results in a therapeutic effect, whether administered in combination, sequentially, or simultaneously. The salts of the compounds of the present invention, particularly the base or acid addition salts of the compound of formula (I), are as described above. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing a salt of a compound of the present invention, particularly a base addition salt or acid addition salt of a compound represented by formula (I), with one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, raw materials, compositions, and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

Pharmaceutical preparations may be in unit dosage form, with each unit dose containing a predetermined amount of the active ingredient. The compounds of the present invention are administered at dosage levels ranging from about 0.01 mg/kg (mg/kg) body weight/day to about 250 mg/kg body weight/day, preferably between about 0.05 mg/kg body weight/day and about 100 mg/kg body weight/day, and are often used as monotherapy to prevent or treat HCV-mediated diseases. The pharmaceutical compositions of the present invention may generally be administered from about 1 to about 5 times daily or as a continuous infusion. This type of administration may be used as a long-term or short-term therapy. The amount of active ingredient mixed with the carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and the patient's age, sex, weight, and condition. Preferred unit dosage forms are those containing the daily dose or divided doses of the active ingredient described herein, or appropriate fractions thereof. Treatment may be initiated with a small dose significantly lower than the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the optimal effect is achieved under the circumstances. In general, the compounds are ideally administered at concentration levels that generally provide effective antiviral results without causing any harmful or deleterious side effects.

When the pharmaceutical composition of the present invention comprises the compound of the present invention and one or more other therapeutic drugs or the combination of preventive drugs, the dosage level of the compound and other medicine is usually in the monotherapy scheme, accounting for about 10-150% of the normal dosage, more preferably accounting for about 10-80% of the normal dosage. Pharmaceutical preparation is suitable for administration by any suitable approach, for example, by oral (including oral cavity or sublingual), rectum, nose, local (including oral cavity, sublingual or transdermal), vagina or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) approach. Such preparations can be prepared by any known method in the field of pharmacy, for example, by mixing active ingredient with carrier or excipient. Preferably, oral administration or injection are administered.

Pharmaceutical formulations suitable for oral administration are provided as discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water emulsions or water-in-oil emulsions.

For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be mixed with a pharmaceutically acceptable oral non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound into a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier (e.g., starch or an edible sugar such as mannitol). Flavoring agents, preservatives, dispersants, and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling it into formed gelatin shells. Before the filling operation, a glidant and a lubricant (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powder mixture. A disintegrant or solubilizer (e.g., agar, calcium carbonate, or sodium carbonate) may also be added to improve the availability of the drug when the capsule is ingested.

In addition, suitable binders, lubricants, disintegrants, and colorants may be added to the mixture as needed or necessary. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets may be prepared by forming a powdered mixture, granulating or pre-compressing the mixture, adding a lubricant and disintegrant, and pressing the mixture into tablets. A powdered mixture may be prepared by mixing the appropriately pulverized compound with a diluent or base as described above, optionally with a binder (e.g., carboxymethylcellulose, alginate, gelatin, or polyvinyl pyrrolidone), a dissolution inhibitor (e.g., paraffin), an absorption accelerator (e.g., a quaternary salt), and/or an absorbent (e.g., bentonite, kaolin, or dicalcium phosphate). The powdered mixture can be granulated after being moistened with a binder (e.g., syrup, starch paste, acacia mucilage, or a solution of a cellulosic or polymeric material) and then pressed and sieved. An alternative to granulation is to run the powdered mixture through a tablet press, resulting in poorly formed lumps being broken up and granulated. The granules can be lubricated by adding stearic acid, a stearate salt, talc, or mineral oil to prevent them from sticking to the tablet press die. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be mixed with a free-flowing inert carrier and compressed into tablets without the need for granulation or pre-compression steps. Transparent or opaque protective coatings consisting of a shellac seal coat, a sugar coat, or a polymeric coating and a wax polish coat can be provided. Dyes can be added to these coatings to distinguish different unit doses.

Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form. Syrups can be prepared by dissolving the compound in an aqueous solution of appropriate flavoring, while elixirs can be prepared by using a non-toxic solvent. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) etc. can also be added.

If appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to delay or sustain the release, for example, by coating or embedding in polymers, wax or the like particulate material.

The base addition salt or acid addition salt of the compound represented by formula (I) of the present invention or its pharmaceutical composition can also be administered via liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be composed of various phospholipids (e.g., cholesterol, octadecylamine, or phosphatidylcholine).

The base addition salt or acid addition salt of the compound represented by formula (I) of the present invention or its pharmaceutical composition can also be delivered by using a monoclonal antibody as a separate carrier (to which the compound molecule is coupled). The compound can also be coupled with a soluble polymer as a targetable drug carrier. Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compound can be coupled with a class of biodegradable polymers for achieving controlled release of the drug, such polymers as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, cross-linked copolymers of polycyanoacrylates and hydrogels or amphiphilic block copolymers.

Pharmaceutical formulations suitable for transdermal administration may be administered as discrete patches to maintain close contact with the recipient's epidermis for an extended period of time. For example, the active ingredient may be delivered via iontophoretic patches, as generally described in Pharmaceutical Research 1986, 3(6), 318.

Pharmaceutical formulations suitable for topical administration can be prepared as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations suitable for nasal administration (wherein the carrier is a solid) include coarse powders having a particle size in the range of, for example, 20-500 microns, which are administered by snorting, i.e., rapid inhalation through the nasal passages from a coarse powder container close to the nose. Suitable formulations suitable for administration as nasal sprays or nose drops, where the carrier is a liquid, include aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists which can be prepared using various types of metered dose compressed aerosols, nebulizers, insufflators or other devices suitable for delivering aerosol sprays.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.

Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and aqueous and non-aqueous sterile suspensions. Aqueous and non-aqueous sterile injection solutions may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the recipient's blood. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. Preparations can be provided in unit dose or multi-dose containers, such as sealed vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Injection solutions and suspensions configured for use can be prepared from sterile powder injections, granules, and tablets.

It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

Uses of the salts and pharmaceutical compositions of the present invention

The present invention provides the use of a base addition salt or acid addition salt of a compound represented by formula (I) of the present invention, or a pharmaceutical composition thereof, in the preparation of a medicament, wherein the medicament can be used to inhibit HCV replication and/or inhibit the function of HCV viral proteins; the HCV replication process includes at least one of HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly, and HCV release; and the HCV viral proteins are selected from at least one of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and the internal ribosome entry site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any compound or pharmaceutical composition of the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, has a strong inhibitory effect on HCV NS3/4A protein.

The therapeutic method comprising administering a base addition salt or acid addition salt or pharmaceutical composition of the compound represented by formula (I) of the present invention further comprises administering other anti-HCV drugs to the patient, thereby enabling the base addition salt or acid addition salt or pharmaceutical composition of the compound represented by formula (I) of the present invention and other anti-HCV drugs to be used for combined treatment, wherein the other anti-HCV drugs are interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, compounds that promote the generation of type 1 helper T cell responses, interfering RNA for silencing or downregulating the HCV positive-strand RNA genome, antisense RNA for silencing or downregulating the HCV positive-strand RNA genome, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, ritonavir, bavituximab, Civacir ^™ , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172), sovap revir (ACH-1625), samatasvir (IDX-719), setrobuvir, veruprevir (ABT-450), erlotinib (erlotinib), simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK-7009), falsedap revir(BI-2013335), VX-135, CIGB-230, furaprevir(TG-2349), pibrentasvir(ABT-530), glecaprevir(ABT-493), uprifosbuvir(IDX-21437), radalbuvir(GS-9669), JHJ-56914845, vedroprevir(GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvirhydrochloride(PPI-668), velpatasvir(GS-5816), MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX- 375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin(EP-013420), VBY-376, TMC-649128, mericitabine(R-7128), sofosbuvir(PSI-7977), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371), VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, consensus alpha-interferon, interferon gamma, or a combination thereof.

The method of treating a patient with a base addition salt, acid addition salt or pharmaceutical composition of a compound of formula (I) of the present invention further comprises administering other anti-HCV drugs, wherein the other anti-HCV drugs can be administered in combination with the base addition salt, acid addition salt or pharmaceutical composition of the compound of formula (I) of the present invention, and the base addition salt, acid addition salt or pharmaceutical composition of the compound of formula (I) of the present invention is administered as a single dosage form or separately as part of a multiple dosage form. The other anti-HCV drugs can be administered simultaneously with the base addition salt or acid addition salt of the compound of formula (I) of the present invention or at different times. In the latter case, administration can be staggered, such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention is an amount effective to treat or alleviate the severity of one or more of the conditions described herein. According to the methods of the present invention, the base addition salts or acid addition salts of the compound of formula (I) and the composition can be administered in any amount and by any route of administration to effectively treat or alleviate the severity of the disease. The exact amount required will vary depending on the patient's condition, which depends on race, age, general condition of the patient, severity of the infection, special factors, mode of administration, etc. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an X-ray powder diffraction (XRPD) pattern of the amorphous N-methylglucamine salt of the compound represented by formula (I);

FIG2 is an X-ray powder diffraction (XRPD) pattern of an amorphous L-arginine salt of the compound represented by formula (I);

FIG3 is an X-ray powder diffraction (XRPD) pattern of the amorphous L-lysine salt of the compound represented by formula (I);

FIG4 is an X-ray powder diffraction (XRPD) pattern of the amorphous sodium salt of the compound represented by formula (I);

FIG5 is an X-ray powder diffraction (XRPD) pattern of the amorphous calcium salt of the compound represented by formula (I);

FIG6 is an X-ray powder diffraction (XRPD) pattern of the amorphous potassium salt of the compound represented by formula (I);

FIG7 is an X-ray powder diffraction (XRPD) pattern of the amorphous lithium salt of the compound represented by formula (I);

FIG8 is an X-ray powder diffraction (XRPD) pattern of the amorphous diethylamine salt of the compound represented by formula (I);

FIG9 is an X-ray powder diffraction (XRPD) pattern of the amorphous form of the tromethamine salt of the compound represented by formula (I);

FIG10 is an X-ray powder diffraction (XRPD) pattern of the amorphous diethylaminoethanol salt of the compound represented by formula (I);

FIG11 is an X-ray powder diffraction (XRPD) pattern of the amorphous piperazine salt of the compound represented by formula (I);

FIG12 is an X-ray powder diffraction (XRPD) pattern of the amorphous magnesium salt of the compound represented by formula (I);

FIG13 is an X-ray powder diffraction (XRPD) pattern of amorphous dimethylethanolamine, a compound represented by formula (I);

FIG14 is an X-ray powder diffraction (XRPD) pattern of the amorphous ethylenediamine salt of the compound represented by formula (I);

FIG15 is an X-ray powder diffraction (XRPD) pattern of the amorphous triethanolamine salt of the compound represented by formula (I);

FIG16 is an X-ray powder diffraction (XRPD) pattern of the amorphous ethanolamine salt of the compound represented by formula (I);

FIG17 is an X-ray powder diffraction (XRPD) pattern of an amorphous imidazole salt of the compound represented by formula (I);

FIG18 is an X-ray powder diffraction (XRPD) pattern of the amorphous citrate salt of the compound represented by formula (I);

FIG19 is an X-ray powder diffraction (XRPD) pattern of the amorphous p-toluenesulfonate salt of the compound represented by formula (I);

FIG20 is an X-ray powder diffraction (XRPD) pattern of the amorphous benzenesulfonate salt of the compound represented by formula (I);

FIG21 is an X-ray powder diffraction (XRPD) pattern of the amorphous methanesulfonate salt of the compound represented by formula (I);

FIG22 is an X-ray powder diffraction (XRPD) pattern of the amorphous sulfate salt of the compound represented by formula (I);

FIG23 is an X-ray powder diffraction (XRPD) pattern of the amorphous phosphate salt of the compound represented by formula (I);

FIG24 is an X-ray powder diffraction (XRPD) pattern of the amorphous nitrate salt of the compound represented by formula (I);

Figure 25 is an X-ray powder diffraction (XRPD) pattern of amorphous 1,5-naphthalene disulfonate salt of the compound represented by formula (I);

Figure 26 is an X-ray powder diffraction (XRPD) pattern of amorphous 1,2-ethanedisulfonate salt of the compound represented by formula (I);

FIG27 is an X-ray powder diffraction (XRPD) pattern of amorphous β-naphthalenesulfonate of the compound represented by formula (I);

FIG28 is an X-ray powder diffraction (XRPD) pattern of the amorphous form of the cyclamate salt of the compound represented by formula (I);

FIG29 is an X-ray powder diffraction (XRPD) pattern of the amorphous isethionate salt of the compound represented by formula (I);

FIG30 is an X-ray powder diffraction (XRPD) pattern of the amorphous maleate salt of the compound represented by formula (I);

FIG31 is an X-ray powder diffraction (XRPD) pattern of the amorphous hydrobromide salt of the compound represented by formula (I);

Figure 32 is an X-ray powder diffraction (XRPD) pattern of the amorphous hydrochloride of the compound represented by formula (I); and

FIG33 is an X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound represented by formula (I).

General synthetic methods

In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

NMR spectral data were measured on a Bruker Avance 400 NMR spectrometer or a Bruker Avance IIIHD 600 NMR spectrometer using CDCl ₃ , DMSO-d ₆ , CD ₃ OD or d ₆ -acetone as solvents (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), ddt (doublet of doublet of triplets), td (triplet of doublets), br.s (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

The X-ray powder diffraction analysis method used in this invention is to obtain X-ray powder diffraction patterns using an Empyrean diffractometer using Cu-Kα radiation (45 kV, 40 mA). A thin layer of powdered sample was prepared on a single crystal silicon sample holder and placed on a rotating sample stage. Analysis was performed over a range of 3° to 40° with a step size of 0.0168°. Data were collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

The element content detection data of the present invention was determined by an Agilent 7700X series ICP-MS equipped with a G31XXB vacuum system. An HMI high matrix system injector and a new dual-mode detector were used for the analysis, and an inductively coupled plasma (ICP) source was used for the ICP-MS mass spectrometer.

The solubility of the present invention was determined using an Aglient 1200 high performance liquid chromatograph with a VWD detector, a Waters Xbridge-C18 column (4.6×150 mm, 5 μm), a detection wavelength of 250 nm, a flow rate of 1.0 mL/min, a column temperature of 35° C., and a mobile phase of acetonitrile-water (v/v=40/60).

Low-resolution mass spectrometry (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL/min; HPLC peaks were recorded at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phases consisted of 0.1% formic acid in acetonitrile (Phase A) and 0.1% formic acid in ultrapure water (Phase B). Gradient elution conditions are shown in Table 1:

Table 1: Gradient elution conditions for low-resolution mass spectrometry mobile phase

Time (min) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

Compound purity was assessed by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1 × 30 mm, 4 μm, 10 min, a flow rate of 0.6 mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.

Chromatographic preparative separation of compounds was achieved by an Agilent 1260 series high performance liquid chromatography (HPLC), with UV detection at 278 nm, a Calesil ODS-120 (4.6 × 250 mm, 120A, 10u) column, a flow rate of 1.0 mL/min, and a mobile phase of (10 mM ZnSO ₄ + 20 mM L-valine buffer): methanol (v:v) = 50:50, and the column temperature was maintained at 30°C.

The following abbreviations are used throughout this disclosure:

Ac acetyl

Ac ₂ O acetic anhydride

BOC, Boc tert-butoxycarbonyl

(Boc) ₂ O Di-tert-butyl dicarbonate

CHCl ₃ Chloroform

CDC1 _3- deuterated chloroform

CH ₂ Cl ₂ , DCM dichloromethane

CDI N,N'-Carbonyldiimidazole

DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

DIPEA Diisopropylethylamine

DIAD Diisopropyl azodicarboxylate

DME Ethylene glycol dimethyl ether

EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc

EA Ethyl acetate

Et ₃ N, TEA triethylamine

EtOH

MeCN, CH ₃ CN, acetonitrile

THF Tetrahydrofuran

HCl·EA, HCl/EA Hydrogen chloride in ethyl acetate solution

HOAt, HOAT 1-hydroxy-7-azabenzotriazole

HOAc acetic acid

g grams

mg milligrams

ml, mL milliliters

IPA Isopropyl alcohol

Pd(PPh ₃ ) ₄ -Tetrakistriphenylphosphine Palladium

RT, rt room temperature

RF reflux

Rt retention time

DETAILED DESCRIPTION

The present invention is further described in the following examples; however, these examples should not be construed as limiting the scope of the present invention.

Synthesis method of amorphous compound (I)

Step 1: Synthesis of compound 1-2

Compound 1-1 (50 g, 216 mmol), triphenylphosphine (68 g, 259 mmol), and dichloromethane (375 mL) were added to a reaction flask. Under nitrogen, the temperature was lowered to -10°C, and DIAD (52.5 g, 260 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at -10°C for 3 hours. After the reaction was complete, methanesulfonic acid (62.5 g, 650 mmol) was added, and the temperature was raised to 40°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed once with a small amount of dichloromethane. The resulting solid was dried in vacuo at 40°C for 4 hours to obtain compound 1-2 (40 g, 88.4% yield) as a white solid.

Step 2: Synthesis of Compounds 1-3

Compound 1-2 (10 g, 47.8 mmol), compound 7 (10 g, 36.8 mmol), ethyl 2-oxime cyanoacetate (1.3 g, 9.1 mmol), DIPEA (9.0 mL, 54 mmol), and dichloromethane (250 mL) were added to a round-bottom flask. EDCI (0.85 g, 4.4 mmol) was added under nitrogen protection, and the reaction mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, 250 mL of water was added to the reaction solution. The organic phase was washed once with 10% citric acid aqueous solution (250 mL), saturated sodium bicarbonate (250 mL), and saturated sodium chloride solution (250 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain compound 1-3 (12.7 g, 94.1% yield) as a brown-red oily liquid.

Step 3: Synthesis of Compounds 1-5

Compound 1-3 (13.37 g, 36.49 mmol) was added to a 250 mL single-necked flask, followed by toluene (13 mL) and water (130 mL). Finally, compound 1-4 (11.66 g, 37.20 mmol) and sodium isooctanoate (10.00 g, 54.85 mmol) were added. The resulting mixture was allowed to react overnight at room temperature. After the reaction was complete, ethyl acetate (150 mL × 2) was added for extraction. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (150 mL), hydrochloric acid (1 mol/L, 150 mL), and saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure to obtain compound 1-5 (18.52 g, yield: 100%) as a brownish-red oily liquid.

Step 4: Synthesis of Compounds 1-7

Compound 1-5 (18.5 g, 36.4 mmol), compound 1-6 (10.48 g, 47.3 mmol) and toluene (100 mL) were added to a 250 mL single-necked flask. The reaction mixture was cooled to -10°C, and a solution of potassium tert-butoxide (6.12 g, 54.6 mmol) in anhydrous tetrahydrofuran (20 mL) was slowly added dropwise to the reaction mixture, controlling the reaction temperature to no higher than -5°C. After the addition was complete, the reaction mixture was stirred at -5°C for 3 hours. After the reaction was complete, 1% hydrochloric acid solution (100 mL, 1 mol/L) was added, and the reaction mixture was warmed to room temperature and stirred for 30 minutes. The mixture was then separated, the aqueous phase was extracted with toluene (100 mL), and the organic phases were combined. The combined organic phases were washed once with saturated sodium bicarbonate solution (100 mL) and hydrochloric acid (150 mL, 1 mol/L), respectively, and finally washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure to obtain a brown-red oily liquid compound 1-7 (24.0 g, yield 97.6%).

Step 5: Synthesis of Compound 1-9

Compound 1-7 (24 g, 35.4 mmol), compound 1-8 (10 g, 31.8 mmol), cesium carbonate (15 g, 46 mmol) and N-methylpyrrolidone (70 mL) were added to a 250 mL single-necked flask, heated to 50°C and stirred overnight. After the reaction was complete, water (100 mL) and methyl tert-butyl ether (70 mL) were added, the liquid was separated, the aqueous phase was extracted with methyl tert-butyl ether (70 mL), and the combined organic phase was washed with saturated sodium bicarbonate aqueous solution (70 mL) and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure to obtain a brown-red oily liquid. The brown-red oily liquid was then dissolved in isopropanol (210 mL) by heating and then cooled to room temperature to precipitate white solid compound 1-9 (20.0 g, yield 80%).

Step 6: Synthesis of Compound 1-10

Compound 1-9 (20 g, 24.8 mmol) and toluene (1400 mL) were added to a reaction flask, heated to 110°C, refluxed, and stirred for one hour. Jan's catalyst (0.08 g, 0.1 mmol) was dissolved in toluene (200 mL) and slowly added dropwise to the reaction solution under nitrogen over a period of 3 hours. After completion, the reaction solution was refluxed and stirred for 2 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a brown-gray oily liquid. Methyl tert-butyl ether (80 mL) was added and the temperature was raised to reflux to dissolve the brown-gray oily liquid. After the reaction was complete, the mixture was cooled to room temperature to precipitate compound 1-10 (15.0 g, yield: 80%) as a white solid.

Step 7: Synthesis of Compound 1-11

Compound 1-10 (10 g, 12.89 mmol), lithium hydroxide monohydrate (1.1 g, 26 mmol), methanol (40 mL), tetrahydrofuran (40 mL), and water (20 mL) were added to a 250 mL single-necked flask and stirred at room temperature overnight. After the reaction was complete, the organic solvent was evaporated under reduced pressure, and hydrochloric acid (50 mL, 1 mol/L) and ethyl acetate (50 mL) were added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to obtain 1-11 (9.15 g, yield: 93.2%) as a white solid.

Step 8: Synthesis of Compound 1-13

Compound 1-11 (2 g, 2.625 mmol), CDI (0.87 g, 5.3 mmol), and dichloromethane (20 mL) were added to a round-bottom flask and stirred at room temperature for 3 hours. DBU (0.82 g, 5.3 mmol) and compound 1-12 (0.72 g, 5.3 mmol) were then added, and the reaction mixture was stirred at room temperature overnight. After the reaction was complete, hydrochloric acid (40 mL, 1 mol/L) was added, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL), and the combined organic phases were washed with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to obtain compound 1-13 (2.2 g, yield: 94.42%) as a light yellow solid.

MS(ESI,pos.ion)m/z:880.8[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ10.31(s,1H),8.03(d,J＝7.5Hz,1H),7.93(s,1H),7.84–7.79(m,2H),7.54(s,1H),7.06–7.01(m,2H),5.70(dd,J＝17.9,8.7Hz,1H) ,5.52(s,1H),5.03–4.98(m,1H),4.76–4.69(m,2H),4.65–4.60(m,1H),4.13–4.09(m,1H),3.89(s,3H),3.73(s,3H),3.26–3.19(m,2H) ,2.75(dd,J＝13.8,7.4Hz,1H),2.65(s,3H),2.31(d,J＝8.6Hz,1H),2.07–2.04(m,1H),1.85(dd,J＝15.5,9.2Hz,2H),1.78(dd,J＝10.5, 5.1Hz,1H),1.66–1.62(m,1H),1.50(d,J＝7.3Hz,4H),1.40(d,J＝6.9Hz,7H),1.26(d,J＝4.2Hz,3H),1.20(s,3H),0.86–0.77(m,3H)ppm.

Step 9: Synthesis of compound (I)

Compound 1-13 (0.2 g, 0.2 mmol) was dissolved in isopropanol (2 mL) and cooled to 0°C. A solution of hydrogen chloride in isopropanol (40% by mass, 5 mL) was then added until no gas was released. The reaction was complete. Filter the resulting white solid and rinse with ethyl acetate (5 mL). The resulting white solid, compound 1-14 (0.1 g, 0.7 mmol), EDCI (0.2 g, 1.5 mmol), and HOAT (0.15 g, 1.1 mmol) were added to a round-bottom flask. Under nitrogen, dichloromethane (10 mL) was added, the mixture was cooled to 0°C, and DIPEA (0.5 mL, 3 mmol) was added. The reaction mixture was heated to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with water (10 mL), and the resulting mixture was extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (V/V) = 2/1 as eluent to obtain Compound (I) (0.150 g, 70% yield) as a white solid.

MS(ESI,pos.ion)m/z:874.3[M+1] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ10.30(s,1H),8.40(s,1H),7.95(d,J＝7.4Hz,1H),7.87(d,J＝9.1Hz,1H),7 .81(s,1H),7.55(s,1H),7.04(d,J＝9.2Hz,2H),6.57(s,1H),5.63(dd,J＝17.8 ,8.6Hz,1H),5.51(d,J＝27.3Hz,1H),4.92(t,J＝9.4Hz,1H),4.76(t,J＝7.3Hz, 1H),4.70(t,J＝7.8Hz,1H),4.58(d,J＝11.4Hz,1H),4.16–4.10(m,1H),3.88(s ,3H),3.26–3.20(m,2H),2.75(dd,J＝13.6,7.7Hz,1H),2.65(d,J＝18.3Hz,4H) ,2.54–2.48(m,1H),2.38(s,1H),2.26(dd,J＝17.2,8.5Hz,1H),2.05(dd,J＝21 .8,10.4Hz,1H),1.89–1.83(m,1H),1.79–1.69(m,2H),1.43(d,J＝5.5Hz,2H), 1.39(d,J＝6.9Hz,7H),1.28–1.23(m,3H),1.19(s,3H),0.96–0.66(m,3H)ppm.

The product was identified by Empyrean X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation. The experimental results are shown in FIG33 .

Example 1 Preparation and Identification of Compound (I) N-Methylglucamine Salt Amorphous Form

1. Preparation of Compound (I) N-methylglucamine salt amorphous form

Compound (I) (0.437 g, 0.491 mmol) and N-methylglucamine (0.106 g, 0.543 mmol) were added to methanol (20.0 mL), and the solid slowly dissolved. The reaction mixture was reacted at room temperature for 7 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the solid was dried in vacuo at room temperature to obtain compound (I) N-methylglucamine salt as an amorphous white solid powder (0.523 g, 0.489 mmol, 99.61%).

2. Identification of the Amorphous Form of Compound (I) N-Methylglucamine Salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(s,1H),8.45(d,J＝5.6Hz,1H),8.01(d,J＝9.1Hz,2H),7.50(d,J＝31.5Hz,2H),7.35(d,J＝9.3Hz,1H),6.82(s,1H),5.62(s ,1H),5.51(t,J＝9.7Hz,1H),5.34(d,J＝6.8Hz,1H),4.77(s,1H),4.57–4.37(m,3H),4.21(d,J＝9.7Hz,1H),3.93(s,3H),3.81(d,J ＝4.1Hz,1H),3.66(d,J＝4.3Hz,1H),3.60(dd,J＝10.7,3.2Hz,2H),3.52–3.47(m,2H),3.45–3.41(m,4H),3.21–3.12(m,2H),2.88( dt,J＝11.9,8.7Hz,3H),2.58(s,3H),2.53(d,J＝9.4Hz,2H),2.27–1.87(m,5H),1.74(s,1H),1.51–1.10(m,20H),0.48(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in Figure 1.

Example 2 Preparation and Identification of Compound (I) L-Arginine Salt Amorphous Form

1. Preparation of amorphous L-arginine salt of compound (I)

Compound (I) (0.437 g, 0.50 mmol) and L-arginine (0.092 g, 0.531 mmol) were added to methanol (20.0 mL), and the solid slowly dissolved. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous white solid powder of compound (I) L-arginine salt (0.52 g, 0.497 mmol, 99.31%).

2. Identification of the amorphous form of compound (I) L-arginine salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(d,J＝1.2Hz,1H),8.43(s,1H),8.16–7.95(m,2H),7.49(d,J＝30.5Hz,5H),7.35(d,J＝9.3Hz ,1H),6.82(d,J＝1.2Hz,1H),5.56(dd,J＝24.0,13.9Hz,2H),5.33(dd,J＝16.5,9.5Hz,1H),4.78(s,1 H),4.53(t,J＝7.8Hz,1H),4.42(d,J＝11.6Hz,1H),4.20(d,J＝8.2Hz,1H),3.92(s,3H),3.30(d,J＝6 .0Hz,3H),3.21–3.02(m,4H),2.57(s,5H),2.22–1.84(m,4H),1.79–1.06(m,24H),0.46(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG2 .

Example 3 Preparation and Identification of Compound (I) L-Lysine Salt Amorphous Form

1. Preparation of amorphous L-lysine salt of compound (I)

Compound (I) (0.449 g, 0.514 mmol) and L-lysine (0.083 g, 0.568 mmol) were added to methanol (20.0 mL), and the solid slowly dissolved. The reaction mixture was reacted at room temperature for 4.5 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous white solid powder of compound (I) L-lysine salt (0.524 g, 0.514 mmol, 99.98%).

2. Identification of the amorphous form of compound (I) L-lysine salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(s,1H),8.41(s,1H),8.10–7.88(m,2H),7.50(d,J＝29.0Hz,2H),7.36(d,J＝9.3Hz,1H),6.83(s,1 H),5.56(dd,J＝24.7,14.4Hz,2H),5.31(dd,J＝16.9,9.3Hz,1H),4.79(s,1H),4.52(t,J＝7.8Hz,1H),4.4 2(d,J＝11.5Hz,1H),4.22(d,J＝9.6Hz,1H),3.93(s,3H),3.16(dd,J＝14.4,7.2Hz,3H),2.73(t,J＝7.1Hz, 2H), 2.56(d,J＝16.2Hz,5H),2.17–1.84(m,5H),1.81–1.54(m,4H),1.53–1.03(m,24H),0.45(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG3 .

Example 4 Preparation and Identification of Compound (I) Sodium Salt Amorphous Form

1. Preparation of amorphous sodium salt of compound (I)

Compound (I) (501 mg, 0.573 mmol) was dispersed in methanol (15 mL), and a solution of sodium hydroxide (23 mg, 0.564 mmol) in water (1.4 mL) was added. The reaction mixture was reacted at room temperature for 5.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous sodium salt of compound (I) as a slightly yellow solid (0.502 g, 0.56 mmol, 97.7%).

2. Identification of the amorphous sodium salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(s,1H),8.41(d,J＝6.5Hz,1H),8.05–7.91(m,2H),7.53(s,1H),7.46(s,1H),7.35(d,J＝9.3Hz,1H),6 .84(d,J＝1.3Hz,1H),5.66–5.54(m,2H),5.32(dd,J＝16.7,9.5Hz,1H),4.80(s,1H),4.53(t,J＝7.8Hz,1H),4 .41(d,J＝11.6Hz,1H),4.21(d,J＝8.4Hz,1H),3.93(s,3H),3.16(dt,J＝13.7,6.8Hz,1H),2.56(d,J＝13.8Hz, 4H), 2.12(s,2H),1.93(dt,J＝17.9,7.9Hz,2H),1.75(t,J＝12.2Hz,1H),1.51–1.10(m,20H),0.47(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG4 .

3) Detection and analysis of the metal element content: The molar ratio of compound (I) to sodium ion is 1:1.

Example 5 Preparation and Identification of Compound (I) Calcium Salt Amorphous Form

1. Preparation of amorphous calcium salt of compound (I)

The sodium salt of compound (I) (2000 mg, 2.232 mmol) was added to methanol (40 mL), and the mixture was heated to reflux to dissolve the solid. Then, an aqueous solution (60 mL) of calcium chloride (123.9 mg, 1.116 mmol) was added dropwise within 1 hour. The resulting mixture was stirred at this temperature for 3 hours. The heating was stopped, and the reaction mixture was naturally cooled to room temperature and stirred overnight. Then, water (60 mL) was added dropwise to precipitate a solid. The mixture was stirred at room temperature for another 2 hours and filtered. The filter cake was washed with a mixed solvent of methanol and water (methanol/water (V/V) = 1/1) and then dried in vacuo at 70°C overnight to obtain an amorphous calcium salt of compound (I) as a light yellow powder (1.10 g, 0.62 mmol, 55%).

2. Identification of the amorphous calcium salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(s,1H),8.42(d,J＝6.1Hz,1H),8.08(s,1H),8.02(d,J＝9.2Hz,1H),7.53(s,1H),7.46( s,1H),7.36(d,J＝9.3Hz,1H),6.83(s,1H),5.67–5.50(m,2H),5.35(d,J＝7.3Hz,1H),4.77(s,1 H),4.53(t,J＝7.8Hz,1H),4.42(d,J＝11.3Hz,1H),4.19(d,J＝8.0Hz,1H),3.93(s,3H),3.16(d t,J＝13.6,6.7Hz,1H),2.64–2.52(m,5H),2.24–1.66(m,5H),1.53–1.07(m,19H),0.51(s,2H).

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG5 .

Example 6 Preparation and Identification of Amorphous Potassium Salt of Compound (I)

1. Preparation of amorphous potassium salt of compound (I)

Method 1: Compound (I) (498 mg, 0.557 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/1). A solution of potassium isooctanoate (102 mg, 0.557 mmol) in methanol and dichloromethane (5 mL, methanol/dichloromethane (V/V) = 1/1) was slowly added dropwise under stirring at room temperature. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was dried in vacuo at room temperature for 4 hours to obtain an amorphous potassium salt of compound (I) as a light yellow solid (0.506 g, 0.555 mmol, 99.6%).

Method 2: Compound (I) (502 mg, 0.574 mmol) was dispersed in methanol (15 mL), and a solution of potassium hydroxide (32 mg, 0.570 mmol) in water (0.58 mL) was slowly added dropwise. The system gradually became clear. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous potassium salt of compound (I) as a slightly yellow solid (0.50 g, 0.55 mmol, 95.0%).

2. Identification of the amorphous potassium salt of compound (I)

1) ¹ H NMR (600 MHz, DMSO-d ₆ )δ9.07(s,1H),8.47(s,1H),8.01(d,J＝9.1Hz,2H),7.53(s,1H),7.45(s,1H),7 .34(d,J＝9.2Hz,1H),6.83(s,1H),5.78–5.24(m,3H),4.76(s,1H),4.64–4.33( m,2H),4.16(dd,J＝24.8,7.1Hz,1H),3.92(s,3H),3.23–3.10(m,1H),2.57(s,4 H),2.19(s,1H),1.97(s,3H),1.72(s,1H),1.55–1.00(m,20H),0.51(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG6 .

Example 7 Preparation and Identification of Amorphous Lithium Salt of Compound (I)

1. Preparation of amorphous lithium salt of compound (I)

Compound (I) (500 mg, 0.572 mmol) was dispersed in methanol (10 mL) and stirred at room temperature. A self-made lithium hydroxide (24 mg, 0.572 mmol) solution in water (1 mL) was slowly added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure and the residue was dried in vacuo at 60°C for 4 hours to obtain an amorphous lithium salt of compound (I) as a slightly yellow solid (0.49 g, 0.557 mmol, 97.3%).

2. Identification of the amorphous lithium salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(s,1H),8.43(s,1H),8.05(s,1H),8.02(d,J＝9.2Hz,1H),7.54(s,1H),7.46(s,1H),7.36(d, J＝9.3Hz,1H),6.83(s,1H),5.58(d,J＝29.7Hz,2H),5.36(s,1H),4.77(s,1H),4.53(t,J＝7.8Hz,1H), 4.42(d,J＝10.3Hz,1H),4.19(d,J＝9.0Hz,1H),3.93(s,3H),3.24–3.11(m,1H),2.58(s,5H),2.18(s, 1H),2.07(s,1H),1.96(s,2H),1.73(s,1H),1.52–1.32(m,16H),1.24–1.08(m,3H),0.50(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG7 .

Example 8 Preparation and Identification of Compound (I) Diethylamine Salt Amorphous Form

1. Preparation of amorphous diethylamine salt of compound (I)

Compound (I) (499 mg, 0.561 mmol) was added to a 50 mL single-necked flask, followed by methanol (10 mL). The mixture was stirred at room temperature, and then a solution of diethylamine (41.8 mg, 0.561 mmol) in methanol (1 mL) was slowly added dropwise. After completion of the addition, the resulting mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous form of compound (I) diethylamine salt as a slightly yellow solid powder (0.522 g, 0.551 mmol, 98.3%).

2. Identification of the amorphous diethylamine salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(d,J＝1.2Hz,1H),8.56(s,1H),8.27(s,1H),8.03(d,J＝9.2Hz,1H),7.54(s,1H),7.46(s,1H), 7.35(d,J＝9.3Hz,1H),6.82(d,J＝1.2Hz,1H),5.64(s,1H),5.41(s,2H),4.72(s,1H),4.50(dd,J＝14.8 ,7.1Hz,2H),4.17(d,J＝8.4Hz,1H),3.93(s,3H),3.17(dt,J＝13.6,6.8Hz,2H),2.90(q,J＝7.2Hz,4H) ,2.58(s,5H),2.29(s,1H),1.99(d,J＝11.0Hz,3H),1.69(s,1H),1.53–1.09(m,25H),0.57(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG8 .

Example 9 Preparation and Identification of Amorphous Form of Compound (I) Tromethamine Salt

1. Preparation of amorphous tromethamine salt of compound (I)

Compound (I) (500 mg, 0.562 mmol) was added to a 50 mL single-necked flask, followed by a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/1). The mixture was stirred at room temperature to dissolve, and then a solution of tromethamine (69.5 mg, 0.562 mmol) in methanol (2 mL) was slowly added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature for 60 minutes. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous form of compound (I) tromethamine salt as a light yellow solid (0.551 g, 0.554 mmol, 99.3%).

2. Identification of the Amorphous Form of Compound (I) Tromethamine Salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(d,J＝0.8Hz,1H),8.48(d,J＝6.2Hz,1H),8.24–7.95(m,2H),7.54(s,1H),7.46(s,1H),7.35(d,J＝9.3H z,1H),6.82(d,J＝1.1Hz,1H),5.62(s,1H),5.48(t,J＝9.9Hz,1H),5.35(dd,J＝16.7,9.4Hz,1H),5.02(s,3H), 4.76(s,1H),4.59–4.39(m,2H),4.21(d,J＝8.2Hz,1H),3.92(s,3H),3.45(s,6H),3.17(dt,J＝16.1,6.9Hz,2H ),2.57(s,5H),2.19(s,1H),1.99(dt,J＝17.6,8.4Hz,3H),1.73(s,1H),1.57–1.08(m,20H),0.50(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG9 .

Example 10 Preparation and Identification of Compound (I) Diethylaminoethanol Salt Amorphous Form

1. Preparation of amorphous diethylaminoethanol salt of compound (I)

Compound (I) (501 mg, 0.563 mmol) was added to a 25 mL single-necked flask, followed by a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/1). The mixture was stirred at room temperature to dissolve, and a solution of N,N-dimethylethanolamine (67.2 mg, 0.563 mmol) in ethanol (0.95 mL) was slowly added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous form of compound (I) diethylaminoethanol salt as a light yellow solid (0.552 g, 0.557 mmol, 98.9%).

2. Identification of the amorphous form of compound (I) diethylaminoethanol salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(s,1H),8.65(s,1H),8.44(s,1H),8.04(d,J＝9.1Hz,1H),7.55(s,1H),7.46(s,1H),7.34(d,J＝9.3Hz, 1H),6.80(s,1H),5.65(s,1H),5.38(d,J＝53.9Hz,2H),4.67(s,1H),4.58–4.44(m,2H),4.14(d,J＝9.1Hz,1H) ,3.93(s,3H),3.58(t,J＝5.7Hz,2H),3.17(dt,J＝13.6,6.8Hz,2H),2.83(s,6H),2.69–2.55(m,4H),2.38(s,1 H),2.13(s,1H),2.04–1.85(m,2H),1.65(s,1H),1.55–1.18(m,20H),1.08(t,J=7.1Hz,6H),0.66(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG10 .

Example 11 Preparation and Identification of Compound (I) Piperazine Salt Amorphous Form

1. Preparation of amorphous piperazine salt of compound (I)

Compound (I) (0.212 g, 0.243 mmol) and piperazine (0.029 g, 0.337 mmol) were added to methanol (10.0 mL), and the solid slowly dissolved. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous piperazine salt of compound (I) as a white solid powder (0.23 g, 0.24 mmol, 98.75%).

2. Identification of the amorphous piperazine salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(s,1H),8.43(d,J＝5.7Hz,1H),8.13–7.97(m,2H),7.53(s,1H),7.46(s,1H),7.36(d,J＝9.3Hz,1H),6. 83(s,1H),5.58(dd,J＝21.4,11.3Hz,2H),5.34(dd,J＝16.5,9.7Hz,1H),4.78(s,1H),4.53(t,J＝7.8Hz,1H),4. 42(d,J＝11.6Hz,1H),4.19(d,J＝8.1Hz,1H),3.93(s,3H),3.16(dt,J＝13.7,6.9Hz,1H),2.80(s,8H),2.61–2. 52(m,5H),2.01(ddd,J＝30.3,27.2,21.7Hz,4H),1.72(d,J＝12.0Hz,1H),1.51–1.05(m,21H),0.47(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG11 .

Example 12 Preparation and Identification of Amorphous Magnesium Salt of Compound (I)

1. Preparation of amorphous magnesium salt of compound (I)

Compound (I) (500 mg, 0.562 mmol) was dispersed in methanol (15 mL), and a solution of magnesium hydroxide (16.4 mg, 0.281 mmol) in water (1 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous magnesium salt of compound (I) as a slightly yellow solid powder (0.497 g, 0.279 mmol, 99.1%).

2. Identification of the amorphous magnesium salt of compound (I)

1) ¹ H NMR (600 MHz, DMSO-d ₆ )δ9.07(s,1H),8.44(s,1H),8.02(d,J＝8.8Hz,1H),7.54(s,1H),7.46(s,1 H),7.36(d,J＝9.2Hz,1H),6.82(s,1H),5.63(s,2H),5.39(s,1H),4.74(s,1 H),4.59–4.35(m,2H),4.30–4.02(m,1H),3.93(s,3H),3.25–3.08(m,1H), 2.58(s,5H),1.97(t,J＝101.9Hz,5H),1.61–0.81(m,20H),0.57(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG12 .

Example 13 Preparation and Identification of Compound (I) Dimethylethanolamine Salt Amorphous Form

1. Preparation of amorphous dimethylethanolamine salt of compound (I)

Compound (I) (500 mg, 0.562 mmol) was added to a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/1) and dissolved by stirring at room temperature. Then, a solution of dimethylethanolamine (51.1 mg, 0.562 mmol) in methanol (1 mL) was added thereto. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting residue was dried in vacuo at room temperature to obtain an amorphous dimethylethanolamine salt of compound (I) as a slightly yellow solid powder (0.526 g, 0.546 mmol, 97.2%).

2. Identification of the amorphous dimethylethanolamine salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(s,1H),8.68(d,J＝5.4Hz,1H),8.49(s,1H),8.04(d,J＝9.2Hz,1H),7.56(s,1H),7.47(s,1H),7.34(d,J＝9.3Hz,1H),6.80(s,1 H),5.66(s,1H),5.48(dd,J＝17.5,8.5Hz,1H),5.30(t,J＝9.3Hz,1H),4.79(s,1H),4.66(s,1H),4.55(d,J＝11.5Hz,1H),4.49(t,J＝8.1 Hz,1H),4.13(d,J＝8.2Hz,1H),3.93(s,3H),3.57(t,J＝5.8Hz,2H),3.17(dt,J＝14.3,6.9Hz,2H),2.69(t,J＝5.8Hz,2H),2.63(dd,J＝1 3.7,7.5Hz,1H),2.58(s,3H),2.44(s,6H),2.15(d,J＝8.2Hz,1H),1.97(dd,J＝24.2,13.6Hz,2H),1.69–1.18(m,21H),0.68(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG13 .

Example 14 Preparation and Identification of Compound (I) Amorphous Ethylenediamine Salt

1. Preparation of amorphous ethylenediamine salt of compound (I)

Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/1). To the resulting solution was added a solution of ethylenediamine (34.7 mg, 0.565 mmol) in methanol (1 mL) with stirring at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed under reduced pressure and the residue was dried in vacuo at room temperature to obtain an amorphous form of compound (I) ethylenediamine salt as a slightly yellow solid powder (0.523 g, 0.560 mmol, 99.1%).

2. Identification of the amorphous form of compound (I) ethylenediamine salt

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(s,1H),8.43(s,1H),8.01(d,J＝9.2Hz,2H),7.54(s,1H),7.46(s,1H),7.36(d,J＝9.3Hz,1H),6.83(s,1 H),5.62(s,1H),5.55(t,J＝10.0Hz,1H),5.33(dd,J＝16.5,9.6Hz,1H),4.78(d,J＝6.0Hz,1H),4.52(t,J＝7.8Hz, 1H),4.43(d,J＝11.6Hz,1H),4.20(d,J＝7.8Hz,1H),3.93(s,3H),3.74(s,4H),3.17(dq,J＝13.7,6.9Hz,2H),2.7 4(s,4H),2.58(s,3H),2.23–2.01(m,2H),2.02–1.86(m,2H),1.74(s,1H),1.51–1.05(m,20H),0.47(s,2H)ppm.

2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are shown in FIG14 .

Example 15 Preparation and Identification of Amorphous Triethanolamine Salt of Compound (I)

1. Preparation of amorphous triethanolamine salt of compound (I)

Compound (I) (505 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/2). To the resulting solution was added a solution of triethanolamine (85.9 mg, 0.565 mmol) in methanol (1.5 mL) with stirring at room temperature. The resulting mixture was stirred at room temperature for 3.5 hours. After the reaction was complete, the solvent was evaporated under reduced pressure and the residue was dried in vacuo at room temperature to obtain an amorphous triethanolamine salt of compound (I) as a slightly yellow solid powder (0.565 g, 0.552 mmol, 97.8%).

2. Identification of the amorphous triethanolamine salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(d,J＝1.4Hz,1H),8.83(s,2H),8.32–8.29(m,1H),8.05(d,J＝9.2Hz,1H),7.57(s,1H),7.47( s,1H),7.34(d,J＝9.3Hz,1H),6.79(d,J＝1.2Hz,1H),5.62(d,J＝48.4Hz,2H),5.16(s,1H),5.16(s,2 H),4.50(dd,J＝35.3,27.2Hz,6H),4.10(s,1H),3.94(s,3H),3.48(s,6H),3.17(dt,J＝13.6,6.8Hz, 2H), 2.63(d,J＝36.4Hz,10H),2.33(s,1H),2.14–1.72(m,2H),1.65–1.14(m,21H),0.80(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG15 .

Example 16 Preparation and Identification of Amorphous Form of Compound (I) Ethanolamine Salt

1. Preparation of amorphous ethanolamine salt of compound (I)

Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) = 1/2). To the resulting solution was added a solution of ethanolamine (35.2 mg, 0.565 mmol) in methanol (1 mL) with stirring at room temperature. The resulting mixture was stirred at room temperature for 3.5 hours. After the reaction was complete, the solvent was evaporated under reduced pressure and the residue was dried in vacuo at room temperature to obtain an amorphous form of compound (I) ethanolamine salt as a slightly yellow solid powder (0.52 g, 0.560 mmol, 98.0%).

2. Identification of the amorphous form of the ethanolamine salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.08(d,J＝0.9Hz,1H),8.43(d,J＝5.3Hz,1H),8.01(d,J＝8.9Hz,2H),7.53(s,1H),7.46(s,1H),7.35(d,J＝9.3 Hz,1H),6.83(d,J＝1.0Hz,1H),5.56(dd,J＝24.7,14.5Hz,2H),5.33(dd,J＝16.6,9.8Hz,1H),4.78(s,1H),4.60–4 .36(m,2H),4.21(d,J＝8.1Hz,1H),3.93(s,3H),3.56–3.53(m,2H),3.17(dq,J＝13.8,6.9Hz,2H),2.82(t,J＝5.4 Hz,2H),2.56(d,J＝13.0Hz,5H),2.22–1.86(m,4H),1.74(t,J＝12.1Hz,1H),1.55–1.04(m,20H),0.47(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG16 .

Example 17 Preparation and Identification of Compound (I) Imidazole Salt Amorphous Form

1. Preparation of amorphous imidazole salt of compound (I)

Compound (I) (0.38 g, 0.435 mmol) and imidazole (0.03 g, 0.441 mmol) were added to acetone (10 mL), the solid dissolved, and the mixture was reacted at room temperature for 7.5 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dried in vacuo at room temperature to obtain an amorphous white solid powder of compound (I) imidazole salt (0.39 g, 0.414 mmol, 95.21%).

2. Identification of the amorphous imidazole salt of compound (I)

1) ¹ H NMR (600MHz, DMSO-d ₆ )δ9.07(s,1H),8.98–8.73(m,2H),8.06(d,J＝9.2Hz,1H),7.71(s,1H),7.57(s,1H),7.47(s,1H),7.34(d,J＝9.3 Hz,1H),7.05(s,2H),6.78(d,J＝1.3Hz,1H),5.76–5.50(m,2H),5.12(t,J＝9.5Hz,1H),4.65(d,J＝11.5Hz,1H),4. 55(s,1H),4.49–4.43(m,1H),4.06(d,J＝8.8Hz,1H),3.94(s,3H),3.17(dt,J＝13.6,6.8Hz,1H),2.75–2.54(m,5 H),2.49–2.30(m,2H),2.00(d,J＝10.9Hz,1H),1.77(d,J＝5.1Hz,1H),1.64–1.13(m,20H),0.91–0.75(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG17 .

Example 18 Preparation and Identification of Compound (I) Citrate Amorphous Form

1. Preparation of Compound (I) Citrate Amorphous Form

Compound (I) (204 mg, 0.228 mmol) was dispersed in methanol (4.0 mL), and then a solution of citric acid (46.1 mg, 0.239 mmol) in methanol (1.0 mL) was added, followed by dichloromethane (4.0 mL). The mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain an amorphous citrate salt of compound (I) as a light yellow solid (206 mg, 0.201 mmol, 88.2%).

2. Identification of Compound (I) Citrate Amorphous Form

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.16(s,1H),8.44(d,J＝1.5Hz,1H),8.03(d,J＝7.1Hz,1H),7.91(d,J＝9.1Hz, 1H),7.64(d,J＝7.6Hz,1H),7.57(s,1H),7.27(s,1H),7.11(d,J＝9.2Hz,1H),7.0 6(s,1H),6.62(d,J＝1.5Hz,1H),5.73(dd,J＝18.1,8.6Hz,1H),5.09–4.93(m,1H) ,4.80(t,J＝7.2Hz,1H),4.70(t,J＝7.9Hz,1H),4.58(d,J＝11.5Hz,1H),4.16(dd, J＝11.4,3.6Hz,1H),3.93(s,3H),3.24(dt,J＝13.8,6.9Hz,1H),2.97(s,2H),2.8 9(s,2H),2.79–2.73(m,2H),2.70(s,3H),2.58(s,1H),2.31(dd,J＝17.4,8.8Hz, 1H),2.06(dd,J＝23.1,11.4Hz,1H),1.83(ddd,J＝27.3,19.0,9.2Hz,8H),1.53–1 .48(m,6H),1.41(d,J＝6.9Hz,6H),1.30(d,J＝14.1Hz,2H),0.87–0.79(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG18 .

Example 19 Preparation and Identification of Amorphous p-Toluenesulfonate of Compound (I)

1. Preparation of amorphous p-toluenesulfonate of compound (I)

Compound (I) (623 mg, 0.705 mmol) was dispersed in a mixed solvent of methanol (12.0 mL) and dichloromethane (7.0 mL), and then a solution of p-toluenesulfonic acid (137 mg, 0.706 mmol) in methanol (4.5 mL) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain an amorphous p-toluenesulfonate salt of compound (I) as a yellow solid (720 mg, 0.69 mmol, 97.9%).

2. Identification of the amorphous p-toluenesulfonate salt of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.37(s,1H),8.38(s,1H),8.20(s,1H),8.07(d,J＝9.1Hz,1H),7.95(s ,1H),7.78(d,J＝7.7Hz,2H),7.48(d,J＝7.1Hz,1H),7.36(s,1H),7.18(dd, J＝19.0,8.5Hz,3H),6.48(s,1H),5.80(s,1H),5.65(dd,J＝18.1,8.5Hz,1 H),5.05(t,J＝9.5Hz,1H),4.87(t,J＝7.8Hz,1H),4.65(s,1H),4.37(d,J＝1 1.7Hz,1H),4.12(d,J＝8.9Hz,1H),3.93(s,5H),3.40(dd,J＝13.5,6.7Hz, 1H),2.82–2.61(m,2H),2.56(s,3H),2.41(s,1H),2.39–2.20(m,4H),2.01 (dd,J＝23.5,11.7Hz,2H),1.80–1.64(m,3H),1.56(dd,J＝9.0,5.7Hz,1H),1.41(dd,J＝21.4,15.2Hz,12H),1.27(s,2H),0.80(d,J＝12.1Hz,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG19 .

Example 20 Preparation and Identification of Compound (I) Benzenesulfonate Amorphous Form

1. Preparation of amorphous benzenesulfonate of compound (I)

Compound (I) (633 mg, 0.716 mmol) was dispersed in a mixed solvent of methanol (12.0 mL) and dichloromethane (1.0 mL), and then a solution of benzenesulfonic acid (118 mg, 0.709 mmol) in methanol (4.5 mL) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain an amorphous benzenesulfonate salt of compound (I) as a yellow solid (710 mg, 0.69 mmol, 96.4%).

2. Identification of the amorphous benzenesulfonate salt of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.38(s,1H),8.38(s,1H),8.27(s,1H),8.11(d,J＝9.0Hz,1H),7.98(s,1H),7.89(s,2H),7.47(d,J＝7.0Hz,1H),7.37(d,J＝13. 1Hz,3H),7.23(d,J＝9.1Hz,1H),6.47(s,1H),5.85(s,1H),5.64(dd,J＝17.9,8.2Hz,1H),5.04(t,J＝9.5Hz,1H),4.89(d,J＝7.0Hz, 1H),4.64(s,1H),4.39(d,J＝11.6Hz,1H),4.17(d,J＝10.3Hz,2H),3.94(s,4H),3.52–3.32(m,2H),2.71(d,J＝29.9Hz,2H),2.56(s ,3H),2.47–2.25(m,2H),1.97(s,2H),1.83–1.62(m,3H),1.56(s,1H),1.47–1.36(m,11H),1.27(d,J=6.9Hz,2H),0.78(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG20 .

Example 21 Preparation and Identification of Amorphous Methanesulfonate of Compound (I)

1. Preparation of amorphous methanesulfonate of compound (I)

Compound (I) (644 mg, 0.729 mmol) was dissolved in tetrahydrofuran (13.0 mL), and then a solution of methanesulfonic acid (74.3 mg, 0.765 mmol) in tetrahydrofuran (2.0 mL) was slowly added dropwise. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and methanol (19.0 mL) was added. The mixture was stirred at room temperature to dissolve. The solvent was evaporated under reduced pressure again. The residue was dried in vacuo at 60°C overnight to obtain an amorphous methanesulfonate of compound (I) as a yellow solid (680 mg, 0.70 mmol, 96.0%).

2. Identification of the amorphous methanesulfonate of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.34(s,1H),8.42(d,J＝1.6Hz,1H),8.07(d,J＝9.2Hz,1H),7.99(s,1H),7.89(s,1H),7.54(d,J＝7.5Hz,1H),7.33(s,1H),7.26 (s,1H),6.57(d,J＝1.5Hz,1H),5.86(s,1H),5.68(dd,J＝18.3,8.5Hz,1H),5.10(t,J＝9.6Hz,1H),4.85–4.59(m,2H),4.46–4.31(m, 2H),3.96(s,3H),3.71(s,3H),3.47(dt,J＝13.6,6.8Hz,2H),2.87–2.76(m,5H),2.64–2.55(m,3H),2.50–2.38(m,1H),2.30(d,J＝8 .8Hz,1H),2.09–1.95(m,2H),1.89–1.69(m,3H),1.64–1.51(m,5H),1.47(d,J＝6.9Hz,6H),1.27(s,2H),0.82(t,J＝5.8Hz,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG21 .

Example 22 Preparation and Identification of Compound (I) Sulfate Amorphous Form

1. Preparation of amorphous sulfate salt of compound (I)

Compound (I) (718 mg, 0.803 mmol) was dissolved in tetrahydrofuran (14.0 mL), and a solution of sulfuric acid (80.1 mg, 0.803 mmol) in tetrahydrofuran (1.0 mL) was slowly added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dried under vacuum at 60°C overnight to obtain an amorphous sulfate salt of compound (I) as a yellow solid (730 mg, 0.75 mmol, 93.4%).

2. Identification of the amorphous sulfate salt of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.55(s,1H),8.41(d,J＝1.5Hz,1H),8.15(d,J＝9.3Hz,1H),7.92(d,J＝10.7Hz,2H),7.57(d,J＝7.6Hz,1H),7.45(s,1H),7.35(d,J＝9.4Hz,1 H),6.58(s,1H),5.88(s,1H),5.66(dd,J＝18.5,8.6Hz,1H),5.11(t,J＝9.6Hz,1H),4.88(t,J＝8.0Hz,1H),4.79(t,J＝7.1Hz,1H),4.52(d,J＝9.7 Hz,1H),4.36(d,J＝11.4Hz,1H),3.99(s,3H),3.47(dd,J＝13.8,6.9Hz,1H),2.86(dd,J＝17.2,8.7Hz,2H),2.57(s,3H),2.44–2.18(m,2H),2.1 5–1.96(m,2H),1.91–1.78(m,2H),1.73–1.60(m,2H),1.46(dd,J＝7.8,4.5Hz,12H),1.38–1.26(m,3H),0.89(d,J＝7.0Hz,1H),0.78(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG22 .

Example 23 Preparation and Identification of Compound (I) Phosphate Amorphous Form

1. Preparation of amorphous phosphate of compound (I)

Compound (I) (967 mg, 1.095 mmol) was dissolved in tetrahydrofuran (20.0 mL), and then a solution of phosphoric acid (126 mg, 1.093 mmol) in tetrahydrofuran (2.0 mL) was slowly added. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous phosphate salt of compound (I) as a yellow solid (980 mg, 1.0 mmol, 91.3%).

2. Identification of the amorphous phosphate of compound (I)

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.18(s,1H),8.43(d,J＝1.5Hz,1H),7.90(d,J＝9.1Hz,1H),7.70(d,J＝7. 6Hz,1H),7.57(s,1H),7.32(s,1H),7.10(d,J＝9.2Hz,1H),7.05(s,1H),6.6 1(d,J＝1.4Hz,1H),5.80–5.65(m,1H),5.58(s,1H),5.05–4.96(m,1H),4.80 (t,J＝7.4Hz,1H),4.69(t,J＝7.9Hz,1H),4.58(d,J＝11.4Hz,1H),4.16(dd,J ＝11.2,3.5Hz,1H),4.02–3.82(m,4H),3.78–3.63(m,1H),3.23(dt,J＝13.6, 6.8Hz,1H),2.83–2.64(m,5H),2.52(dd,J＝17.0,8.5Hz,1H),2.39–2.21(m, 1H),2.12–1.99(m,2H),1.91–1.85(m,3H),1.82–1.65(m,3H),1.51(s,4H), 1.41(d,J＝6.9Hz,6H), 1.29(dd,J＝19.5,7.4Hz,2H), 0.91–0.77(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG23 .

Example 24 Preparation and Identification of Amorphous Nitrate of Compound (I)

1. Preparation of amorphous nitrate of compound (I)

Compound (I) (672 mg, 0.755 mmol) was dissolved in tetrahydrofuran (14.0 mL), and then a solution of nitric acid (73.5 mg, 0.758 mmol) in tetrahydrofuran (2.0 mL) was slowly added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous nitrate salt of compound (I) as a yellow solid (650 mg, 0.69 mmol, 91.4%).

2. Identification of the amorphous nitrate salt of compound (I)

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.32(s,1H),8.42(d,J＝1.5Hz,1H),8.09(d,J＝9.2Hz,1H),7.97(s,1H), 7.77(s,1H),7.50(d,J＝7.3Hz,1H),7.36(s,1H),7.29(d,J＝4.9Hz,1H),6.53 (d,J＝1.5Hz,1H),5.80–5.61(m,2H),5.13–5.02(m,1H),4.83(t,J＝7.9Hz,1 H),4.73(t,J＝6.9Hz,1H),4.53(d,J＝11.8Hz,1H),4.25(dd,J＝11.7,3.6Hz,1 H),3.97(s,3H),3.38(dd,J＝13.7,6.9Hz,1H),2.77(d,J＝7.6Hz,2H),2.60( s,3H),2.46(d,J＝9.1Hz,1H),2.32(dd,J＝17.5,8.8Hz,1H),2.00(dd,J＝15.9 ,6.9Hz,2H),1.79(ddd,J＝32.8,14.6,8.8Hz,3H),1.59(dd,J＝8.8,5.2Hz,1H ),1.54–1.39(m,13H),1.28(dd,J＝20.6,10.6Hz,3H),0.90–0.76(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG24 .

Example 25 Preparation and Identification of Compound (I) 1,5-Naphthalene Disulfonate Amorphous Form

1. Preparation of amorphous 1,5-naphthalene disulfonate of compound (I)

Compound (I) (665 mg, 0.747 mmol) was dispersed in methanol (14.0 mL), and then a solution of 1,5-naphthalenedisulfonic acid (216.8 mg, 0.745 mmol) in methanol (2.0 mL) was slowly added dropwise. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous yellow solid of compound (I) 1,5-naphthalenedisulfonic acid salt (780 mg, 0.67 mmol, 89.7%).

2. Identification of the amorphous form of compound (I) 1,5-naphthalene disulfonate

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.59(s,1H),8.54(s,1H),8.47(s,1H),8.39(d,J＝8.0Hz,1H),7.88(d,J＝9.3Hz,1H),7.70(d,J＝6.9Hz,1H),7.48(d,J＝7.8Hz,1 H),7.34(s,1H),7.17(s,1H),7.10(d,J＝9.5Hz,1H),6.70(d,J＝7.1Hz,1H),6.55(s,1H),5.76–5.61(m,1H),5.47(s,1H),5.17–5.03 (m,1H),4.90(d,J＝7.7Hz,1H),4.70(s,1H),4.44(d,J＝11.6Hz,1H),4.12–3.93(m,3H),3.74(dd,J＝14.0,6.9Hz,1H),3.26(dd,J＝1 3.5, 6.8Hz, 1H), 2.57 (s, 3H), 2.44 (d, J = 8.7Hz, 2H), 2.15 (s, 7H), 1.85–1.60 (m, 4H), 1.59–1.23 (m, 16H), 0.84 (d, J = 5.9Hz, 2H) ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG25 .

Example 26 Preparation and Identification of Compound (I) 1,2-Ethanedisulfonate Amorphous Form

1. Preparation of amorphous 1,2-ethanedisulfonate of compound (I)

Compound (I) (695 mg, 0.781 mmol) was dispersed in methanol (14.0 mL), and then a solution of 1,2-ethanedisulfonic acid (153.1 mg, 0.781 mmol) in methanol (2.0 mL) was slowly added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous yellow solid of compound (I) 1,2-ethanedisulfonic acid salt (810 mg, 0.76 mmol, 97.3%).

2. Identification of the amorphous form of compound (I) 1,2-ethanedisulfonate

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.33(s,1H),8.43(t,J＝7.3Hz,1H),8.12–7.98(m,1H),7.69(d,J＝7.4H z,1H),7.60(d,J＝7.3Hz,1H),7.25(s,1H),7.22(d,J＝4.4Hz,1H),6.69(s,1 H),6.61(s,1H),5.69(dd,J＝18.6,7.8Hz,2H),5.33(dd,J＝48.2,38.5Hz,1H ),5.10–4.96(m,1H),4.84(ddd,J＝25.3,15.9,7.1Hz,2H),4.55(d,J＝11.4H z,1H),4.25(t,J＝19.1Hz,1H),3.98(d,J＝10.2Hz,3H),3.49(s,1H),3.30(d ,J＝6.8Hz,3H),2.79(dd,J＝27.7,8.3Hz,2H),2.63(d,J＝5.7Hz,4H),2.37–2 .17(m,2H),2.16–1.85(m,3H),1.85–1.64(m,3H),1.61–1.55(m,2H),1.50( s, 3H), 1.43 (t, J = 6.6 Hz, 8H), 1.28 ( s, 2H), 0.83 ( dd, J = 8.0, 6.6 Hz, 2H) ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG26 .

Example 27 Preparation and Identification of Compound (I) β-Naphthalenesulfonate Amorphous Form

1. Preparation of amorphous β-naphthalenesulfonate of compound (I)

Compound (I) (693 mg, 0.775 mmol) was suspended in methanol (14.0 mL), and then a solution of β-naphthalenesulfonic acid (179.6 mg, 0.78 mmol) in methanol (2.0 mL) was slowly added dropwise, followed by the addition of dichloromethane (6.0 mL). The mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain compound (I) β-naphthalenesulfonate as a yellow solid (790 mg, 0.73 mmol, 94.2%).

2. Identification of the amorphous β-naphthalenesulfonate of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.43(s,1H),8.37(d,J＝10.5Hz,2H),8.27(s,1H),8.09(d,J＝9.2Hz,1 H),7.92(d,J＝8.4Hz,2H),7.82(d,J＝7.8Hz,1H),7.76(t,J＝7.0Hz,2H),7 .47(dd,J＝18.4,7.1Hz,3H),7.33(s,1H),7.11(d,J＝9.4Hz,1H),6.46(s, 1H),5.90(s,1H),5.63(dd,J＝18.1,8.3Hz,1H),5.06(t,J＝9.6Hz,1H),4. 95(t,J＝7.9Hz,1H),4.64(s,1H),4.39(d,J＝11.7Hz,1H),4.18(d,J＝9.1H z,1H),3.86(s,3H),3.42–3.23(m,5H),2.90–2.61(m,2H),2.52(s,3H),2 .45–2.22(m,2H),1.96(s,2H),1.79–1.64(m,3H),1.58(dd,J＝9.2,5.7Hz ,1H),1.48(s,3H),1.38–1.33(m,7H),1.28(s,2H),0.84–0.72(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG27 .

Example 28 Preparation and Identification of Compound (I) Cyclamate Salt Amorphous Form

1. Preparation of amorphous cyclamate of compound (I)

Compound (I) (730 mg, 0.816 mmol) was dispersed in methanol (22.0 mL), and then a solution of cyclamic acid (149.3 mg, 0.816 mmol) in methanol (2.0 mL) was slowly added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at 60°C overnight to obtain an amorphous cyclamate salt of compound (I) as a yellow solid (820 mg, 0.78 mmol, 95.6%).

2. Identification of the amorphous form of compound (I) cyclamate

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.22(s,1H),8.44(d,J＝1.6Hz,1H),7.97(d,J＝9.1Hz,1H),7.63(d,J＝7.5Hz ,1H),7.58(s,1H),7.51(s,1H),7.16(s,2H),6.62(d,J＝1.6Hz,1H),5.72(dd,J＝ 18.3,8.5Hz,1H),5.62(s,1H),5.06(t,J＝9.5Hz,1H),4.91–4.65(m,2H),4.54( d,J＝11.6Hz,1H),4.21(dd,J＝11.3,3.3Hz,1H),3.93(s,3H),3.44(d,J＝11.0Hz, 1H),3.25(dt,J＝20.7,6.9Hz,2H),2.78(p,J＝14.2Hz,3H),2.65(s,3H),2.52(d ,J＝9.2Hz,1H),2.37–2.16(m,3H),1.94(ddd,J＝26.6,14.0,9.0Hz,4H),1.76(t, J＝11.6Hz,4H),1.65–1.54(m,3H),1.52(s,4H),1.48(d,J＝6.5Hz,3H),1.42(d, J＝6.9Hz,6H),1.30(d,J＝16.3Hz,4H),1.23–1.13(m,1H),0.86–0.76(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG28 .

Example 29 Preparation and Identification of Amorphous Isethionate Salt of Compound (I)

1. Preparation of amorphous isethionate salt of compound (I)

Compound (I) (651 mg, 0.732 mmol) was dispersed in methanol (14.0 mL), and then a solution of isethionic acid (115.9 mg, 0.735 mmol) in methanol (2.0 mL) was slowly added, followed by the addition of dichloromethane (2.0 mL). The mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain an amorphous isethionic salt of compound (I) as a yellow solid (710 mg, 0.71 mmol, 97.0%).

2. Identification of the amorphous isethionate salt of compound (I)

1) ¹ H NMR (400 MHz, CDCl ₃ )δ10.37(s,1H),8.43(d,J＝1.2Hz,1H),8.24–8.04(m,2H),7.82(s,1H),7.4 9(d,J＝7.3Hz,1H),7.39(s,1H),7.31(d,J＝9.5Hz,1H),6.54(d,J＝1.2Hz,1H) ,5.90(s,1H),5.67(dd,J＝17.9,8.4Hz,1H),5.06(t,J＝9.6Hz,1H),4.87(t,J ＝8.0Hz,1H),4.71(t,J＝6.9Hz,1H),4.49(d,J＝11.6Hz,1H),4.30(d,J＝8.5Hz ,1H),3.99(d,J＝10.1Hz,5H),3.43(dt,J＝13.5,6.7Hz,1H),3.16–3.04(m,2H ),2.82(dd,J＝19.8,11.8Hz,2H),2.59(s,3H),2.45(s,1H),2.32(dd,J＝17.4 ,8.7Hz,1H),2.00(dd,J＝23.7,10.9Hz,2H),1.85–1.67(m,3H),1.61(dd,J＝9 .4,5.8Hz,1H),1.55–1.39(m,13H),1.29(d,J＝15.1Hz,3H),0.81(s,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG29 .

Example 30 Preparation and Identification of Amorphous Maleate Salt of Compound (I)

1. Preparation of amorphous maleate salt of compound (I)

Compound (I) (622 mg, 0.699 mmol) was dissolved in acetone (12.0 mL), and then a solution of maleic acid (81.5 mg, 0.699 mmol) in acetone (3.0 mL) was slowly added. The mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo at 60°C overnight to obtain an amorphous maleate salt of compound (I) as a yellow solid (650 mg, 0.66 mmol, 94.4%).

2. Identification of the amorphous maleate salt of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.23(s,1H),8.45(d,J＝1.3Hz,1H),8.01(d,J＝9.2Hz,1H),7.68–7.49(m,3H),7.19(t,J＝4.6Hz,2H),6.6 1(d,J＝1.3Hz,1H),6.33(s,2H),5.78–5.57(m,2H),5.11–4.95(m,1H),4.76(t,J＝7.5Hz,2H),4.61(d,J＝11.7 Hz,1H),4.16(s,1H),3.96(s,3H),3.27(dt,J＝13.7,6.9Hz,1H),2.84–2.69(m,2H),2.65(s,3H),2.53(s,1H) ,2.32(dd,J＝17.3,8.6Hz,1H),2.14–1.83(m,3H),1.82–1.68(m,2H),1.62–1.22(m,18H),0.92–0.77(m,2H).

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG30 .

Example 31 Preparation and Identification of Compound (I) Hydrobromide Amorphous Form

1. Preparation of amorphous hydrobromide of compound (I)

Compound (I) (697 mg, 0.789 mmol) was dissolved in tetrahydrofuran (14.0 mL), and then hydrobromic acid (146.3 mg, 0.868 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight and filtered. The filter cake was washed with tetrahydrofuran (0.5 mL × 2), evacuated to near dryness, and then dried in vacuo at 60°C overnight to obtain an amorphous hydrobromide salt of compound (I) as a yellow solid (520 mg, 0.54 mmol, 68.4%).

2. Identification of the amorphous hydrobromide salt of compound (I)

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.20(s,1H),8.42(d,J＝1.4Hz,2H),8.04(d,J＝8.9Hz,1H),7.54(s,1H),7.43(d,J＝7.1Hz,1H),7.36(s,1H) ,7.28–7.22(m,1H),6.54(s,1H),5.93(s,1H),5.73(dd,J＝18.5,9.0Hz,1H),5.18–4.94(m,1H),4.78(s,1H),4. 44(s,1H),3.99(s,3H),3.62(s,1H),2.88(s,1H),2.79(d,J＝6.8Hz,1H),2.65(s,3H),2.49(s,1H),2.30(dd,J ＝16.7,7.9Hz,1H),2.02–1.75(m,10H),1.60–1.47(m,10H),1.29(d,J＝11.2Hz,4H),0.85(d,J＝10.9Hz,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in Figure 31.

Example 32 Preparation and Identification of Compound (I) Hydrochloride Amorphous Form

1. Preparation of amorphous compound (I) hydrochloride

Compound (I) (685 mg, 0.766 mmol) was dispersed in methanol (14.0 mL), and then a solution of hydrogen chloride in ethyl acetate (1.91 mmol, 0.1 mL) was slowly added. The mixture was stirred at room temperature for 4 hours, and then dichloromethane (1.0 mL) was added. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo at room temperature overnight to obtain an amorphous hydrochloride of compound (I) as a yellow solid (655 mg, 0.719 mmol, 93.9%).

2. Identification of Compound (I) Hydrochloride Amorphous Form

1) ¹ H NMR (400MHz, CDCl ₃ )δ10.17(s,1H),8.44(s,1H),7.93(d,J＝9.2Hz,1H),7.71(s,1H),7.55(d, J＝7.0Hz,1H),7.18–7.06(m,3H),6.63(s,1H),5.74(dd,J＝18.0,8.5Hz,1H) ,5.62(s,1H),5.04(t,J＝9.4Hz,1H),4.80(t,J＝7.4Hz,1H),4.69(t,J＝7.8H z,1H),4.54(d,J＝11.5Hz,1H),4.23(s,1H),3.95(s,3H),3.28(s,1H),2.77 (d,J＝5.2Hz,2H),2.69(s,3H),2.54(s,1H),2.47(dd,J＝14.7,7.3Hz,1H),2 .31(dd,J＝17.5,8.7Hz,1H),2.16(s,1H),2.05(dd,J＝23.1,12.2Hz,1H),1. 99–1.88(m,2H),1.79(d,J＝10.8Hz,2H),1.53(d,J＝7.9Hz,6H),1.43(d,J＝6 .8Hz,6H),1.35–1.26(m,2H),1.08(t,J＝7.3Hz,1H),0.88–0.79(m,2H)ppm.

2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, the experimental results are shown in FIG32 .

Example 33: PK assay of the salt of compound (I) of the present invention in male SD rats

1. Experimental methods:

Male Sprague-Dawley rats weighing 190-250 g were grouped into groups of three for each salt form and orally administered with 100 mg/kg of the test compound. Blood was collected at 0.25, 0.5, 1, 2, 5, 7, and 24 hours after administration. A standard curve within an appropriate range was established based on the sample concentrations, and the concentrations of the test compound in plasma samples were determined using an ABSCIEX API4000 LC-MS/MS in MRM mode. Pharmacokinetic parameters were calculated using non-compartmental methods using WinNonLin 6.3 software based on the drug concentration-time curves.

2. Experimental results: see Table 2

Table 2: PK data of the salt of compound (I) in SD rats

The results in Table 2 show that after oral administration to SD rats, the exposure levels of the salts of the compound (I) of the present invention were relatively high, especially the amorphous sodium salt of the compound (I), the amorphous L-arginine salt of the compound (I) and the amorphous nitrate salt of the compound (I), with exposure levels of 14110 h*ng/ml, 15000 h*ng/ml and 16100 h*ng/ml, respectively, indicating that the salts of the compound (I) of the present invention were well absorbed in the body.

Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims (7)

1. Pharmaceutically acceptable base addition salts of the compounds shown in formula (I): The salt is selected from at least one of lithium salts, sodium salts, and potassium salts; or the salt is selected from at least one of the salts formed by the compound of formula (I) with diethylamine, aminobutanetriol, diethylaminoethanol, ethanolamine, triethanolamine, piperazine, imidazole, L-arginine, and L-lysine. 2. Pharmaceutically acceptable acid addition salts of the compounds shown in formula (I): The inorganic acid salt is selected from at least one of nitrate, hydroxyethyl sulfonate, and maleate. 3. A pharmaceutical composition comprising the base addition salt or the acid addition salt according to any one of claims 1 to 2, optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 4. The pharmaceutical composition of claim 3, further comprising other anti-HCV drugs; wherein said other anti-HCV drugs are interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, compounds that promote type 1 helper T cell responses, interfering RNA for silencing or downregulating HCV positive-sense RNA genome, antisense RNA for silencing or downregulating HCV positive-sense RNA genome, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, ritonavir, bavitimab, Civacir ^™ Popreprevir, Tiraprevir, Sofosbuvir, Leadipasvir, Daclatasvir, Danoprevir, Ciluprevir, Nalapivir, Deleobuvir, Dasabuvir, Beclabuvir, Elbasvir, Ombitasvir, Neceprevir, Tegobuvir, Grazoprevir, Sovaprevir, Samatasvir, Veruprevir, Erlotinib, Simeprevir, Asunaprevir, Vaniprevir, Faldaprevir, VX-135, CIGB-230, Furaprevir, Pibrentasvir, Glecaprevir, Uprifosbuvir, Radalbuvir, JHJ-56914845, Vedroprevir, BZF-961, GS-9256, ANA975, EDP239, Ravidasvir hydrochloride, velpatasvir, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-205 4. IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6 130, PSI-938, PSI-879, HCV-796, nesbuvir, VCH-916, lomibuvir, setrobuvir, MK-3281, ABT-072, filibuvir, A-837093, JKT-109, GL-59728, GL-60667, AZD-2795, TMC-647055 or combinations thereof; wherein the interferon is interferon α-2b, PEGylated interferon α, interferon α-2a, PEGylated interferon α-2a, complex α-interferon, interferon γ or combinations thereof. 5. The pharmaceutical composition according to claim 3, further comprising at least one HCV inhibitor, wherein the HCV inhibitor is used to inhibit the HCV replication process and/or inhibit the function of HCV viral proteins; wherein the HCV replication process is selected from at least one of the processes of HCV entry, uncoating, translation, replication, assembly, and release; wherein the HCV viral proteins are selected from at least one of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and internal ribosome entry sites and inosine monophosphate dehydrogenase required for HCV viral replication. 6. Use of a base addition salt or acid addition salt according to any one of claims 1-2 or a pharmaceutical composition according to any one of claims 4-5 in the preparation of a medicament, said medicament being used to inhibit HCV replication and/or inhibit HCV viral protein function, wherein the HCV replication process is selected from at least one of the processes of HCV entry, uncoating, translation, replication, assembly, and release; and said HCV viral protein is selected from at least one of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and internal ribosome entry sites and inosine monophosphate dehydrogenase required for HCV viral replication. 7. Use of a base addition salt or acid addition salt according to any one of claims 1 to 2 or a pharmaceutical composition according to any one of claims 4 to 5 in the preparation of a medicament for the prevention, treatment, or relief of HCV infection or hepatitis C in a patient.