Salts of compounds and their crystalline forms, methods of preparation and uses

Abstract

The present application provides a salt of a compound, or a hydrate, solvate, prodrug, metabolite, or deuterated salt thereof, wherein the salt is a triphenylacetate salt of a compound of Formula (I), wherein L is a bond, an alkyl group, or an alkoxy group substituted at any central carbon atom with an aryl group, and G is hydrogen, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group. The present application also provides several crystalline forms of the salt, as well as methods for making and using the same. JPEG2026507085000048.jpg6668

Description

[Technical Field]

[0001] This application relates to the biopharmaceutical field, and specifically to salts of compounds and their crystalline forms, methods of preparation and uses. [Background technology]

[0002] Rifamycins are natural products with potential antimicrobial activity. Naturally derived rifamycins (e.g., rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV, and rifamycin Y (Brufani, M., Cerrini, S., Fedeli, W., Vaciago, AJ Mol. Biol. 1974, 87, 409-435)) have limited therapeutic applications, including relatively poor pharmacokinetics, low oral bioavailability, weak activity against gram-negative pathogens, and low distribution in infected tissues. In the prior art, various semisynthetic rifamycin derivatives with improved antibacterial spectra and pharmacological properties have been produced by chemical modification. Among these semisynthetic compounds, for example, rifampin and rifabutin have already been developed as therapeutic agents and are currently used to treat tuberculosis and other microbial infections (Farr, B.M. Rifamycins, in Principles and Practice of Infectious Diseases, Mandell, G.L., Bennett, J.E., Dolin, R., Eds., Churchill, 11 Livingstone, Philadelphia, pp. 348-361). Also, for example, TNP-2198 is a dual-targeted rifamycin-nitroimidazole conjugate that has potent activity against microaerophilic and anaerobic bacterial pathogens and good activity against strains resistant to both rifamycins and nitroimidazoles. However, in the development and application process, such innovative drug molecules with antibacterial activity often have difficulty meeting the demand for drug discoverability as a pharmaceutical due to the influence of their physicochemical properties such as high relative molecular mass in the free form, high lipophilicity, low water solubility and hygroscopicity, as well as bioavailability and stability (chemical stability, thermal stability, melting point, crystalline form stability). In this field, research on new drugs of rifamycin derivatives, such as crystalline forms of rifabutin (e.g., CN103408571B), has also progressed in recent years, but the experiments provided in this application reveal that they still face the problem of low purity and difficulty in meeting the demand for drug discoverability.Therefore, the search and screening of new molecular entities (eg, salt forms or crystalline forms) of such original drug molecules plays a vital role in realizing their medicinal value. Summary of the Invention

[0003] In order to overcome the above-mentioned deficiencies of the prior art, the present application provides a salt form of the compound as represented by formula (I) and a stable crystalline form of the salt form, which have better stability and solubility that can meet pharmaceutical requirements, as well as methods for preparing and using the same. In one aspect, the present application provides a triphenylacetate salt of a compound of formula (I) or a hydrate, solvate, prodrug, metabolite, or deuterated salt thereof: [ka] wherein L is a bond, an alkyl group, or [ka] wherein Ar is an optionally substituted aryl group and G is hydrogen, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group.

[0004] In some embodiments, the molar ratio of the compound of formula (I) to triphenylacetic acid is 0.8 to 1.2. In some embodiments, the salt is a monotriphenylacetate salt. In some embodiments, L is a C1 to C6 alkyl group.

[0005] In some embodiments, the structure of L is: [ka] is. In some embodiments, G is a C1 to C6 alkyl group, a C2 to C6 alkenyl group, or a C2 to C6 alkynyl group. In some embodiments, G is a C1-C3 monohaloalkyl group or a C1-C3 dihaloalkyl group. In some embodiments, G is an optionally substituted C3-C8 cycloalkyl group, an optionally substituted 3-8 membered heteroatom-containing monocyclic substituent, or an optionally substituted 4-12 membered heteroatom-containing bicyclic substituent.

[0006] In some embodiments, G is [ka] The structure is described in any one of the above. In some embodiments, the optionally substituted substituents are selected from halogen, hydroxy, carboxy, carbonyl, amino, nitro, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylamino, alkoxy, and carbonyl ester groups.

[0007] In some embodiments, the [ka] The structure of [ka] The structure is described in any one of the above.

[0008] In some embodiments, the triphenylacetic acid salt is a crystal that is Form I formed by crystallization of a salt of Formula (II): [ka] Among them, the X-ray powder diffraction of the above Crystal I has characteristic peaks at diffraction angle 2θ values ​​of 6.11±0.2°, 9.93±0.2°, 11.49±0.2°, 14.41±0.2°, 16.15±0.2° and 18.86±0.2°.

[0009] In some embodiments, the X-ray powder diffraction of Form I has characteristic peaks at one or more of the following diffraction angles 2θ: 12.46±0.2°, 14.89±0.2°, 16.81±0.2°, 19.31±0.2°, 20.34±0.2°, and 24.35±0.2°. In some embodiments, the X-ray powder diffraction of crystalline Form I has characteristic peaks at diffraction angles 2θ of 12.46±0.2°, 14.89±0.2°, 16.81±0.2°, 19.31±0.2°, 20.34±0.2°, and 24.35±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I is essentially in accordance with FIG. In some embodiments, the crystalline form I is anhydrous. In some embodiments, the differential scanning calorimetry curve of crystalline Form I has an endothermic peak at 174.2°C. In some embodiments, the differential scanning calorimetry diagram of crystalline Form I essentially corresponds to Figure 3B.

[0011] In some embodiments, the triphenylacetic acid salt is a crystal that is crystalline Form II formed by crystallization of a salt represented by Formula (II): [ka] Among them, the X-ray powder diffraction of the above Crystal II has characteristic peaks at diffraction angles 2θ of 11.37±0.2°, 12.06±0.2°, 16.10±0.2°, 18.14±0.2°, 19.80±0.2° and 24.36±0.2°.

[0012] In some embodiments, the X-ray powder diffraction of the crystalline form II has characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 4.83±0.2°, 5.61±0.2°, 6.85±0.2°, 8.51±0.2°, 10.16±0.2°, 14.54±0.2°, and 17.01±0.2°. In some embodiments, the X-ray powder diffraction of crystalline Form II has characteristic peaks at diffraction angles 2θ of 4.83±0.2°, 5.61±0.2°, 6.85±0.2°, 8.51±0.2°, 10.16±0.2°, 14.54±0.2°, and 17.01±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II is essentially in accordance with FIG. In some embodiments, the method for preparing the crystalline form II includes crystallizing the salt of formula (II) in an MTBE solvent to form the crystalline form II. In some embodiments, the differential scanning calorimetry curve of crystalline Form II has endothermic peaks at 61.9°C, 146.8°C, and 184.6°C. In some embodiments, the differential scanning calorimetry diagram of crystalline Form II essentially corresponds to Figure 5B.

[0014] In some embodiments, the triphenylacetic acid salt is a crystalline form III formed by crystallization of a salt of Formula (II): [ka] Among them, the X-ray powder diffraction of the above-mentioned crystalline III has characteristic peaks at diffraction angle 2θ values ​​of 9.57±0.2°, 11.49±0.2°, 12.14±0.2°, 16.18±0.2°, 18.26±0.2°, 19.61±0.2° and 19.92±0.2°.

[0015] In some embodiments, the X-ray powder diffraction of the crystalline form III has characteristic peaks at one or more of the following diffraction angles 2θ: 4.10±0.2°, 5.00±0.2°, 5.76±0.2°, 19.15±0.2°, 20.81±0.2°, 21.60±0.2°, and 24.52±0.2°. In some embodiments, the X-ray powder diffraction of the crystalline form III has characteristic peaks at diffraction angles 2θ of 4.10±0.2°, 5.00±0.2°, 5.76±0.2°, 19.15±0.2°, 20.81±0.2°, 21.60±0.2°, and 24.52±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of crystalline Form III is essentially in accordance with FIG. In some embodiments, the method for preparing crystalline Form III comprises crystallizing the salt of Formula (II) in a mixed solvent of 2-methyltetrahydrofuran and n-heptane to form crystalline Form III. In some embodiments, the differential scanning calorimetry curve of crystalline Form III has endothermic peaks at 64.7°C, 142.8°C, 159.4°C, and 177.0°C. In some embodiments, the differential scanning calorimetry diagram of crystalline Form III essentially corresponds to Figure 7B.

[0017] In some embodiments, the triphenylacetic acid salt is crystalline and is Form IV formed by crystallization of a salt of Formula (II): [ka] Among them, the X-ray powder diffraction of the above Crystal IV has characteristic peaks at diffraction angles 2θ of 10.64±0.2°, 11.54±0.2°, 14.64±0.2°, 16.06±0.2°, 18.08±0.2° and 23.89±0.2°.

[0018] In some embodiments, the X-ray powder diffraction of Form IV has characteristic peaks at one or more of the following diffraction angles 2θ: 4.85±0.2°, 7.21±0.2°, 18.82±0.2°, 20.09±0.2°, 24.26±0.2°, and 30.24±0.2°. In some embodiments, the X-ray powder diffraction of the crystalline form IV has characteristic peaks at diffraction angles 2θ of 4.85±0.2°, 7.21±0.2°, 18.82±0.2°, 20.09±0.2°, 24.26±0.2°, and 30.24±0.2°. In some embodiments, the X-ray powder diffraction pattern of Form IV is essentially in accordance with FIG. In some embodiments, the method for preparing crystalline Form IV comprises heating the crystalline form of any one of claims 26-32 to 160°C to form crystalline Form IV. In some embodiments, the differential scanning calorimetry curve of crystalline Form IV has an endothermic peak at 182.8°C. In some embodiments, the differential scanning calorimetry diagram of crystalline Form IV essentially corresponds to Figure 9B.

[0019] In some embodiments, the triphenylacetic acid salt is a crystalline form V formed by crystallization of a salt of Formula (I-II): [ka] Among these, the X-ray powder diffraction of the crystalline form V has characteristic peaks at diffraction angles 2θ of 7.65±0.2°, 10.84±0.2°, 11.71±0.2°, 12.26±0.2°, 20.60±0.2° and 24.83±0.2°.

[0020] In some embodiments, the X-ray powder diffraction of Form V has characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 6.45±0.2°, 16.44±0.2°, 18.18±0.2°, 18.47±0.2°, and 26.54±0.2°. In some embodiments, the X-ray powder diffraction of crystalline form V has characteristic peaks at diffraction angles 2θ of 6.45±0.2°, 16.44±0.2°, 18.18±0.2°, 18.47±0.2°, and 26.54±0.2°. In some embodiments, the X-ray powder diffraction pattern of Form V is essentially in accordance with FIG. In some embodiments, the method for preparing crystalline Form V includes crystallizing triphenylacetic acid salt of Formula (I-II) in an ethyl acetate solvent to form crystalline Form V. In some embodiments, the differential scanning calorimetry curve of crystalline form V has an endothermic peak at 164.0°C. In some embodiments, the differential scanning calorimetry pattern of crystalline Form V essentially corresponds to Figure 15B.

[0021] In some embodiments, the triphenylacetic acid salt is crystalline and is Form VI formed by crystallization of a salt of Formula (I-II): [ka] The X-ray powder diffraction of Form VI has characteristic peaks at diffraction angles 2θ of 11.05±0.2°, 11.76±0.2°, 12.45±0.2°, 16.45±0.2°, 18.15±0.2°, 20.59±0.2°, and 24.77±0.2°.

[0022] In some embodiments, the X-ray powder diffraction of Form VI has characteristic peaks at one or more of the following diffraction angles 2θ: 5.89±0.2°, 6.63±0.2°, 8.87±0.2°, 9.31±0.2°, 17.87±0.2°, 20.00±0.2°, and 24.26±0.2°. In some embodiments, the X-ray powder diffraction of Form VI has characteristic peaks at diffraction angles 2θ of 5.89±0.2°, 6.63±0.2°, 8.87±0.2°, 9.31±0.2°, 17.87±0.2°, 20.00±0.2°, and 24.26±0.2°. In some embodiments, the X-ray powder diffraction pattern of Form VI is essentially in accordance with FIG. In some embodiments, the method for preparing crystalline Form VI includes crystallizing triphenylacetate salt of Formula (I-II) in a methyl tert-butyl ether solvent to form crystalline Form VI. In some embodiments, the differential scanning calorimetry curve for Form VI has endothermic peaks at 127.2°C, 140.6°C, and 161.8°C. In some embodiments, the differential scanning calorimetry diagram of crystalline Form VI essentially corresponds to Figure 17B.

[0023] In another aspect, the present application provides a method for preparing a salt, comprising forming a triphenylacetic acid salt described herein from the free base of the compound of formula (I) and triphenylacetic acid. In some embodiments, the method comprises reacting the free base of the compound of Formula (I) and triphenylacetic acid in one or a combination of solvents selected from (1) ethyl acetate, (2) 2-methyltetrahydrofuran and isopropyl acetate, (3) 2-methyltetrahydrofuran and n-heptane, (4) 2-butanone and n-heptane, (5) methyl tert-butyl ether, (6) methyl tert-butyl ether and n-heptane, (7) toluene, (8) isopropanol and n-heptane, (9) isopropyl acetate, (10) acetone, (11) methanol and methyl tert-butyl ether, or (12) n-heptane.

[0024] In some embodiments, the method comprises combining the free base of the compound of Formula (I), ethyl acetate, and triphenylacetic acid, in the order stated above, to form a reaction mixture. In some embodiments, the method includes bringing the reaction mixture to a reaction temperature of 20 to 40°C. In some embodiments, the method comprises combining triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of Formula (I) above, and isopropyl acetate, in the order listed above, to form a reaction mixture. In some embodiments, the method comprises combining triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of Formula (I) above, and n-heptane in the order stated above to form a reaction mixture. In some embodiments, the method includes bringing the reaction mixture to a reaction temperature of 50 to 75°C.

[0025] In some embodiments, the method comprises combining the free base of the compound of Formula (I), 2-butanone, triphenylacetic acid, and n-heptane, in the order stated above, to form a reaction mixture. In some embodiments, the method includes bringing the reaction mixture to a reaction temperature of 40-60°C. In some embodiments, the salt formed from the free base of the compound of Formula (I) and triphenylacetic acid is crystalline, and the method further comprises recrystallizing the crystalline form in a suitable solvent to improve purity. In some embodiments, the suitable solvent comprises 2-butanone and n-heptane, or comprises acetone and n-heptane.

[0026] In another aspect, the present application provides a method of manufacturing a medicament, the method comprising providing a triphenylacetic acid salt described herein. In some embodiments, the method includes the steps of: 1) dissolving the triphenylacetate salt in a suitable organic solvent to convert it to the free base; 2) adjusting the free base to a suitable concentration using a suitable organic solvent; and 3) obtaining the drug using an organic solvent that can precipitate purified drug solids from the solution of the free base. In some embodiments, the suitable organic solvents in steps 1) and 2) above are selected from dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and 2-methyltetrahydrofuran, respectively, and the suitable organic solvents used in steps 1) and 2) above have different solubilities. In some embodiments, the solvent in which the purified drug solids can be precipitated is n-heptane.

[0027] In some embodiments, the method includes the steps of: 1) dissolving a triphenylacetic acid salt described herein in a suitable organic solvent, washing with a washing solution one or more times, collecting the washed organic phase, and washing it with water, and collecting the water-washed organic phase; 2) adding an organic solvent having a different solubility from the organic solvent described in 1) to the collected water-washed organic phase described in 1) and concentrating under reduced pressure, repeating the procedure until a concentrated solution of the free base of the compound of Formula (I) is obtained; and 3) adding the concentrated free base solution described in 3) to an organic solvent capable of precipitating a purified drug solid under nitrogen gas protection, and obtaining the drug after filtering, washing, and drying. In some embodiments, the cleaning solution is selected from a suitable weakly basic solution. In some embodiments, the cleaning solution is a sodium bicarbonate solution, a sodium carbonate solution, a potassium bicarbonate solution, or a potassium carbonate solution.

[0028] In some embodiments, the suitable organic solvent in step 1) has a residual concentration of 10.0% or less in the free base concentrate. In some embodiments, the step 3) includes adding the free base concentrate dropwise to n-heptane while stirring, maintaining the internal temperature at 10-20°C, for 3-8 hours, and continuing stirring for 1-2 hours after the completion of the addition. In another aspect, the present application provides a pharmaceutical composition comprising a triphenylacetic acid salt described herein and, optionally, a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a second therapeutic agent. In some embodiments, the second therapeutic agent is selected from a proton pump inhibitor, an acid secretion inhibitor, an efflux pump inhibitor, an anesthetic, an antifungal agent, an antiviral agent, an antibacterial agent, an antiprotozoal agent, an anti-inflammatory agent, an anticoagulant, a platelet aggregation inhibitor, an antipyretic, a lipid-lowering agent, and a zinc salt.

[0029] In another aspect, the present application provides a kit comprising a triphenylacetic acid salt described herein and / or a pharmaceutical composition described herein. In some embodiments, the kit includes instructions in tangible form and / or in machine-readable electronic form.

[0030] In another aspect, the present application provides a method for inhibiting or preventing bacterial growth, the method comprising administering an effective amount of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein. In another aspect, the present application provides a method of treating a disease, comprising administering to a patient in need thereof an effective amount of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein. In some embodiments, the patient has a bacterial infection. In some embodiments, the bacteria is selected from Helicobacter pylori, Mycobacterium tuberculosis, nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridium difficile, Clostridium acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharolytica, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula.

[0031] Use of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein to inhibit or prevent bacterial growth. Use of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein for the manufacture of a medicament for treating and / or preventing a disease or condition caused by a bacterial infection.

[0032] In some embodiments, the bacteria is selected from Helicobacter pylori, Mycobacterium tuberculosis, nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridium difficile, Clostridium acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharolytica, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula. In some embodiments, the disease or condition is selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, septic arthritis, liver abscess, sinusitis, pelvic inflammation, and bacteremia, as well as upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, lung infections, abdominal infections, eye infections, ear infections, oral infections, and surgical infections.

[0033] Those skilled in the art will readily appreciate other aspects and advantages of the present application from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. Those skilled in the art will recognize that the present application may enable them to modify the specific embodiments disclosed without departing from the spirit and scope of the present invention. Accordingly, the drawings and description herein are merely illustrative, and not limiting. [Brief explanation of the drawings]

[0034] Specific features of the present invention are set forth in the appended claims. A better understanding of the features and advantages of the present invention can be obtained by reference to the exemplary embodiments and drawings described in detail below, the brief description of which follows.

[0035] [Figures 1A-1C] FIG. 1 shows the XRPD pattern, TGA / mDSC pattern, and 1H NMR pattern of a starting sample of an exemplary compound of the present application. [Figure 2] 1 shows the XRPD pattern of crystalline form I of the present application. [Figure 3A-3B] 1 shows the TGA and DSC patterns of crystalline form I of the present application. [Figure 4] 1 shows the XRPD pattern of crystalline form II of the present application. [Figure 5A-5B] 1 shows the TGA and DSC patterns of crystalline form II of the present application. [Figure 6] 1 shows the XRPD pattern of crystalline form III of the present application. [Figures 7A-7B] 1 shows the TGA and DSC patterns of crystalline form III of the present application. [Figure 8] 1 shows the XRPD pattern of crystalline form IV of the present application. [Figure 9A-9B] 1 shows the TGA and DSC patterns of crystalline form IV of the present application. [Figures 10A-10D] 1 shows the 1H NMR spectra of crystalline forms I to IV of the present application.

[0036] [Figures 11A-11B] 1 shows the XRPD and TGA patterns of crystalline form I of the present application at high temperature (120° C.). [Figures 12A-12B] 1 shows the evaluation results of the crystalline form I of the present application in a DVS experiment. [Figure 13] 1 shows the XRPD patterns of the present crystalline form I in water and four biological media (after 24 hours). [Figure 14] 1 shows the XRPD pattern of crystalline form V of the present application. [Figures 15A-15B]1 shows the TGA and DSC patterns of crystalline form V of the present application. [Figure 16] 1 shows the XRPD pattern of crystalline form VI of the present application. [Figures 17A-17B] 1 shows the TGA and DSC patterns of crystalline form VI of the present application. [Figure 18] 1 shows comparative XRPD patterns of crystalline form V, crystalline form VI and amorphous rifabutin of the present application. [Figure 19] 1 shows the morphology of crystalline form V and crystalline form VI of the present application under polarized light microscope (PLM). DETAILED DESCRIPTION OF THE INVENTION

[0037] Hereinafter, embodiments of the present invention will be described with reference to specific examples, and those skilled in the art will easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0038] Definition of Terms As used herein, the terms "solvate" and "solvate" are used interchangeably and generally refer to an association or complex of one or more solvent molecules with a salt-form compound of the present application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" generally refers to a complex in which the solvent molecule is water. In this application, the term "prodrug" generally refers to a prodrug substance that can be administered to a subject and then metabolized to form a substance having the structure of the compound of this application, and the term "metabolite" generally refers to a substance that can be obtained when the compound of this application is administered to a subject and then metabolized, and prodrugs and metabolites contained in such derivatives are included within the scope of the invention of this application. In this application, the terms "deuteride" and "deuterated compound" can be used interchangeably and generally refer to a new compound obtained after one or more hydrogen atoms in an organic compound are replaced with deuterium atoms. In this application, the term "hydrogen" generally refers to a single hydrogen atom. Such an atom may be linked to other groups, for example, to an oxygen atom to form a hydroxy group.

[0039] As used herein, the term "alkyl group" typically refers to a residue derived by removing a hydrogen atom from an alkane. An alkyl group may be substituted or unsubstituted, substituted or unsubstituted. The term "alkyl group" typically refers to a saturated, straight-chain or branched-chain aliphatic hydrocarbon group having a residue derived by removing hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and may be a straight-chain or branched-chain group containing 1 to 20 carbon atoms, for example, 1 to 12 carbon atoms, such as an open-chain alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and the like. An alkyl group can be substituted or unsubstituted, substituted or unsubstituted; for example, when substituted, the substituents can be substituted at any available point of attachment, and the substituents can be independently and optionally substituted with one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkyloxy groups, heterocycloalkyloxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0040] As used herein, the term "aryl group" generally refers to a group having a residue derived by removing a hydrogen atom from an aromatic ring. The term "aromatic ring" may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (i.e., rings sharing adjacent pairs of carbon atoms) having a conjugated π-electron system, and may be 6- to 10-membered, such as benzene and naphthalene. The aromatic ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted, and if substituted, the substituents may independently be one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio. Aryl groups may be optionally substituted as described herein.

[0041] In this application, the term "alkenyl group" generally refers to a straight-chain or branched-chain hydrocarbon group containing one or more double bonds. Illustrative examples of alkenyl groups include allyl groups, homoallyl groups, vinyl groups, crotyl groups, butenyl groups, pentenyl groups, and hexenyl groups. Illustrative examples of C2-6 chain alkenyl groups having one or more double bonds include butadienyl groups, pentadienyl groups, hexadienyl groups, and hexatrienyl groups, as well as branched forms thereof. The position of the unsaturated bond (double bond) may be at any position in the carbon chain. The alkenyl group may be substituted or unsubstituted. In this application, the term "alkynyl group" generally refers to unsaturated straight-chain or branched-chain alkynyl groups, such as ethynyl, 1-propynyl, propargyl, and butynyl groups. Alkynyl groups can be substituted or unsubstituted.

[0042] As used herein, the term "optionally substituted" generally refers to the referenced group being unsubstituted or substituted with one or more additional groups, singly and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, mercapto, cyano, halogen, carbonyl, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The location and number of such substituents are determined according to the well-known valence limitations of each group.

[0043] In this application, the term "cycloalkyl group" generally refers to a cyclic form of an "alkyl group," including saturated monocyclic, bicyclic, or polycyclic alkyl groups. Bicyclic or polycyclic rings can be fused and linked through a single shared atom, i.e., they form a spirocyclic or bridged ring system. A cycloalkyl group can contain 3 to 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, to form a ring. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl groups. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, or bicyclo[4.2.0]octyl. Cycloalkyl groups may be optionally substituted as described herein.

[0044] As used herein, the term "heterocyclyl group" generally refers to a monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated, non-aromatic ring system having 3 to 20 ring atoms, including systems containing fused rings in which at least one ring atom is a heteroatom. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system or a 3- to 8-membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl group refers to a 5- to 8-membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl group refers to a 5- to 6-membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl group contains 1 to 4 heteroatoms. In some embodiments, a heterocyclyl group contains a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group comprises a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In another example, the heterocyclyl group comprises a 3-membered monocyclic ring. In another example, the heterocyclyl group comprises a 4-membered monocyclic ring. In another example, the heterocyclyl group comprises a 5- to 6-membered monocyclic ring. In one example, the heterocyclyl group comprises 0-3 double bonds.

[0045] As used herein, the term "heteroatom" generally refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized ammonium form of a basic nitrogen. As will be apparent to those skilled in the art, in this application, terms such as "alkyl group," "alkenyl group," "cycloalkyl group," etc., can have a prefix before the name to indicate the number of atoms present in the group in a particular case, for example, in C1-C4 alkyl group, C3-C7 cycloalkyloxy group, C1-C4 alkylcarbonylamino group, etc., the subscript number following "C" indicates the number of carbon atoms present in the group. For example, a C3 alkyl group refers to an alkyl group having 3 carbon atoms (e.g., n-propyl group, isopropyl group), and in C1-10, the members of the group may have any number of carbon atoms included in the range of 1 to 10.

[0046] As used herein, the term "pharmaceutically acceptable carrier" generally refers to a pharmaceutically acceptable substance, composition, or vehicle involved in the delivery or transfer of a chemical reagent, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Pharmaceutically acceptable carriers include pharmaceutically acceptable salts, of which the term "pharmaceutically acceptable salt" includes salts of active compounds prepared with relatively non-toxic acids or bases, as determined by the specific substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained, either in pure form or in a suitable inert solvent, by contacting the neutral form of such compounds with a sufficient amount of the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained, either in pure form or in a suitable inert solvent, by contacting the neutral form of such compounds with a sufficient amount of the desired acid. Illustrative examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids and relatively non-toxic organic acids. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0047] As used herein, the term "bacteria" refers to a type of prokaryotic organism that typically lacks a distinct nucleus and membranous organelles. Bacteria may include spherical, rod-shaped, and spiral-shaped organisms. The bacteria include species that grow interlike with one another, such as Escherichia, Salmonella, Shigella, Klebsiella, Vibrio, Pasteurella, Borrelia, Leptospira, Campylobacter, Clostridium, Corynebacterium, Yersinia, Treponema, Rickettsia, Chlamydia, Mycoplasma, and the like. The genera "bacterial infection" may include, but are not limited to, Mycoplasma, Coxiella, Neisseria, Listeria, Haemophilus, Helicobacter, Legionella, Pseudomonas, Bordetella, Brucella, Staphylococcus, Streptococcus, Enterococcus, Bacillus, Mycobacterium, and Nocardia. The term "bacterial infection" generally refers to any disorder due to the proliferation and / or presence in a cell or subject of bacteria as described herein. Bacterial infections can be caused by the proliferation of bacteria (eg, pathogenic bacteria), producing toxins and other metabolites.

[0048] As used herein, the term "subject in need thereof" generally refers to any organism to which the compounds and / or compositions described herein can be administered, e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes; typical subjects include animals (e.g., mammals such as mice, rats, rabbits, dogs, non-human primates, and humans) and / or plants. As used herein, the term "effective amount" generally refers to an amount sufficient to achieve or at least partially achieve a desired therapeutic effect. An "effective amount" of a drug or therapeutic agent generally refers to an amount sufficient to cure or at least partially prevent the disease and its complications in a patient already suffering from the disease. Amounts effective for such uses will depend on the severity of the infection and the overall state of the patient's own immune system. In this application, the term "comprising" generally refers to the inclusion of the explicitly specified features but not the exclusion of other elements. The terms "equivalent to" and "equal to" generally refer to an inclusive number. As used herein, the term "chosen from" generally refers to the inclusion of the selected object and all combinations thereof. For example, "chosen from A, B, and C" means including all combinations of A, B, and C, such as A, B, C, A+B, A+C, B+C, or A+B+C.

[0049] [Detailed Description of the Invention] Compounds and their salt forms In one aspect, the present application provides a triphenylacetate salt of a compound of formula (I) or a hydrate, solvate, prodrug, metabolite, or deuterated salt thereof: [ka] wherein L is a bond, an alkyl group, or [ka] wherein Ar is an optionally substituted aryl group and G is hydrogen, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group.

[0050] In some embodiments, the molar ratio of the compound of Formula (I) to triphenylacetic acid is 0.8 to 1.2. For example, the molar ratio of the compound of Formula (I) to triphenylacetic acid may be 0.80, 0.90, 1.00, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, or 1.20. More specifically, the molar ratio of the compound of Formula (I) to triphenylacetic acid is 1:1, and the formed salt is a monotriphenylacetic acid salt.

[0051] In some embodiments, L may be a C1 to C6 alkyl group. For example, L may be a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, or a C6 alkyl group. For example, the structure of L may also be: [ka] may be.

[0052] In some embodiments, G may be a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group. For example, G may be a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, a C6 alkyl group, a C2 alkenyl group, a C3 alkenyl group, a C4 alkenyl group, a C5 alkenyl group, a C6 alkenyl group, a C2 alkynyl group, a C3 alkynyl group, a C4 alkynyl group, a C5 alkynyl group, or a C6 alkynyl group. In some embodiments, G may be a C1 to C3 monohaloalkyl group or a C1 to C3 dihaloalkyl group. For example, G may be a C1 monohaloalkyl group, a C2 monohaloalkyl group, a C3 monohaloalkyl group, a C1 dihaloalkyl group, a C2 dihaloalkyl group, or a C3 dihaloalkyl group.

[0053] In some embodiments, G may also be an optionally substituted C3-C8 cycloalkyl group, an optionally substituted 3-8-membered heteroatom-containing monocyclic substituent, or an optionally substituted 4-12-membered heteroatom-containing bicyclic substituent. For example, G may also be a C3 cycloalkyl group, a C4 cycloalkyl group, a C5 cycloalkyl group, a C6 cycloalkyl group, a C7 cycloalkyl group, a C8 cycloalkyl group, a 3-membered heteroatom-containing monocyclic substituent, a 4-membered heteroatom-containing monocyclic substituent, a 5-membered heteroatom-containing monocyclic substituent, a 6-membered heteroatom-containing monocyclic substituent, a 7-membered heteroatom-containing monocyclic substituent, an 8-membered heteroatom-containing monocyclic substituent, a 4-membered heteroatom-containing bicyclic substituent, a 5-membered heteroatom-containing bicyclic substituent, a 6-membered heteroatom-containing bicyclic substituent, The G group may be a 7-membered heteroatom-containing bicyclic substituent, an 8-membered heteroatom-containing bicyclic substituent, a 9-membered heteroatom-containing bicyclic substituent, a 10-membered heteroatom-containing bicyclic substituent, an 11-membered heteroatom-containing bicyclic substituent, or a 12-membered heteroatom-containing bicyclic substituent, and (1) any of the G groups may be unsubstituted or substituted with any substituent, and (2) any of the heteroatom-containing monocyclic or bicyclic substituents may contain 1, 2, 3, or 4 heteroatoms selected from N, O, and S. For example, the G group may be substituted with any of the above substituents, and the substituents may be selected from halogen, hydroxy, carboxy, carbonyl, amino, nitro, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylamino, alkoxy, and carbonyl ester groups.

[0054] Illustratively, G is [ka] The structure may be any one of the structures described above.

[0055] In some embodiments, the compound according to formula (I) [ka] An exemplary structure of is [ka] The structure may be any one of the structures described above.

[0056] Illustratively, the compound of formula (I) is [ka] [ka] The structure may be any one of the structures described above.

[0057] In some embodiments, the triphenylacetic acid salt is crystalline, and the crystals can form crystalline forms I, II, III, and IV by crystallization of the salt of formula (II), and the crystals can also form crystalline forms V and VI by crystallization of the salt of formula (I-II). The following examples are provided to further understand the characteristics of the crystalline forms and the methods for preparing them, but are not intended to limit the scope of the present application. [ka]

[0058] Manufacturing method In another aspect, the present application provides a method for preparing a salt, comprising forming a salt described herein from the free base of the compound of formula (I) and triphenylacetic acid. In some embodiments, the method comprises reacting the free base of the compound of Formula (I) and triphenylacetic acid in one or a combination of solvents selected from (1) ethyl acetate, (2) 2-methyltetrahydrofuran and isopropyl acetate, (3) 2-methyltetrahydrofuran and n-heptane, (4) 2-butanone and n-heptane, (5) methyl tert-butyl ether, (6) methyl tert-butyl ether and n-heptane, (7) toluene, (8) isopropanol and n-heptane, (9) isopropyl acetate, (10) acetone, (11) methanol and methyl tert-butyl ether, or (12) n-heptane.

[0059] For example, the method may include combining the free base of the compound of Formula (I), ethyl acetate, and triphenylacetic acid in the above order to form a reaction mixture, and further including bringing the reaction mixture to a reaction temperature of 20 to 40°C. For example, the method may include combining triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of Formula (I), and isopropyl acetate in the above order to form a reaction mixture, and further including subjecting the reaction mixture to a reaction temperature of 50 to 75°C. For example, the method may include combining triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of Formula (I), and n-heptane in the order described above to form a reaction mixture, and further including subjecting the reaction mixture to a reaction temperature of 50 to 75°C. For example, the method may also include combining the free base of the compound of Formula (I), 2-butanone, triphenylacetic acid, and n-heptane in the above order to form a reaction mixture, and further including subjecting the reaction mixture to a reaction temperature of 40 to 60°C.

[0060] In some embodiments, the salt formed from the free base of the compound of Formula (I) and triphenylacetic acid is crystalline, and the method further comprises recrystallizing the crystalline form in a suitable solvent to improve purity. In some embodiments, the suitable solvent includes 2-butanone and n-heptane, or acetone and n-heptane. For example, the crystals may be recrystallized one or more times in a solvent system including 2-butanone and n-heptane to obtain a crystalline form of higher purity than the previous one, or the crystals may be recrystallized one or more times in a solvent system including acetone and n-heptane to obtain a crystalline form of higher purity than the previous one.

[0061] In another aspect, the present application provides a method for manufacturing a medicament using the triphenylacetic acid salts described herein. In some embodiments, the method includes the steps of: 1) dissolving the triphenylacetate salt in a suitable organic solvent to convert it to a free base; 2) adjusting the free base to a suitable concentration using a suitable organic solvent; and 3) obtaining the drug using an organic solvent capable of precipitating a purified drug solid from the solution of the free base. For example, the suitable organic solvent for dissolving the salt may be selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and 2-methyltetrahydrofuran. For example, the organic solvent capable of adjusting the free base to a suitable concentration must be a solvent in which the salt has a higher solubility than the organic solvent in which the salt was originally dissolved. For example, the solvent capable of precipitating the purified drug solid may be n-heptane.

[0062] An exemplary method for producing a drug using the salts described herein may include the following steps. 1) The triphenylacetic acid salt described in the present application is dissolved in a suitable organic solvent, washed one or more times with a washing solution, and the organic phase after the washing is collected and washed with water, and the organic phase after the water washing is collected. For example, the washing solution may be selected from a suitable weakly basic solution. Specifically, the washing solution may be a sodium bicarbonate solution, a sodium carbonate solution, a potassium bicarbonate solution, or a potassium carbonate solution. 2) To the collected water-washed organic phase described in 1), an organic solvent having a different solubility from the organic solvent described in 1) is added, and the mixture is concentrated under reduced pressure, and the procedure is repeated until a concentrated solution of the free base of the compound of formula (I) is obtained. For example, the organic solvent in step 1) remains at 10.0% or less in the concentrated solution of the free base. 3) Adding the free base concentrate to an organic solvent capable of precipitating a purified drug solid under nitrogen gas protection, filtering, washing, and drying to obtain the desired drug. For example, this step may include adding the free base concentrate dropwise to n-heptane with stirring, maintaining the internal temperature at 10-20°C, for 3-8 hours, and continuing stirring for 1-2 hours after the completion of the addition.

[0063] composition In another aspect, the present application provides a pharmaceutical composition comprising the triphenylacetic acid salt described herein and, optionally, a pharmaceutically acceptable carrier. For example, the composition may be in the form of a solution, aerosol, gel, ointment, spray, or suspension, and the composition in the form can be prepared by a method known and conventional in the art. For example, the pharmaceutically acceptable carrier may be selected from excipients for increasing solubility, adjuvants for improving viscosity, and adjuvants for improving penetration ability. In some embodiments, the composition may also include a second therapeutic agent. For example, the second therapeutic agent may be selected from another rifamycin drug or analog thereof, a proton pump inhibitor, an acid secretion inhibitor, an efflux pump inhibitor, an anesthetic, an antifungal agent, an antiviral agent, an antibacterial agent, an antiprotozoal agent, an anti-inflammatory agent (e.g., a nonsteroidal anti-inflammatory drug or a steroid), an anticoagulant, a platelet aggregation inhibitor, an antipyretic, a lipid-lowering agent, and a zinc salt. All therapeutic agents used in the compositions of the present application may be used within the dosage ranges currently known and used in these formulations.

[0064] kit In another aspect, the present application provides a kit containing the triphenylacetic acid salts described herein and / or the pharmaceutical compositions described herein. For example, the kit may also include at least one container for placing the salts and / or pharmaceutical compositions. For example, the kit may also include one or more components, and may also include second, third, and / or other containers other than the container, in which the one or more components are separately placed. For example, the kit may also include various combinations of the salts and / or pharmaceutical compositions in containers. For example, the kit may also further include buffer reagents, devices for mixing different components, devices for measuring, devices for sorting components, and / or devices for marking components. For example, the kit may also include packaging for housing the various containers. For example, the kit may also include instructions for using the kit components. For example, the instructions may be in physical paper form and / or in machine-readable electronic form.

[0065] method In another aspect, the present application provides methods for inhibiting or preventing bacterial growth, the methods comprising administering an effective amount of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein. In some embodiments, the method comprises contacting a site affected by a bacterial infection with a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein. For example, the site of infection may be within an animal, on an animal, or within or on a plant.

[0066] In another aspect, the present application provides methods for treating a disease, comprising administering to a subject in need thereof an effective amount of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein. In certain embodiments, the method of treatment may further comprise combining a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein with a therapeutic agent. In some embodiments, the method of treatment may comprise systemically delivering a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein to a subject in need thereof, such that the triphenylacetic acid salt is widely exposed to most of the body. This step may be performed by any means known in the art, including, but not limited to, intravenous, intraarterial, subcutaneous, and intraperitoneal delivery. In other embodiments, the method of treatment may comprise locally delivering a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein to a subject in need thereof, either directly to a target site within an organism or to a site of bacterial infection on the surface of an organism, or by direct contact with the site of bacterial infection on the body surface. For example, such local delivery does not preclude systemic pharmacological effects. In certain embodiments, the method of treatment can include administering to a subject in need thereof an effective amount of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein by intramuscular injection, subcutaneous or intradermal injection, intravenous injection, intrathecal injection, inhalation, oral administration, or topical application.

[0067] In the above method, the bacterium may be selected from Helicobacter pylori, Mycobacterium tuberculosis, nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridium difficile, Clostridium acidophilus, E. lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharolytica, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula. In the present application, the bacterium may also include drug-resistant strains of the above bacteria. For example, the drug-resistant bacterial strain may be anti-rifamycin single-drug resistant, anti-nitroimidazole single-drug resistant, or anti-rifamycin and nitroimidazole double-drug resistant. For example, the drug-resistant bacterial strain may also be resistant to other antibiotics, including macrolides such as clarithromycin, azithromycin, and roxithromycin; fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin; aminoglycosides such as streptomycin and amikacin; β-lactams such as ampicillin and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidinones such as linezolid and tedizolid; nitrofurans such as furazolidone; glycopeptides such as vancomycin; diarylquinolines such as bedaquiline; and clofazimine.

[0068] Furthermore, in some embodiments, the subject may have a bacterial infection or may be suffering from a disease or condition caused by a bacterial infection. For example, the disease may be selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, septic arthritis, liver abscess, sinusitis, pelvic inflammation, and bacteremia. For example, the disease may be selected from upper respiratory tract infection, lower respiratory tract infection, skin and soft tissue infection, bone and joint infection, lung infection, abdominal infection, eye infection, ear infection, oral infection, and surgical infection.

[0069] use In another aspect, the present application provides the use of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein to inhibit or prevent bacterial growth. In another aspect, the present application provides use of a triphenylacetic acid salt described herein, a pharmaceutical composition described herein, and / or a kit described herein for the manufacture of a medicament for treating and / or preventing a disease or condition caused by a bacterial infection.

[0070] In the above-mentioned use, the bacterium may be selected from Helicobacter pylori, Mycobacterium tuberculosis, nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus sp., Prevotella, Clostridium perfringens, Clostridium difficile, Clostridium acidophilus, E. lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharolytica, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula. In the present application, the bacterium may also include a drug-resistant strain of the above-mentioned bacteria. For example, the drug-resistant strain may be single-resistant to rifamycin, single-resistant to metronidazole, or dual-resistant to rifamycin and metronidazole. For example, the drug-resistant bacterial strain may also be resistant to other antibiotics, including macrolides such as clarithromycin, azithromycin, and roxithromycin; fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin; aminoglycosides such as streptomycin and amikacin; β-lactams such as ampicillin and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidinones such as linezolid and tedizolid; nitrofurans such as furazolidone; glycopeptides such as vancomycin; diarylquinolines such as bedaquiline; and clofazimine.

[0071] In the above use, the disease may be selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, septic arthritis, liver abscess, sinusitis, pelvic inflammation, and bacteremia. For example, the disease may be selected from upper respiratory tract infection, lower respiratory tract infection, skin and soft tissue infection, bone and joint infection, lung infection, abdominal infection, eye infection, ear infection, oral infection, and surgical infection.

[0072] Without intending to be limited by any theory, the following examples are merely illustrative of the triphenylacetate salts of the compounds of the present application, methods of preparation, and uses thereof, and are not intended to limit the scope of the present invention. [Example]

[0073] Example 1 Preparation of monotriphenylacetate salts of exemplary compounds (1) Characterization of the starting sample of the example compound The exemplary compound has the structure shown in Formula (II) (hereinafter referred to as TNP-2198), and the starting free-state sample was characterized as amorphous (Figure 1A). As can be seen from the TGA / mDSC results (Figure 1B), the sample had a weight loss of 1.8% before 200°C and a glass transition temperature of 147.8°C. 1 H NMR results (DMSO-d6, Figure 1C) were consistent with the provided target. [ka] At the same time, the solubility of the starting free base of the exemplary compound represented by formula (II) was roughly tested in five single solvents and nine mixed solvents at room temperature (up to 25°C), and the results are shown in Table 1.

[0074] [Table 1] Notes for Table 1: --: No data collected.

[0075] (2) Preparation and Characterization of Salt Forms of Exemplary Compounds 35 mg of crude free base (92.64% purity) was weighed into an HPLC vial. Weigh the acid ligand in the molar ratio corresponding to the table into an HPLC vial (first add a solvent to dilute the liquid acid, then add the free base), add the corresponding solvent, magnetically stir at room temperature for a while, add the corresponding antisolvent in the table, and if necessary, add a small amount of the corresponding seed crystals. After stirring overnight, the sample was centrifuged (10,000 rpm, 2 mins) and then vacuum dried at room temperature (25° C.) for 4 hours. The solid was collected and characterized, and the results are shown in Table 2.

[0076] [Table 2] Notes for Table 2: The yield was roughly calculated according to the screening system and may not represent the final process system. --: No data collected.

[0077] Example 2 Comparative stability experiment of monotriphenylacetate salts of example compounds (1) The monotriphenylacetate sample of the exemplary compound represented by formula (II) and the comparative examples (the hydrochloride and phosphate salts of the exemplary compound) were dried under vacuum at room temperature (up to 25°C) for 5 hours and then characterized by HPLC. The results are shown in Table 3. [Table 3] Notes for Table 3: The yield was roughly calculated according to the screening system and may not represent the final process system. --: Purity / yield is relatively low, and no further data on acid-base molar ratios have been collected; As can be seen from the salt formation results in Table 3, in the salt formation process of the compound of Formula II with different acids, the phosphate and hydrochloride salts result in a decrease in the purity of the compound and the production of decomposition impurities, whereas the monotriphenylacetate salt not only has better crystallinity but also significantly improves the purity of the compound, thereby achieving the purpose of separation and purification.

[0078] (2) Stability experiment Two types of crystalline forms I and II of the monotriphenylacetate salt of the exemplary compound represented by formula (II) were sampled and left under open conditions of 25°C / 60%RH and 40°C / 75%RH for 3 days. The results are shown in Table 4. As can be seen from the results in Table 4, under the two stability test conditions, the monotriphenylacetate sample showed no significant changes in properties or purity. Combining the results in Tables 3 and 4, compared with the hydrochloride and phosphate, the monotriphenylacetate has a moderate degree of crystallinity, and the crystalline form did not change under the two conditions, proving that the monotriphenylacetate of the example compound has good performance in both crystallinity and stability.

[0079] [Table 4]

[0080] Example 3 Preparation of Crystal Forms I to IV of the Present Application (1) Preparation of Crystal Form I To 10 mL of ethyl acetate (EtOAc), 1.00 g of TNP-2198 compound was added, and a solution of triphenylacetic acid in ethyl acetate (0.30 g + 2 mL of EtOAc) was slowly added dropwise. The mixture was stirred at 20-30°C for 18-20 hours to precipitate a solid. 3 mL of ethyl acetate solution was added to the reaction mixture, and after filtration, the wet cake was washed with 2.5 mL of solvent. The wet cake was dried under vacuum at 20-30°C for 4 hours or more, finally yielding 0.83 g of crystalline powder with a yield of 63.35% and an HPLC purity of 99.94%. A sample was then sampled for XRPD, TGA, and DSC testing. The results are shown in Figure 2, Table 5, and Figures 3A-3B.

[0081] Characterization results of crystalline form I: The diffraction peaks in XRPD showed that crystalline form I had a very high degree of crystallinity. 1 The stoichiometry was determined to be 1.0 (acid / base molar ratio) by H NMR (DMSO-d6), and no solvent residue was observed. TGA results indicated a weight loss of 0.7% (~0.5% H2O) before heating to 180°C. DSC results indicated that 166.5°C was the starting temperature for weight loss. At the same time, Form I showed no morphological change after heating to 120°C, and the heat-treated sample showed negligible weight loss before decomposition (Figures 10A-10B). After heating to 180°C, the melting of Form I samples could be observed. From the above data, Form I is likely to be monotriphenylacetic anhydride.

[0082] Further purification method 1 of crystalline form I: Add 1.8 g of TNP-2198 triphenylacetate crystalline form I (purity 95.1%) to a reaction flask, add 18 mL (10 volumes) of 2-butanone, heat to 50°C, stir and clarify, cool to 25°C, add 18 mg (1%) of seed crystals of TNP-2198 triphenylacetate crystalline form I, stir at this temperature for 1 hour, then slowly add 36 mL (20 volumes) of n-heptane, cool to 0°C and stir at this temperature for 11 hours. The resulting mixture was filtered to obtain 1.45 g of wet product, which was then added to a reaction flask, followed by the addition of 18 mL (10 volumes) of 2-butanone, and the temperature was raised to 50°C and stirred to clarify. After cooling to 25°C, 18 mg (1%) of TNP-2198 triphenylacetate Form I seed crystals were added and stirred at this temperature for 2 hours. After that, 36 mL (20 volumes) of n-heptane was added dropwise, the temperature was gradually lowered to 0°C and stirred at this temperature for 14 hours. After filtering and drying, 1.35 g of product was obtained, with a purity of 99.7%.

[0083] Further purification method 2 of crystalline form I: Add 1.8 g of TNP-2198 triphenylacetate crystalline form I (purity 95.1%) to a reaction flask, add 18 mL (10 volumes) of acetone, heat to 50°C, stir and clarify, cool to 25°C, add 18 mg (1%) of seed crystals of TNP-2198 triphenylacetate crystalline form I, stir at this temperature for 1 hour, slowly add 36 mL (20 volumes) of n-heptane, cool to 0°C and stir at this temperature for 11 hours. The resulting mixture was filtered to obtain 1.45 g of wet product, which was then added to a reaction flask, and 18 mL (10 volumes) of acetone was added. The temperature was raised to 50°C and stirred to clarify. After cooling to 25°C, 18 mg (1%) of TNP-2198 triphenylacetate Form I seed crystals were added and stirred at this temperature for 2 hours. Then, 36 mL (20 volumes) of n-heptane was added dropwise, the temperature was gradually lowered to 0°C and stirred at this temperature for 14 hours. After filtering and drying, 1.29 g of product was obtained, with a purity of 99.0%.

[0084] [Table 5]

[0085] (2) Preparation of Crystal Forms II and III To 13 mL of methyl tert-butyl ether (MTBE) solution, 1.00 g of TNP-2198 compound was added, and a solution of triphenylacetic acid in MTBE (0.30 g + 2 mL of MTBE) was slowly added dropwise. The mixture was stirred at 20-30 °C for 18-20 hours to precipitate a solid. After filtration, the wet cake was washed with 3 mL of solvent. Finally, 0.83 g of crystalline Form II powder was obtained, with a yield of 63.35% and an HPLC purity of 99.28%. A sample was then subjected to XRPD, TGA, and DSC tests. The results of Form II are shown in Figure 4, Table 6, and Figures 5A-5B. Form III was obtained by reactive crystallization of the dried crystalline Form II in a mixed solvent of 2-methyltetrahydrofuran and n-heptane, followed by vacuum drying at 40 °C overnight. The results are shown in Figure 6, Table 7, and Figures 7A-7B.

[0086] Characterization results for crystalline form II: 1 The stoichiometry was determined to be 1.1 (acid / base molar ratio) by H NMR (DMSO-d6), and the MTBE solvent content was determined to be 0.5 (approximately 3.6%) (solvent / API). TGA results showed a weight loss of 2.7% between room temperature and 130°C, followed by a weight loss of 4.0% (MTBE + HO) between 130°C and 185°C. DSC results showed endothermic peaks at 61.9°C, 146.8°C, and 184.6°C. At the same time, Form II showed no morphological changes after heating to 100°C, and after heating to 120°C, the stoichiometry was 0.5 (approximately 3.6%). 1 H NMR (DMSO-d6) showed that the MTBE / API stoichiometry was still 0.2 (approximately 1.7%).

[0087] Characterization results for crystalline form III: 1The stoichiometry was determined to be 0.8 (acid / base molar ratio) by H NMR (DMSO-d6). The solvent content was monitored to determine that the 2-MeTHF / API stoichiometry was 0.2 (approximately 0.9%) and the n-heptane / API stoichiometry was 0.4 (approximately 2.9%). TGA results showed that the weight loss was 5.7% (solvent + HO) before heating to 180°C. DSC results showed endothermic peaks at 64.7°C, 142.8°C, 159.4°C, and 177.0°C. All the above data make it clear that crystalline Forms II and III are likely hydrates or solvates of triphenylacetate.

[0088] [Table 6]

[0089] [Table 7]

[0090] (3) Preparation of Crystalline Form IV The crystalline form obtained in (2) was heated to 160°C and then cooled to room temperature (about 25°C) under N2 purging to obtain crystalline form IV of triphenylacetate, which has a relatively low degree of crystallinity. 1 The stoichiometry was determined to be 1.1 (acid / base molar ratio) by H NMR (DMSO-d6), and the residual amount of MTBE solvent was assumed to be negligible. A sample was then subjected to XRPD, TGA, and DSC tests, with the results shown in Figure 8, Table 8, and Figures 9A-9B. By TGA / DSC, the sample exhibited a 2.0% weight loss (~1.5 H2O) before 180°C and an endothermic peak at 182.8°C. From the above data, it is clear that crystalline Form IV may be a hydrate or an anhydrous form of triphenylacetate.

[0091] [Table 8]

[0092] Example 4 Crystal Form I evaluation experiment (1) Hygroscopicity experiment (Dynamic Vapor Sorption Experiment or DVS) DVS results for Form I (Figure 12A) showed a gradual weight increase from 0 to 60% RH and from 70 to 95% RH, with a rapid weight increase between 60% and 70% RH. A water absorption rate of 1.5% (~1 HO) was observed at 25°C / 80% RH (relative to 0% RH), indicating that Form I is slightly hygroscopic. XRPD results (Figure 12B) showed no change in the morphology of the form before and after DVS evaluation.

[0093] (2) Kinetic solubility Approximately 10 mg / mL of sample (calculated as free radicals) was added to each biological medium. After shaking at 100 rpm at 37°C, samples 01 to 05 (1, 4, and 24 hours) were centrifuged, and the solids were collected and used for XRPD testing, while the supernatants were used for detection and pH measurement. After 24 hours, it can be observed that the solubility of crystalline Form I in FaSSGF (~1.6 mg / mL) was higher than that in the other four media, and no morphological changes were observed in any of the media (in Figure 13, the peak at 31.6° belongs to the NaCl solvent).

[0094] [Table 9] Notes to Table 9: Biomedium: FaSSGF (artificial gastric juice in fasting state) / FeSSGF (artificial gastric juice in fed state) / FaSSIF (artificial intestinal fluid in fasting state) / FeSSIF (artificial intestinal fluid in fed state) S: solubility calculated as free radical (mg / mL); FC: morphological changes; LOQ=0.099 μg / mL.

[0095] Example 5 Preparation of the drug of crystalline form I of the present application Preparation of Crystalline Form I: A crude TNP-2198 ethyl acetate solution (purity 92%, 72 kg) was concentrated and dehydrated by jacket distillation. Triphenylacetic acid (22.4 kg, total 1 eq) was added in several portions and stirred at 25°C for 3 hours. The temperature was then lowered to 5°C and stirring was continued for 2 hours. The mixture was then filtered to obtain Crystalline Form I of TNP-2198 triphenylacetate. Preparation of drug: The wet material obtained in the above process is added to a reactor, and 385.2 kg of 2-butanone is added. The temperature is raised to above 45°C and stirred to clarify. The temperature is lowered to 20-30°C, and 72 g of seed crystals of TNP-2198 triphenylacetate crystalline form I is added. After stirring at 25°C for 2 hours, 655.3 kg of n-heptane is added dropwise. The temperature is slowly lowered to 5°C and stirred for 2 hours. After filtering, the wet material is dried at 40°C to obtain 66.23 kg of product (purity 98.7%). The obtained product can be repeatedly recrystallized in 2-butanone / n-heptane system to obtain TNP-2198 triphenylacetate crystalline form I with a purity of above 99.0%. Crystalline Form I of TNP-2198 triphenylacetate (51.5 kg) obtained in the previous step was dissolved in 1582 kg of dichloromethane at 20-30°C, and 956 kg of 1% diluted Na2CO3 solution was added to wash the dissolved salt. The solvent was replaced with ethyl acetate (less than 10% dichloromethane) by jacket distillation, and the above solution was added dropwise to 1434 kg of n-heptane to precipitate. After filtration and drying at 45°C, free amorphous TNP-2198 (37.2 kg, purity 99.7%) was obtained.

[0096] Example 6 Preparation and Characterization of Forms V and VI of the Present Application 100.04 mg of the compound of formula (I-II) (hereinafter referred to as rifabutin, purity 96.7%) was added to 1.5 mL of ethyl acetate (EtOAc) solution and stirred until completely dissolved. 34.01 mg of triphenylacetic acid was added and stirred at 20-30 °C for 18 hours. 1.5 mL of n-heptane was added to the reaction system, the mixture was filtered, the wet cake was washed with 2 mL of n-heptane, and the wet cake was vacuum dried at 20-30 °C for 8-16 hours to finally obtain 65.11 mg of crystalline form V product with an HPLC purity of 99.5%. 100.01 mg of the same rifabutin was added to 1.5 mL of methyl tert-butyl ether (MTBE) solution and stirred until completely dissolved. 34.03 mg of triphenylacetic acid was added and stirred at 20-30°C for 18 hours. The mixture obtained above was filtered, and the wet cake was washed with 2 mL of MTBE. The wet cake was vacuum dried at 20-30°C for 8-16 hours to finally obtain 54.81 mg of crystalline Form VI product with an HPLC purity of 99.3%. Crystalline Form V and Crystalline Form VI were sampled and subjected to XRPD, TGA and DSC tests, the results of which for Crystalline Form V are shown in Figure 14, Table 10 and Figures 15A-15B, the results of which for Crystalline Form VI are shown in Figure 16, Table 11 and Figures 17A-17B, and a comparison with commercially available amorphous rifabutin product is shown in Figure 18. It can be observed that both Crystalline Form V and Crystalline Form VI are basically identical, with Crystalline Form V having better crystallinity.

[0097] [Table 10]

[0098] [Table 11]

[0099] Example 7 Stability studies of the present crystalline forms V and VI An accelerated experiment was performed on a commercially available amorphous rifabutin product, and crystalline forms V and VI of the present invention, each placed in a constant temperature and humidity chamber at 40°C and 75% humidity, and the change in purity was measured after one month. The results showed that the purity of the amorphous rifabutin product decreased from 95.9% of the original sample to 95.54%, the purity of crystalline form V decreased from 99.34% of the original sample to 99.07%, and the purity of crystalline form VI decreased from 99.1% to 98.87%. This indicates that crystalline forms V and VI of the present invention have the same or higher stability than the commercially available amorphous product.

[0100] Example 8 Crystal purification ability study of the present crystalline form V In this example, amorphous rifabutin crude product was used as the starting material to investigate the crystallization systems of rifabutin triphenylacetate (tetrahydrofuran / n-heptane, butanone / n-heptane, ethyl acetate / n-heptane solvents), and the crystalline rifabutin in Examples 1 and 2 of Patent CN103408571B was used as a control to obtain the purity and yield. The results are shown in Table 12. (1) Comparison of crystalline rifabutin: No. 2: 0.50 g of amorphous rifabutin was added to 35 mL of n-hexane with stirring, and the mixture was heated under reflux and stirred for 30 minutes. The heating was stopped, and the temperature was lowered to 0°C at a rate of 10°C / hour. The mixture was filtered to obtain 0.40 g of crystalline rifabutin, with a purity of 95.46%. Compared with the starting material (No. 1), the purification effect was almost the same. No. 3: 0.50 g of amorphous rifabutin was added to 10 mL of a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 19:1 while stirring, and the mixture was heated under reflux and stirred for 30 minutes. The heating was stopped, and the temperature was lowered to 0°C at a rate of 10°C / hour. The mixture was filtered to obtain 0.22 g of crystalline rifabutin, with a purity of 95.98%. Compared with the starting purity, the purification effect was almost insignificant.

[0101] (2) Crystalline Form V and Crystalline Form VI of the present application: Preparation of crystalline form V (number 4): 7.89g of amorphous rifabutin was added to 40mL of ethyl acetate and stirred to clarify, then 2.68g of triphenylacetic acid and 40mL of n-heptane were added in turn, and the mixture was stirred at room temperature for 4 hours, filtered, and the wet substance was vacuum dried to a constant weight to obtain 7.75g of crystalline form V of rifabutin triphenylacetate, with a purity of 99.3%. Preparation of crystalline form V (No. 5): 8.01 g of amorphous rifabutin was added to 80 mL of methyl tert-butyl ether and stirred to clarify, 2.70 g of triphenylacetic acid was added, and the mixture was stirred at room temperature for 4 hours, filtered, and the wet mass was vacuum dried to a constant weight to obtain 7.10 g of crystalline form VI of rifabutin triphenylacetate, with a purity of 99.2%. As can be seen from the above results, compared with the purification of crystals in Examples 1 and 2 of Patent CN103408571B, crystalline form V significantly improves the purity of the original crude rifabutin under the premise of high yield, and such a purification effect cannot be achieved by the crystalline forms of rifabutin disclosed in the prior art.

[0102] [Table 12] Notes to Table 12: 1 : Refer to Example 1 of the method for preparing crystalline rifabutin in Chengdu Xiaofeng's Patent No. CN103408571B; 2 Reference was made to Example 2 of Chengdu XiaoFeng's Patent No. CN103408571B for the preparation of crystalline rifabutin.

Claims

1. A triphenylacetate salt of a compound of formula (I) or a hydrate, solvate, prodrug, metabolite or deuterated salt thereof, 【Chemistry 1】 wherein L is a bond, an alkyl group, or 【Chemistry 2】 wherein Ar is an optionally substituted aryl group and G is hydrogen, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group. Triphenylacetate.

2. the molar ratio of the compound of formula (I) to triphenylacetic acid is 0.8 to 1.2; The triphenylacetate salt of claim 1.

3. The salt is a monotriphenylacetate salt. The triphenylacetate salt according to claim 1 or 2.

4. The L is C １ ~C ６ is an alkyl group, The triphenylacetate salt according to any one of claims 1 to 3.

5. The structure of L is 【Transformation 3】 That is, The triphenylacetate salt according to any one of claims 1 to 3.

6. The G is C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group or C ２ ~C ６ is an alkynyl group, The triphenylacetate salt according to any one of claims 1 to 5.

7. The G is C １ ~C ３ Monohaloalkyl group or C １ ~C ３ is a dihaloalkyl group, The triphenylacetate salt according to any one of claims 1 to 5.

8. The G is optionally substituted C ３ ~C ８ a cycloalkyl group, an optionally substituted 3- to 8-membered heteroatom-containing monocyclic substituent, or an optionally substituted 4- to 12-membered heteroatom-containing bicyclic substituent; The triphenylacetate salt according to any one of claims 1 to 5.

9. The G is 【Chemistry 4】 One of the following: The triphenylacetate salt according to any one of claims 1 to 8.

10. The optionally substituted substituents are selected from halogen, hydroxyl group, carboxyl group, carbonyl group, amino group, nitro group, thiol group, cyano group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkylamino group, alkoxy group and carbonyl ester group; The triphenylacetate salt according to any one of claims 1 to 9.

11. The aforementioned 【Transformation 5】 The structure of 【Transformation 6】 One of the following: The triphenylacetate salt according to any one of claims 1 to 10.

12. The salt is crystalline, and the crystal is crystalline form I formed by crystallization of the salt represented by formula (II), 【Transformation 7】 The X-ray powder diffraction pattern of the crystalline form I contains characteristic peaks at diffraction angle 2θ values ​​of 6.11±0.2°, 9.93±0.2°, 11.49±0.2°, 14.41±0.2°, 16.15±0.2°, and 18.86±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

13. The X-ray powder diffraction pattern of the crystalline form I contains characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 12.46±0.2°, 14.89±0.2°, 16.81±0.2°, 19.31±0.2°, 20.34±0.2°, and 24.35±0.2°. The triphenylacetate salt of claim 12.

14. The X-ray powder diffraction pattern of the crystalline form I contains characteristic peaks at diffraction angle 2θ values ​​of 12.46±0.2°, 14.89±0.2°, 16.81±0.2°, 19.31±0.2°, 20.34±0.2°, and 24.35±0.2°.

14. The triphenylacetate salt of claim 12 or 13.

15. The X-ray powder diffraction pattern of said crystalline form I is essentially in accordance with FIG. The triphenylacetate salt according to any one of claims 12 to 14.

16. The crystalline form I is an anhydrous form. The triphenylacetate salt according to any one of claims 12 to 15.

17. The differential scanning calorimetry profile of crystalline form I contains an endothermic peak at 174.2°C. The triphenylacetate salt according to any one of claims 12 to 16.

18. The differential scanning calorimetry profile of the crystalline form I essentially corresponds to FIG. 3B. The triphenylacetate salt according to any one of claims 12 to 17.

19. the salt is crystalline, and the crystal is crystalline form II formed by crystallization of the salt represented by formula (II), 【Transformation 8】 The X-ray powder diffraction pattern of Crystal II includes characteristic peaks at diffraction angle 2θ values ​​of 11.37±0.2°, 12.06±0.2°, 16.10±0.2°, 18.14±0.2°, 19.80±0.2°, and 24.36±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

20. The X-ray powder diffraction pattern of the crystalline form II contains characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 4.83±0.2°, 5.61±0.2°, 6.85±0.2°, 8.51±0.2°, 10.16±0.2°, 14.54±0.2°, and 17.01±0.2°.

20. The triphenylacetate salt of claim 19.

21. The X-ray powder diffraction pattern of the crystalline form II contains characteristic peaks at diffraction angle 2θ values ​​of 4.83±0.2°, 5.61±0.2°, 6.85±0.2°, 8.51±0.2°, 10.16±0.2°, 14.54±0.2°, and 17.01±0.2°.

21. The triphenylacetate salt of claim 19 or 20.

22. The X-ray powder diffraction pattern of the crystalline form II is essentially the same as that shown in FIG. The triphenylacetate salt according to any one of claims 19 to 21.

23. The method for producing the crystalline form II includes crystallizing the salt represented by formula (II) in an MTBE solvent to form the crystalline form II. The triphenylacetate salt according to any one of claims 19 to 22.

24. The differential scanning calorimetry profile of the crystalline form II includes endothermic peaks at 61.9°C, 146.8°C, and 184.6°C. The triphenylacetate salt according to any one of claims 19 to 23.

25. The differential scanning calorimetry profile of the crystalline form II essentially corresponds to FIG. 5B. The triphenylacetate salt according to any one of claims 19 to 24.

26. the salt is crystalline, and the crystal is crystalline form III formed by crystallization of the salt represented by formula (II); 【Chemistry 9】 The X-ray powder diffraction pattern of the crystalline III contains characteristic peaks at diffraction angle 2θ values ​​of 9.57±0.2°, 11.49±0.2°, 12.14±0.2°, 16.18±0.2°, 18.26±0.2°, 19.61±0.2°, and 19.92±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

27. The X-ray powder diffraction pattern of the crystalline form III contains characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 4.10±0.2°, 5.00±0.2°, 5.76±0.2°, 19.15±0.2°, 20.81±0.2°, 21.60±0.2°, and 24.52±0.2°.

27. The triphenylacetate salt of claim 26.

28. The X-ray powder diffraction pattern of the crystalline form III contains characteristic peaks at diffraction angle 2θ values ​​of 4.10±0.2°, 5.00±0.2°, 5.76±0.2°, 19.15±0.2°, 20.81±0.2°, 21.60±0.2°, and 24.52±0.2°.

28. The triphenylacetate salt of claim 26 or 27.

29. The X-ray powder diffraction pattern of the crystalline form III is essentially in accordance with FIG. The triphenylacetate salt according to any one of claims 26 to 28.

30. A method for producing the crystalline form III includes crystallizing the salt represented by formula (II) in a mixed solvent of 2-methyltetrahydrofuran and n-heptane to form the crystalline form III. The triphenylacetate salt according to any one of claims 26 to 29.

31. The differential scanning calorimetry profile of the crystalline form III contains endothermic peaks at 64.7°C, 142.8°C, 159.4°C, and 177.0°C. The triphenylacetate salt according to any one of claims 26 to 30.

32. The differential scanning calorimetry profile of the crystalline form III essentially corresponds to FIG. 7B. The triphenylacetate salt according to any one of claims 26 to 31.

33. the salt is crystalline, and the crystal is crystalline form IV formed by crystallization of the salt represented by formula (II), 【Chemistry 10】 The X-ray powder diffraction pattern of the crystalline IV contains characteristic peaks at diffraction angle 2θ values ​​of 10.64±0.2°, 11.54±0.2°, 14.64±0.2°, 16.06±0.2°, 18.08±0.2°, and 23.89±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

34. The X-ray powder diffraction pattern of the crystalline form IV contains characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 4.85±0.2°, 7.21±0.2°, 18.82±0.2°, 20.09±0.2°, 24.26±0.2°, and 30.24±0.2°.

34. The triphenylacetic acid salt of claim 33.

35. The X-ray powder diffraction pattern of the crystalline form IV contains characteristic peaks at diffraction angle 2θ values ​​of 4.85±0.2°, 7.21±0.2°, 18.82±0.2°, 20.09±0.2°, 24.26±0.2°, and 30.24±0.2°.

35. The triphenylacetate salt of claim 33 or 34.

36. The X-ray powder diffraction pattern of the crystalline form IV is essentially in accordance with FIG. The triphenylacetic acid salt according to any one of claims 33 to 35.

37. A method for preparing crystalline form IV comprises heating the crystalline form of any one of claims 26 to 32 to 160°C to form crystalline form IV. The triphenylacetic acid salt according to any one of claims 33 to 36.

38. The differential scanning calorimetry profile of crystalline Form IV includes an endothermic peak at 182.8°C. The triphenylacetate salt according to any one of claims 33 to 37.

39. The differential scanning calorimetry profile of the crystalline form IV essentially corresponds to FIG. 9B. The triphenylacetic acid salt according to any one of claims 33 to 38.

40. The salt is crystalline, and the crystalline form is crystalline form V formed by crystallization of the salt represented by formula (I-II), 【Chemistry 11】 The X-ray powder diffraction pattern of the crystalline form V contains characteristic peaks at diffraction angle 2θ values ​​of 7.65±0.2°, 10.84±0.2°, 11.71±0.2°, 12.26±0.2°, 20.60±0.2°, and 24.83±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

41. The X-ray powder diffraction pattern of the crystalline form V contains characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 6.45±0.2°, 16.44±0.2°, 18.18±0.2°, 18.47±0.2°, and 26.54±0.2°.

41. The triphenylacetate salt of claim 40.

42. The X-ray powder diffraction pattern of the crystalline form V contains characteristic peaks at diffraction angle 2θ values ​​of 6.45±0.2°, 16.44±0.2°, 18.18±0.2°, 18.47±0.2°, and 26.54±0.2°.

42. The triphenylacetate salt of claim 40 or 41.

43. The X-ray powder diffraction pattern of the crystalline form V is essentially in accordance with FIG.

14. The triphenylacetate salt according to any one of claims 40 to 42.

44. A method for producing the crystalline form V includes crystallizing triphenylacetic acid salt represented by formula (I-II) in an ethyl acetate solvent to form the crystalline form V. The triphenylacetate salt according to any one of claims 40 to 43.

45. The differential scanning calorimetry profile of crystalline form V includes an endothermic peak at 164.0°C. The triphenylacetate salt according to any one of claims 40 to 44.

46. The differential scanning calorimetry profile of crystalline form V essentially corresponds to FIG. 15B. The triphenylacetate salt according to any one of claims 40 to 45.

47. the salt is crystalline, and the crystalline form is crystalline form VI formed by crystallization of the salt represented by formula (I-II); 【Chemistry 12】 The X-ray powder diffraction pattern of the crystalline form VI contains characteristic peaks at diffraction angle 2θ values ​​of 11.05±0.2°, 11.76±0.2°, 12.45±0.2°, 16.45±0.2°, 18.15±0.2°, 20.59±0.2°, and 24.77±0.2°. The triphenylacetate salt according to any one of claims 1 to 11.

48. The X-ray powder diffraction pattern of the crystalline form VI includes characteristic peaks at one or more positions having diffraction angle 2θ values ​​of 5.89±0.2°, 6.63±0.2°, 8.87±0.2°, 9.31±0.2°, 17.87±0.2°, 20.00±0.2°, and 24.26±0.2°.

48. The triphenylacetic acid salt of claim 47.

49. The X-ray powder diffraction pattern of the crystalline form VI contains characteristic peaks at diffraction angle 2θ values ​​of 5.89±0.2°, 6.63±0.2°, 8.87±0.2°, 9.31±0.2°, 17.87±0.2°, 20.00±0.2°, and 24.26±0.2°.

49. The triphenylacetate salt of claim 47 or 48.

50. The X-ray powder diffraction pattern of the crystalline form VI is essentially in accordance with FIG.

16. The triphenylacetate salt according to any one of claims 47 to 49.

51. A method for preparing the crystalline form VI includes crystallizing triphenylacetate represented by formula (I-II) in a methyl tert-butyl ether solvent to form the crystalline form VI. The triphenylacetate salt according to any one of claims 47 to 50.

52. The differential scanning calorimetry profile of crystalline Form VI contains endothermic peaks at 127.2°C, 140.6°C, and 161.8°C. The triphenylacetic acid salt according to any one of claims 47 to 51.

53. The differential scanning calorimetry profile of crystalline Form VI essentially corresponds to FIG. 17B. The triphenylacetate salt according to any one of claims 47 to 52.

54. A process for preparing a salt, comprising reacting the free base of the compound of formula (I) with triphenylacetic acid to form a salt according to any one of claims 1 to 53. method.

55. The method comprises reacting the free base of the compound of formula (I) and triphenylacetic acid in one solvent or a combination of solvents selected from (1) ethyl acetate, (2) 2-methyltetrahydrofuran and isopropyl acetate, (3) 2-methyltetrahydrofuran and n-heptane, (4) 2-butanone and n-heptane, (5) methyl tert-butyl ether, (6) methyl tert-butyl ether and n-heptane, (7) toluene, (8) isopropanol and n-heptane, (9) isopropyl acetate, (10) acetone, (11) methanol and methyl tert-butyl ether, or (12) n-heptane; 55. The method of claim 54.

56. mixing the free base of the compound of formula (I), ethyl acetate, and triphenylacetic acid in that order to form a reaction mixture; 56. The method of claim 54 or 55.

57. incubating the reaction mixture at a reaction temperature of 20-40°C; 57. The method of claim 56.

58. mixing triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of formula (I), and isopropyl acetate in that order to form a reaction mixture; 56. The method of claim 54 or 55.

59. mixing triphenylacetic acid, 2-methyltetrahydrofuran, the free base of the compound of formula (I), and n-heptane in that order to form a reaction mixture; 56. The method of claim 54 or 55.

60. incubating the reaction mixture at a reaction temperature of 50-75°C; 60. The method of claim 58 or 59.

61. mixing the free base of the compound of formula (I), 2-butanone, triphenylacetic acid, and n-heptane in that order to form a reaction mixture; 56. The method of claim 54 or 55.

62. incubating the reaction mixture at a reaction temperature of 40-60°C; 62. The method of claim 61.

63. The salt formed from the free base of the compound of formula (I) and triphenylacetic acid is crystalline, and the method further comprises recrystallizing the crystalline in a suitable solvent to improve purity.

63. The method of any one of claims 54 to 62.

64. The suitable solvents include 2-butanone and n-heptane, or acetone and n-heptane.

64. The method of claim 63.

65. A method for producing a medicament, comprising providing a triphenylacetic acid salt according to any one of claims 1 to 53. method.

66. 1) converting the triphenylacetate salt into a free base by dissolving it in a suitable organic solvent; 2) adjusting the free base to a suitable concentration using a suitable organic solvent; and 3) obtaining the drug using an organic solvent capable of precipitating a purified drug solid from the solution of the free base.

66. The method of claim 65.

67. the suitable organic solvents in steps 1) and 2) are each independently selected from dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and 2-methyltetrahydrofuran, and the suitable organic solvents used in steps 1) and 2) have different solubilities; 67. The method of claim 66.

68. The solvent in which the purified drug solids can be precipitated is n-heptane.

67. The method of claim 66.

69. 1) dissolving the triphenylacetic acid salt of any one of claims 1 to 53 in a suitable organic solvent, washing with a washing solution one or more times, collecting the washed organic phase, washing the washed organic phase with water, and collecting the water-washed organic phase; 2) adding a suitable organic solvent having a different solubility from the organic solvent of step 1) to the collected water-washed organic phase of step 1), and concentrating under reduced pressure, repeating this operation until a concentrated solution of the free base of the compound of formula (I) is obtained; and 3) adding the concentrated solution of the free base of step 2) to an organic solvent capable of precipitating a purified drug solid under a nitrogen gas atmosphere, and then filtering, washing, and drying to obtain the drug.

69. The method of any one of claims 65 to 68.

70. The cleaning solution is selected from suitable weakly basic solutions; 70. The method of claim 69.

71. The cleaning solution is a sodium bicarbonate solution, a sodium carbonate solution, a potassium bicarbonate solution or a potassium carbonate solution; 71. The method of claim 69 or 70.

72. The suitable organic solvent in step 1) has a residual content of 10.0% or less in the free base concentrate.

72. The method according to any one of claims 69 to 71.

73. Step 3) comprises adding the free base concentrate dropwise to n-heptane over a period of 3 to 8 hours while stirring, maintaining the internal temperature at 10 to 20°C, and continuing stirring for 1 to 2 hours after the addition is complete; 73. The method of any one of claims 69 to 72.

74. 54. A method for treating a rheumatoid arthritis comprising administering to a subject a rheumatoid arthritis patient in need thereof, ... a method for treating a rheumatoid arthritis patient in need thereof, a method for treating a rheumatoid arthritis patient in need thereof, a method for treating a rheumatoid arthritis patient Pharmaceutical compositions.

75. comprising a second therapeutic agent, 75. The pharmaceutical composition of claim 74.

76. the second therapeutic agent is selected from a proton pump inhibitor, an acid secretion inhibitor, an efflux pump inhibitor, an anesthetic, an antifungal agent, an antiviral agent, an antibacterial agent, an antiprotozoal agent, an anti-inflammatory agent, an anticoagulant, a platelet aggregation inhibitor, an antipyretic, a lipid-lowering agent, and a zinc salt; 76. The pharmaceutical composition of claim 75.

77. 76. A pharmaceutical composition comprising a triphenylacetic acid salt according to any one of claims 1 to 53 and / or a pharmaceutical composition according to any one of claims 74 to 76. kit.

78. including written instructions and / or instructions in machine-readable electronic form, 78. The kit of claim 77.

79. A method for inhibiting or preventing bacterial growth, comprising administering an effective amount of a triphenylacetic acid salt according to any one of claims 1 to 53, a pharmaceutical composition according to any one of claims 74 to 76 and / or a kit according to claim 77 or 78. method.

80. A method for treating a disease, comprising administering to a patient in need thereof an effective amount of a triphenylacetic acid salt according to any one of claims 1 to 53, a pharmaceutical composition according to any one of claims 74 to 76 and / or a kit according to claim 77 or 78. method.

81. The patient has a bacterial infection.

81. The method of claim 80.

82. The bacteria include Helicobacter pylori, Mycobacterium tuberculosis, Nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus spp., Prevotella spp., Clostridium perfringens, Clostridium difficile, Lactobacillus acidophilus, Eggertella lenta, Fusobacterium nucleatum, nucleatum, Gardnerella vaginalis, Mobiluncus mulieris, Peptostreptococcus spp., Porphyromonas asaccharolyticus, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula; 82. The method of any one of claims 79 and 81.

83. Use of a triphenylacetic acid salt according to any one of claims 1 to 53, a pharmaceutical composition according to any one of claims 74 to 76 and / or a kit according to claim 77 or 78 for inhibiting or preventing bacterial growth.

84. Use of a triphenylacetic acid salt according to any one of claims 1 to 53, a pharmaceutical composition according to any one of claims 74 to 76 and / or a kit according to claim 77 or 78 for the manufacture of a medicament for the treatment and / or prevention of a disease or condition caused by a bacterial infection.

85. The bacteria include Helicobacter pylori, Mycobacterium tuberculosis, Nontuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus spp., Prevotella spp., Clostridium perfringens, Clostridium difficile, Lactobacillus acidophilus, Eggertella lenta, Fusobacterium nucleatum, nucleatum, Gardnerella vaginalis, Mobiluncus mulieris, Peptostreptococcus spp., Porphyromonas asaccharolyticus, Prevotella bivia, Propionibacterium acnes, and Veillonella parvula; 85. Use according to claim 83 or 84.

86. The disease or condition is selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, septic arthritis, liver abscess, sinusitis, pelvic inflammation, and bacteremia, as well as upper respiratory tract infection, lower respiratory tract infection, skin and soft tissue infection, bone and joint infection, lung infection, abdominal cavity infection, eye infection, ear infection, oral infection, and surgical infection.

85. The use according to claim 84.

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