Salt form and crystal form of boron compound prodrug, and pharmaceutical composition and use thereof

Abstract

The present invention relates to a salt and crystal form of a boron compound prodrug, and the use thereof. The present invention further relates to a pharmaceutical composition containing the salt, the crystal form, or a combination thereof. Further provided in the present invention is the use of the salt and crystal form of the boron compound prodrug, or the pharmaceutical composition containing the salt for the treatment of microbial infections.

Description

Boron compound prodrug salt form, crystal form and pharmaceutical composition and use thereof Technical Field

[0001] The present invention provides a salt form, a crystal form, a pharmaceutical composition and use of a boron compound prodrug. Background Art

[0002] Due to the increasing bacterial resistance, new types of antimicrobial compounds are needed for the treatment of microbial infections. It is necessary to avoid undesirable cross-infection with existing drugs, with a drug with a new mechanism of action. Such drugs need to have effective activity against major mammalian pathogens, such as Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae, and major Gram-positive bacteria such as multidrug-resistant Staphylococcus and Streptococcus, some anaerobic bacteria such as Bacteroides and Clostridium, such as Clostridium difficile and acid-resistant microorganisms, including Mycobacterium tuberculosis and Mycobacterium avium. The treatment of serious parasitic infections also requires such drugs, such as trypanosomiasis.

[0003] For many patients with bacterial infections, oral medications are the most appropriate option. Advantages of oral therapy over intravenous (IV) therapy include the absence of cannula-related infections, lower medication costs, and reduced hidden costs, such as the need for healthcare professionals and equipment to administer IV antibiotics. For patients requiring long-term treatment, oral therapy is particularly important to improve patient compliance.

[0004] Several antimicrobial boron-containing organic compounds have been described for their activity in WO 2008 / 157726, US 2009 / 0227541 and WO 2010 / 080558. To date, none of these compounds has been approved for use in human anti-infective treatment.

[0005] US2013 / 165411 describes a tricyclic boron compound (as shown in the figure below) that is particularly effective against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. However, there has been no report on the oral bioavailability of this molecule to date. In addition to the required antibacterial activity and safety, effective oral antibacterial drugs must have oral bioavailability suitable for practical application. In fact, many antibiotics, such as cephalosporins, can only be used as intravenous drugs. Because drugs with poor oral bioavailability are not suitable for the development of oral drugs due to lack of sufficient drug exposure, or it will require higher doses, which may cause additional side effects.

[0006] There are two main approaches to improving a compound's membrane permeability (e.g., oral absorption). One involves modifying its chemical structure itself, and the other involves designing a formulation without modifying its chemical structure. The first approach involves attaching a small modifying group (e.g., an alkyl or acyl group) to a compound's active substituent (e.g., a carboxyl or amino group), thereby forming a prodrug.

[0007] The preferred compounds for the above-mentioned prodrugs are compounds that exist in a stable prodrug form before absorption, have improved absorption after forming the prodrug, and are rapidly converted into active forms in the small intestine, liver and / or plasma by chemical or enzymatic action.

[0008] However, it is difficult to develop an ideal prodrug that meets all of the above conditions. For example, prodrugs with ester bonds are more susceptible to hydrolysis, which may have a significant impact on chemical stability before absorption. For prodrugs with amide bonds, significant changes in the physical properties of the compound may have a significant impact on membrane permeability, such as oral absorption. In addition, amide bonds are less likely to be hydrolyzed, which may have a significant impact on the biotransformation of the compound to the active form and plasma concentration. In addition, it is difficult to predict the pharmacokinetic characteristics of prodrugs because the enzymes that control the biotransformation of prodrugs to the active form are substrate-specific, especially when steric hindrance of substituents inserted to form the prodrug prevents the enzyme reaction. For these reasons, it is not easy to increase the plasma concentration of the active form by estimating the membrane permeability of the prodrug and its conversion to the active form. US2013 / 165411 describes a prodrug compound shown below, and reports pharmacokinetic or efficacy studies. In addition, the document neither discloses nor suggests the use of the prodrug of the present invention to improve oral bioavailability. Summary of the Invention

[0009] In response to the above problems, the present application has conducted in-depth research on the different aggregation states of the free base or acid salt of boron compound prodrugs, and obtained a variety of crystalline forms of boron compound prodrugs. These crystalline forms can greatly improve the physicochemical properties of amorphous boron compound prodrugs, such as crystallinity, hygroscopicity, and stability, and improve the process operability, thereby screening out the most suitable aggregation state that is pharmaceutically acceptable, providing a scientific basis for drug development.

[0010] In a first aspect, the present application provides a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, provided that the compound of formula I is not a free base in a non-crystalline form, and the acid addition salt is not a hydrochloride in a non-crystalline form,

[0011] In some embodiments, the present application provides a crystalline form of the free base of the compound of Formula I.

[0012] In some embodiments, the present application provides a pharmaceutically acceptable acid addition salt of the compound of Formula I and the acid addition salt is not a hydrochloride salt.

[0013] In some embodiments, the present application provides a crystalline form of a pharmaceutically acceptable acid addition salt of a compound of Formula I.

[0014] In some embodiments, the acid addition salts described herein are inorganic acid salts or organic acid salts.

[0015] In some embodiments, the inorganic acid salt described herein is hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate, metaphosphate, or any combination thereof.

[0016] In some embodiments, the organic acid salt described herein is formate, acetate, propionate, butyrate, benzoate, malonate, succinate (succinate), pyruvate, methanesulfonate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propiolate, 2-butynoate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1, 2-Ethanedisulfonate, Naphthalenesulfonate, Oxalate, Trifluoroacetate, Trifluoromethanesulfonate, Adipate, Suberate, Sebacate, Butyne-1,4-dioate, Hexyne-1,6-dioate, Hydroxyacetate, Alginate, Ascorbate, Erysoascorbate, Aspartate, L-Aspartate, Glutamate, L-Glutamate, 2-Phenoxybenzoate, 2-(4-hydroxybenzoyl)benzoate, Acetoacetate, 2-Hydroxyethanesulfonate, Benzenesulfonate, Borate, Chlorobenzoate, Camphorate, Itaconate, Camphorsulfonate, L-Camphorsulfonate, Methylbenzoate, Dinitrobenzoate, sulfamate, lactobionate, galacturonate, cyclopentylpropionate, dodecyl sulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, pivalate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pamoate, pectinate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, 3-hydroxy-2-naphthalene Formate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salts, alginate, 4-acetamidobenzenesulfonate, caprate, cholate, octanoate, nonanoate, cyclamate, phthalate, cysteine ​​hydrochloride, sorbate, pamoate, mucate, glycine hydrochloride, naphthalenedisulfonate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyethylenesulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyethylenesulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, valerate, or any combination thereof.

[0017] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof described herein is in crystalline form.

[0018] In some embodiments, the compound represented by formula (I) described in the present application is its free base crystalline form I, and the X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77±0.20°, 9.91±0.20°, 10.10±0.20°, 11.68±0.20°, 15.09±0.20°, 21.46±0.20°, and 23.25±0.20°.

[0019] In some embodiments, the compound represented by formula (I) described herein is its free base crystalline form I, and the X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77±0.20°, 9.22±0.20°, 9.91±0.20°, 10.10±0.20°, 11.68±0.20°, 15.09±0.20°, 17.98±0.20°, 18.35±0.20° , 18.53±0.20°, 19.55±0.20°, 19.89±0.20°, 20.24±0.20°, 21.16±0.20°, 21.46±0.20°, 23.01±0.20°, 23.25±0.20°, 23.57±0.20°, 25.10±0.20°, 25.53±0.20°, 26.74±0.20°, 29.28±0.20°.

[0020] In some embodiments, the compound of formula (I) described herein is a free base crystalline form I, and the X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77°, 9.22°, 9.91°, 10.10°, 11.68°, 11.95°, 15.09°, 15.61°, 17.98°, 18.35°, 18.53°, 18.85°, 19.26°, 19.55°, 19. 89°, 20.24°, 21.16°, 21.46°, 21.87°, 22.21°, 23.01°, 23.25°, 23.57°, 24.05°, 25.10°, 25.53°, 25.88°, 26.4°, 26.74°, 27.50°, 28.12°, 29.28°, 31.20°, 31.62, 32.80°, 34.08°, 36.47°, 37.74°.

[0021] In some embodiments, the compound represented by formula (I) described in the present application is its free base crystal form II, and the X-ray powder diffraction pattern of the free base crystal form II has diffraction peaks at the following 2θ angles: 3.93±0.20°, 7.82±0.20°, 11.72±0.20°, 15.13±0.20°, and 21.50±0.20°.

[0022] In some embodiments, the compound represented by formula (I) described in the present application is its free base crystal form II, and the X-ray powder diffraction pattern of the free base crystal form II has diffraction peaks at the following 2θ angles: 3.93±0.20°, 7.82±0.20°, 10.15±0.20°, 11.72±0.20°, 15.13±0.20°, 15.64±0.20°, 18.01±0.20°, 19.60±0.20°, 21.50±0.20°, 23.28±0.20°, 25.14±0.20°, and 29.32±0.20°.

[0023] In some embodiments, the compound represented by formula (I) described in the present application is its free base crystal form II, and the X-ray powder diffraction pattern of the free base crystal form II has diffraction peaks at the following 2θ angles: 3.93°, 7.82°, 9.11°, 10.15°, 11.72°, 15.13°, 15.64°, 18.01°, 18.40°, 19.60°, 21.50°, 23.28°, 25.14°, 26.78°, 27.56°, 29.32°, 32.87°, and 37.57°.

[0024] In some embodiments, the acid addition salt described in the present application is a fumarate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the fumaric acid form I has diffraction peaks at the following 2θ angles: 3.22±0.20°, 9.51±0.20°, 13.00±0.20°, 15.86±0.20°, and 20.19±0.20°.

[0025] In some embodiments, the acid addition salt described in the present application is a fumarate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the fumaric acid form I has diffraction peaks at the following 2θ angles: 3.22±0.20°, 9.51±0.20°, 11.52±0.20°, 13.00±0.20°, 15.86±0.20°, 19.61±0.20°, 20.19±0.20°, 21.65±0.20°, 22.41±0.20°, 24.58±0.20°, and 26.34±0.20°.

[0026] In some embodiments, the acid addition salt described in the present application is a fumarate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the fumaric acid form I has diffraction peaks at the following 2θ angles: 3.22°, 9.51°, 10.13°, 11.52°, 13.00°, 13.63°, 14.76°, 15.86°, 16.69°, 18.75°, 19.61°, 20.19°, 21.19°, 21.65°, 22.41°, 24.58°, 26.34°, 28.75°, 29.83°, and 35.27°.

[0027] In some embodiments, the acid addition salt described herein is a malate crystalline form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the malate crystalline form I has diffraction peaks at the following 2θ angles: 7.31±0.20°, 11.75±0.20°.

[0028] In some embodiments, the acid addition salt described herein is a malate crystalline form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the malate crystalline form I has diffraction peaks at the following 2θ angles: 7.31°, 11.75°.

[0029] In some embodiments, the acid addition salt described herein is a citrate salt crystalline form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt crystalline form I has diffraction peaks at the following 2θ angles: 6.30±0.20°, 6.74±0.20°, 9.04±0.20°, 12.10±0.20°, and 18.55±0.20°.

[0030] In some embodiments, the acid addition salt described herein is a citrate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt form I has diffraction peaks at the following 2θ angles: 6.30±0.20°, 6.74±0.20°, 9.04±0.20°, 12.10±0.20°, 13.35±0.20°, 17.28±0.20°, 18.55±0.20°, 20.11±0.20°, and 21.02±0.20°.

[0031] In some embodiments, the acid addition salt described herein is a citrate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt form I has diffraction peaks at the following 2θ angles: 6.30°, 6.74°, 9.04°, 12.10°, 13.35°, 17.28°, 18.55°, 20.11°, and 21.02°.

[0032] In some embodiments, the acid addition salt described in the present application is a citrate salt form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt form II has diffraction peaks at the following 2θ angles: 6.72±0.20°, 9.04±0.20°, 15.11±0.20°, 18.59±0.20°, 21.51±0.20°, 24.03±0.20°, and 24.62±0.20°.

[0033] In some embodiments, the acid addition salt described in the present application is a citrate salt crystalline form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt crystalline form II has diffraction peaks at the following 2θ angles: 6.72±0.20°, 9.04±0.20°, 13.97±0.20°, 15.11±0.20°, 18.59±0.20°, 20.17±0.20°, 21.09±0.20°, 21.51±0.20°, 24.03±0.20°, 24.62±0.20°, and 28.11±0.20°.

[0034] In some embodiments, the acid addition salt described herein is the citrate salt crystal form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt crystal form II is substantially as shown in Figure 24.

[0035] In some embodiments, the acid addition salt described herein is a citrate salt crystalline form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the citrate salt crystalline form II has diffraction peaks at the following 2θ angles: 6.72°, 9.04°, 11.46°, 12.10°, 13.38°, 13.97°, 14.70°, 15.11°, 15.56°, 16.67°, 18.59°, 1 9.05°, 19.41°, 20.17°, 21.09°, 21.51°, 22.21°, 23.29°, 24.03°, 24.62°, 25.33°, 26.20°, 26.74°, 28.11°, 29.49°, 31.32°, 32.21°, 33.82°, 35.88°, 36.38°, 37.27°, 38.54°.

[0036] In some embodiments, the acid addition salt described in the present application is a tartrate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the tartrate salt form I has diffraction peaks at the following 2θ angles: 3.87±0.20°, 7.66±0.20°.

[0037] In some embodiments, the acid addition salt described herein is a tartrate salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the tartrate salt form I has diffraction peaks at the following 2θ angles: 3.87°, 7.66°.

[0038] In some embodiments, the acid addition salt described herein is the hydrochloride salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt form I has diffraction peaks at the following 2θ angles: 5.04±0.20°, 10.05±0.20°, 14.38±0.20°, 15.88±0.20°, and 25.53±0.20°.

[0039] In some embodiments, the acid addition salt described herein is the hydrochloride salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt form I has diffraction peaks at the following 2θ angles: 5.04±0.20°, 8.59±0.20°, 10.05±0.20°, 14.38±0.20°, 15.88±0.20°, 18.81±0.20°, 22.79±0.20°, 23.81±0.20°, 25.53±0.20°, 26.45±0.20°, and 28.34±0.20°.

[0040] In some embodiments, the acid addition salt described herein is the hydrochloride salt form I of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt form I has diffraction peaks at the following 2θ angles: 5.04°, 8.59°, 10.05°, 12.24°, 14.38°, 15.88°, 16.64°, 17.12°, 18.81°, 21.07°, 22.79°, 23.81°, 25.53°, 25.95°, 26.45°, 26.81°, 28.34°, and 31.38°.

[0041] In some embodiments, the acid addition salt described in the present application is the hydrochloride crystal form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form II has diffraction peaks at the following 2θ angles: 4.96±0.20°, 9.88±0.20°, 14.23±0.20°, 16.43±0.20°, and 23.46±0.20°.

[0042] In some embodiments, the acid addition salt described in the present application is the hydrochloride crystal form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form II has diffraction peaks at the following 2θ angles: 4.96±0.20°, 9.88±0.20°, 14.23±0.20°, 14.83±0.20°, 16.43±0.20°, 18.78±0.20°, 23.46±0.20°, 25.58±0.20°, 26.41±0.20°, 29.94±0.20°, and 30.79±0.20°.

[0043] In some embodiments, the acid addition salt described herein is a hydrochloride salt crystalline form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt crystalline form II has diffraction peaks at the following 2θ angles: 4.96±0.20°, 8.60±0.20°, 9.88±0.20°, 10.23±0.20°, 12.12±0.20°, 14.23±0. 20°, 14.83±0.20°, 15.94±0.20°, 16.43±0.20°, 17.39±0.20°, 18.78±0.20°, 19.83±0.20°, 21.06±0.20°, 22.43±0.20°, 22.83±0.20°, 23.46±0.20°, 23.92±0.2 0°, 24.53±0.20°, 24.85±0.20°, 25.58±0.20°, 26.02±0.20°, 26.41±0.20°, 28.36±0.20°, 28.66±0.20°, 29.27±0.20°, 29.94±0.20°, 30.79±0.20°, 31.26±0.20 °, 31.79±0.20°, 32.54±0.20°, 33.26±0.20°, 33.66±0.20°, 34.93±0.20°, 35.55±0.20°, 37.02±0.20°, 37.72±0.20°, 38.37±0.20°, 39.16±0.20°, 39.90±0.20°.

[0044] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form II is substantially as shown in Figure 30.

[0045] In some embodiments, the acid addition salt described herein is a hydrochloride salt crystalline form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt crystalline form II has diffraction peaks at the following 2θ angles: 4.96°, 8.60°, 9.88°, 10.23°, 12.12°, 14.23°, 14.83°, 15.94°, 16.43°, 17.39°, 18.78°, 19.83°, 21.06°, 22.43°, 22.83° , 23.46°, 23.92°, 24.53°, 24.85°, 25.58°, 26.02°, 26.41°, 28.36°, 28.66°, 29.27°, 29.94°, 30.79°, 31.26°, 31.79°, 32.54°, 33.26°, 33.66°, 34.93°, 35.55°, 37.02°, 37.72°, 38.37°, 39.16°, 39.90°.

[0046] In some embodiments, the acid addition salt described in the present application is the hydrochloride crystal form III of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form III has diffraction peaks at the following 2θ angles: 3.77±0.20°, 5.59±0.20°, 10.72±0.20°, 12.70±0.20°, 15.38±0.20°, 17.39±0.20°, and 20.43±0.20°.

[0047] In some embodiments, the acid addition salt described herein is a hydrochloride salt crystalline form III of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt crystalline form III has diffraction peaks at the following 2θ angles: 3.77±0.20°, 3.99±0.20°, 5.59±0.20°, 7.98±0.20°, 8.34±0.20°, 8.66±0.20°, 10.72±0.20°, 11.20±0.20°, 11.80±0.20°, 12.12±0.20°, 12.38±0.20°, 12.70±0.20°, 14.10±0.20°, 14.41±0.20°, 15.03±0.20°, 15.38±0.20° , 16.10±0.20°, 16.73±0.20°, 17.39±0.20°, 18.87±0.20°, 19.17±0.20°, 20.43±0.20°, 21.92±0.20°, 22.36±0.20°, 23.12±0.20°, 23.55±0.20°, 24.30 ±0.20°, 25.07±0.20°, 25.65±0.20°, 26.57±0.20°, 27.01±0.20°, 27.55±0.20°, 32.97±0.20°, 33.80±0.20°, 36.93±0.20°, 37.70±0.20°, 37.90±0.20°.

[0048] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form III of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form III is substantially as shown in Figure 33.

[0049] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form IV of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form IV has diffraction peaks at the following 2θ angles: 9.15±0.20°, 10.09±0.20°, 12.35±0.20°, 13.73±0.20°, 14.41±0.20°, 18.71±0.20°, and 21.30±0.20°.

[0050] In some embodiments, the acid addition salt described herein is a hydrochloride crystalline form IV of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystalline form IV has diffraction peaks at the following 2θ angles: 8.57±0.20°, 9.15±0.20°, 10.09±0.20°, 10.44±0.20°, 11.82±0.20°, 12.35±0.20°, 12.68±0.20°, 13.73±0.20°, 14.12±0.20°, 14.41±0.20°, 14.68±0.20°, 15.26±0.20°, 15.87±0.2 0°, 16.69±0.20°, 18.60±0.20°, 18.71±0.20°, 19.12±0.20°, 20.80±0.20°, 21.14±0.20°, 21.30±0.20°, 21.96±0.20°, 22.54±0.20°, 23.08±0.20°, 23.63±0.20°, 24.96±0.20°, 25.86±0.20°, 26.12±0.20°, 29.09±0.20°, 31.72±0.20°, 38.13±0.20°, and 38.91±0.20°.

[0051] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form IV of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form IV is substantially as shown in Figure 36.

[0052] In some embodiments, the acid addition salt described in the present application is the hydrochloride salt form V of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt form V has diffraction peaks at the following 2θ angles: 5.69±0.20°, 9.13±0.20°, 12.51±0.20°, 13.03±0.20°, 14.73±0.20°, 16.30±0.20°, and 18.40±0.20°.

[0053] In some embodiments, the acid addition salt described herein is a hydrochloride crystalline form V of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystalline form V has diffraction peaks at the following 2θ angles: 5.69±0.20°, 7.83±0.20°, 8.22±0.20°, 9.13±0.20°, 11.39±0.20°, 12.51±0.2 0°, 13.03±0.20°, 14.44±0.20°, 14.73±0.20°, 15.76±0.20°, 16.30±0.20°, 17.10±0.20°, 17.85±0.20°, 18.40±0.20°, 19.17±0.20°, 19.77±0.20°, 20.19±0.20 °, 21.22±0.20°, 21.45±0.20°, 23.26±0.20°, 23.79±0.20°, 24.07±0.20°, 24.94±0.20°, 25.27±0.20°, 25.99±0.20°, 26.30±0.20°, 26.95±0.20°, 27.85±0.20° , 28.96±0.20°, 29.25±0.20°, 29.82±0.20°, 30.61±0.20°, 31.86±0.20°, 32.27±0.20°, 32.67±0.20°, 33.08±0.20°, 33.96±0.20°, 34.44±0.20°, 39.43±0.20°.

[0054] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form V of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form V is substantially as shown in Figure 39.

[0055] In some embodiments, the acid addition salt described herein is a hydrochloride salt form VI of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride salt form VI has diffraction peaks at the following 2θ angles: 4.95±0.20°, 7.12±0.20°, 10.69±0.20°, 11.97±0.20°, 12.99±0.20°, 13.85±0.20°, and 16.68±0.20°.

[0056] In some embodiments, the acid addition salt described herein is a hydrochloride crystalline form VI of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystalline form VI has diffraction peaks at the following 2θ angles: 4.95±0.20°, 5.34±0.20°, 6.48±0.20°, 7.12±0.20°, 8.12±0.20°, 8.52±0.20°, 9.74±0.20°, 10.46±0.20°, 10.69±0.20°, 10.93±0.20°, 11.97±0.20°, 12.53±0.20°, 12.99±0.20°, 13.85±0.20°, 14.06 ±0.20°, 15.11±0.20°, 15.45±0.20°, 16.26±0.20°, 16.68±0.20°, 17.02±0.20°, 18.05±0.20°, 18.75±0.20°, 19.00±0.20°, 1934±0.20°, 20.88±0.20°, 22.10±0.20°, 22.61±0.20°, 24.79±0.20°, 25.66±0.20°, 26.38±0.20°, 29.38±0.20°, 29.60±0.20°, 29.94±0.20°, and 31.28±0.20°.

[0057] In some embodiments, the acid addition salt described herein is the hydrochloride crystal form VI of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form VI is substantially as shown in Figure 42.

[0058] In some embodiments, the free base crystalline form I of the compound represented by formula (I) described herein has a differential scanning calorimetry curve diagram comprising an endothermic peak at 82.70°C ± 3.00°C.

[0059] In some embodiments, the free base crystal form II of the compound represented by formula (I) described herein has a differential scanning calorimetry curve diagram comprising an endothermic peak at 78.30°C ± 3.00°C.

[0060] In some embodiments, the acid addition salt of the present invention is a fumarate salt form I of the compound represented by formula (I), and the differential scanning calorimetry curve of the fumarate salt form I comprises an endothermic peak at 84.90°C±3.00°C.

[0061] In some embodiments, the acid addition salt of the present invention is a malate crystalline form I of the compound represented by formula (I), and the differential scanning calorimetry curve of the malate crystalline form I comprises an endothermic peak at 90.20°C±3.00°C.

[0062] In some embodiments, the acid addition salt of the present invention is a citrate salt crystalline form I of the compound represented by formula (I), and the differential scanning calorimetry curve of the citrate salt crystalline form I comprises an endothermic peak at 142.40°C±3.00°C.

[0063] In some embodiments, the acid addition salt of the present invention is a citrate salt crystal form II of the compound represented by formula (I), and the differential scanning calorimetry curve of the citrate salt crystal form II comprises an endothermic peak at 138.20°C±3.00°C.

[0064] In some embodiments, the acid addition salt of the present invention is a tartrate salt form I of the compound represented by formula (I), and the differential scanning calorimetry curve of the tartrate salt form I comprises an endothermic peak at 67.60°C±3.00°C.

[0065] In some embodiments, the acid addition salt of the present invention is the hydrochloride crystal form I of the compound represented by formula (I), and the differential scanning calorimetry curve of the hydrochloride crystal form I comprises an endothermic peak at 144.10°C±3.00°C.

[0066] In some embodiments, the acid addition salt of the present invention is the hydrochloride crystal form II of the compound represented by formula (I), and the differential scanning calorimetry curve of the hydrochloride crystal form II comprises an endothermic peak at 148.90°C±3.00°C.

[0067] In some embodiments, the acid addition salt of the present invention is a citrate salt crystalline form I of the compound represented by formula (I), and the thermogravimetric analysis curve of the citrate salt crystalline form I shows a weight loss of approximately 8.32% at 150.00°C±3.00°C.

[0068] In some embodiments, the acid addition salt of the present invention is a citrate salt of the compound represented by formula (I) in Form II, and the thermogravimetric analysis curve of the citrate salt in Form II shows a weight loss of approximately 8.79% at 150.00°C±3.00°C.

[0069] In some embodiments, the acid addition salt of the present invention is the hydrochloride crystal form I of the compound represented by formula (I), and the thermogravimetric analysis curve of the hydrochloride crystal form I shows a weight loss of about 6.28% at 150.00°C±3.00°C.

[0070] In some embodiments, the acid addition salt of the present invention is hydrochloride crystal form II of the compound represented by formula (I), and the thermogravimetric analysis curve of the hydrochloride crystal form II shows a weight loss of about 0.96% at 140.00°C±3.00°C.

[0071] In a second aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof; the pharmaceutical composition further comprises a combination of one or more pharmaceutically acceptable carriers, excipients, diluents, and adjuvants; provided that the compound is not an amorphous free base, and the acid addition salt is not an amorphous hydrochloride.

[0072] In some embodiments, the acid addition salt in the pharmaceutical composition of the present invention can be any crystalline form of the salt of the present invention, specifically any crystalline form, amorphous form or any combination thereof.

[0073] In some embodiments, the pharmaceutical composition of the present invention comprises any acid addition salt of the compound represented by formula (I), or any crystalline form or amorphous form described in the present invention, or any combination of the salt, crystalline form and amorphous form.

[0074] In a third aspect, the present invention further provides use of the compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to treat microbial infections in mammals.

[0075] In a fourth aspect, the present invention further provides the compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or the pharmaceutical composition, for use in treating microbial infections in mammals.

[0076] In a fifth aspect, the present invention also provides a method for treating microbial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or the pharmaceutical composition.

[0077] In a sixth aspect, the present invention also provides a method for preparing Form II of the hydrochloride salt of the compound of Formula I, comprising dissolving the hydrochloride salt of the compound of Formula I in isopropanol and then adding heptane. Optionally, the mass-to-volume ratio of the hydrochloride salt of the compound of Formula I to isopropanol is 1:(4-6). Optionally, the volume ratio of isopropanol to heptane is 1:(3-5).

[0078] In some embodiments, the microbial infection described herein is a Gram-negative bacterial infection.

[0079] In some embodiments, the Gram-negative bacteria of the present invention are selected from one or more of Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae).

[0080] In some embodiments, the microbial infection described herein is a nontuberculous mycobacterial infection.

[0081] In some embodiments, the non-tuberculous mycobacteria of the present invention are selected from one or more of Mycobacterium scrofulaceum, Mycobacterium gordonae, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intercelluare, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium smegmatis, and Mycobacterium massiliense.

[0082] In some embodiments, the microbial infection of the present invention is a microbial infection of the skin, soft tissue, respiratory tract, blood, intraperitoneal cavity, urinary tract, or eye.

[0083] In some embodiments, the mammal of the present invention is a human.

[0084] In some embodiments, the compound of formula I of the present invention or its pharmaceutically acceptable acid addition salt, or the pharmaceutical composition described above is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, by inhalation, vaginally, topically, by subcutaneous injection, by fat injection, by intraarticular injection, by intraperitoneal injection, or by intrathecal injection. In some embodiments, the compound of formula I of the present invention or its pharmaceutically acceptable acid addition salt, or the pharmaceutical composition described above is administered orally. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG1 shows the test results of quantitative analysis of CFU of Mycobacterium abscessus in the lungs of mice in a Mycobacterium abscessus lung infection model 2 weeks after infection.

[0086] Figure 2 is an H&E-stained tissue section image of a mouse Mycobacterium abscessus lung infection model 2 weeks after infection; Figure 2a is an uninfected tissue, Figure 2b is a tissue section image of a control group that did not receive treatment on the 14th day, and Figure 2c is a tissue section image of a treatment group that received the compound of Example 6 on the 14th day.

[0087] FIG3 is an X-ray powder diffraction analysis diagram of the free base crystal form I.

[0088] FIG4 is a thermogravimetric analysis diagram of the free base form I.

[0089] FIG5 is a differential scanning calorimetry diagram of the free base Form I.

[0090] FIG6 is an X-ray powder diffraction analysis diagram of the fumarate salt form I.

[0091] FIG7 is a thermogravimetric analysis diagram of the fumarate salt form I.

[0092] FIG8 is a differential scanning calorimetry diagram of the fumarate salt form I.

[0093] FIG9 is an X-ray powder diffraction analysis diagram of malate crystal form I.

[0094] FIG10 is a thermogravimetric analysis diagram of malate crystal form I.

[0095] FIG11 is a differential scanning calorimetry diagram of malate salt Form I.

[0096] FIG12 is an X-ray powder diffraction analysis diagram of citrate crystal form I.

[0097] FIG13 is a thermogravimetric analysis diagram of citrate crystal form I.

[0098] FIG14 is a differential scanning calorimetry diagram of citrate salt Form I.

[0099] FIG15 is an X-ray powder diffraction analysis diagram of hydrochloride crystal form A.

[0100] FIG16 is a thermogravimetric analysis diagram of hydrochloride form A.

[0101] FIG17 is a differential scanning calorimetry diagram of hydrochloride form A.

[0102] FIG18 is an X-ray powder diffraction analysis diagram of tartrate salt form I.

[0103] FIG19 is a thermogravimetric analysis diagram of tartrate salt form I.

[0104] FIG20 is a differential scanning calorimetry diagram of tartrate salt form I.

[0105] Figure 21 is an X-ray powder diffraction analysis diagram of the free base crystal form II.

[0106] FIG22 is a thermogravimetric analysis diagram of the free base Form II.

[0107] Figure 23 is a differential scanning calorimetry graph of the free base Form II.

[0108] FIG24 is an X-ray powder diffraction analysis diagram of citrate crystal form II.

[0109] FIG25 is a thermogravimetric analysis diagram of citrate crystal form II.

[0110] FIG26 is a differential scanning calorimetry diagram of citrate salt Form II.

[0111] Figure 27 is an X-ray powder diffraction analysis diagram of hydrochloride form I.

[0112] Figure 28 is a thermogravimetric analysis diagram of hydrochloride form I.

[0113] FIG29 is a differential scanning calorimetry diagram of hydrochloride Form I.

[0114] Figure 30 is an X-ray powder diffraction analysis diagram of hydrochloride form II.

[0115] Figure 31 is a thermogravimetric analysis diagram of hydrochloride crystal form II.

[0116] FIG32 is a differential scanning calorimetry diagram of hydrochloride form II.

[0117] FIG33 is an X-ray powder diffraction analysis diagram of hydrochloride crystal form III.

[0118] FIG34 is a thermogravimetric analysis diagram of hydrochloride form III.

[0119] FIG35 is a differential scanning calorimetry diagram of hydrochloride Form III.

[0120] FIG36 is an X-ray powder diffraction analysis diagram of hydrochloride crystal form IV.

[0121] FIG37 is a thermogravimetric analysis diagram of hydrochloride crystal form IV.

[0122] FIG38 is a differential scanning calorimetry diagram of hydrochloride Form IV.

[0123] Figure 39 is an X-ray powder diffraction analysis diagram of hydrochloride form V.

[0124] FIG40 is a thermogravimetric analysis diagram of hydrochloride form V.

[0125] FIG41 is a differential scanning calorimetry diagram of hydrochloride form V.

[0126] FIG42 is an X-ray powder diffraction analysis diagram of hydrochloride form VI.

[0127] FIG43 is a thermogravimetric analysis diagram of hydrochloride form VI.

[0128] FIG44 is a differential scanning calorimetry diagram of hydrochloride Form VI.

[0129] Figure 45 is a 1H NMR spectrum of the free base Form I.

[0130] Figure 46 is a 1H NMR chart of fumarate Form I.

[0131] Figure 47 is a 1H NMR chart of malate salt Form I.

[0132] Figure 48 is a 1H NMR chart of citrate salt Form I.

[0133] FIG49 is a 1H NMR chart of hydrochloride salt form A.

[0134] Figure 50 is a 1H NMR chart of tartrate salt Form I.

[0135] Figure 51 is a 1H NMR chart of the free base Form II.

[0136] Figure 52 is a 1H NMR chart of citrate salt Form II.

[0137] Figure 53 is a 1H NMR chart of hydrochloride Form I.

[0138] Figure 54 is a 1H NMR chart of hydrochloride Form II. DETAILED DESCRIPTION

[0139] The present invention is further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the accompanying drawings and the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0140] the term

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications to which this invention pertains are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

[0142] In the present invention, "room temperature" refers to a temperature from about 10° C. to about 40° C. In some embodiments, "room temperature" refers to a temperature from about 20° C. to about 30° C.; in other embodiments, "room temperature" refers to 20° C., 22.5° C., 25° C., 27.5° C., etc.

[0143] "Pharmaceutically acceptable acid addition salts" refer to salts formed between the compound represented by formula (I) of the present invention and pharmaceutically acceptable non-toxic acids, including but not limited to the various organic acid salts and inorganic acid salts described in the present invention.

[0144] "Acid addition salts of the compound represented by formula (I)" refer to salts formed by the reaction of the compound represented by formula (I) (free base) with various suitable organic acids or inorganic acids, including but not limited to the hydrochloride, hydrobromide, sulfate, maleate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, oxalate, methanesulfonate, etc. described in the present invention. Among them, the "acid addition salts of the compound represented by formula (I)" include the amorphous form or crystalline form of the salt, including its solvate form (for example, hydrate form), and also include polymorphic forms of the salt. For example, the hydrochloride salt of the compound represented by formula (I) includes the amorphous form, various crystalline forms, various solvates, various hydrates of such salts, and also includes polymorphic forms of such salts.

[0145] "Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, and hydrates of salts of a compound. Crystalline forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0146] "Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity, characterized by a diffuse, unsharp X-ray powder diffraction pattern. Amorphous is a special physical form of solid matter, and its locally ordered structure suggests that it is inextricably linked to crystalline forms. Amorphous forms of substances can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

[0147] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0148] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0149] "Solvate" refers to a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, and the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. A hydrate may or may not have other solvents other than water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice of the substance.

[0150] Crystalline or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0151] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in this experiment, there is an error tolerance of ±0.2° for the diffraction peak.

[0152] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of the DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in this experiment, the endothermic peak has an error tolerance of ±3°.

[0153] Solids with identical chemical compositions often form isomers, or variants, with different crystal structures under different thermodynamic conditions. This phenomenon is known as polymorphism or polyphasic phenomena. When temperature and pressure conditions change, these variants transform into each other, a phenomenon known as crystal transformation. Crystal transformations can significantly alter the mechanical, electrical, and magnetic properties of a crystal. When the temperature of a crystal transformation is within a measurable range, this transformation can be observed on a differential scanning calorimetry (DSC) chart. The DSC chart is characterized by an exothermic peak reflecting this transformation, along with two or more endothermic peaks, representing the characteristic endothermic peaks of the different crystal forms before and after the transformation.

[0154] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. The amorphous material described herein is characterized by a TGA-detected weight loss range of 1.75% to 4.10%. Depending on the instrumentation used in this test, the mass change has an error tolerance of ±0.1%.

[0155] In the context of the present invention, the 2θ values ​​in the X-ray powder diffraction pattern are all given in degrees (°).

[0156] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and is not attributable to background noise.

[0157] The pharmaceutical composition of the present invention is characterized by comprising an acid addition salt of a compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the acid addition salt of the compound in the pharmaceutical composition of the present invention is effective to detectably treat or alleviate a disease caused by a microbial infection in a patient.

[0158] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, such as any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for the specific target dosage form, as described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. The literature herein indicates that various carriers can be used in the formulation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional carrier media are incompatible with the compounds of the present invention or their acid addition salts, such as by producing any undesirable biological effects or interacting in a deleterious manner with any other components of the pharmaceutically acceptable compositions, their use is contemplated by the present invention.

[0159] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocked polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; and cellulose and its derivatives, such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coatings; sweeteners; flavoring agents; fragrances; preservatives and antioxidants.

[0160] The pharmaceutical compositions of the present invention may be in the form of capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; and may be administered orally, by injection, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable drug cartridge.

[0161] Oral administration can be in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs; topical administration can be in the form of ointments, gels, medicated adhesive tapes, and the like.

[0162] Pharmaceutical compositions can be prepared in a conventional manner with one or more physiologically acceptable carriers, including excipients and adjuvants that can help process the active compound or its salt into a pharmaceutically acceptable formulation. The selected route of administration determines the appropriate dosage form. Any well-known technology, carrier and excipient can be used appropriately according to the understanding in the prior art. Pharmaceutical compositions containing the compounds of the present invention or its salt can be prepared according to conventional methods, for example, by conventional mixing, dissolving, granulating, tableting, grinding, emulsifying, encapsulating, encapsulating or compressing processes. Pharmaceutical compositions containing the compounds of the present invention or its salt can be used in the form of a pharmaceutical composition of a therapeutically effective amount, in conventional forms and approaches known in the art, including but not limited to: intravenous, oral, rectal, aerosol, parenteral, eye, lung, transdermal, vaginal, ear, nasal and topical administration.

[0163] The pharmaceutical composition will comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and a compound of the present invention in free acid, free base, or pharmaceutically acceptable salt form, or a salt thereof, as the active ingredient. In addition, the pharmaceutical composition may include other medicinal or pharmaceutically active agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubility promoters, salts for regulating osmotic pressure, or buffers. Furthermore, the pharmaceutical composition may contain other therapeutically valuable substances.

[0164] Methods for preparing compositions containing the compounds of the present invention or their salts include preparing the compounds in a solid, semisolid, or liquid form together with one or more inert, pharmaceutically acceptable excipients or carriers. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions, and creams. Compositions can be in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or emulsions. These compositions may also contain small amounts of non-toxic adjuvants, such as wetting or emulsifying agents, pH buffers, and the like.

[0165] The term "about" when used in relation to the peak position of an X-ray powder diffraction pattern refers to the inherent variability of the peak, which depends on, for example, the calibration of the equipment used, the method used to produce polymorphs, the age of the crystalline material, etc., depending on the instrument used. In this case, the measurement variability of the instrument is about ±0.2°2θ, and those skilled in the art will understand the use of "about" in this context. When used to modify a certain value or range of values, the term "about" as used herein refers to the value or range of values ​​and the acceptable error range for those skilled in the art for the value or range of values, for example, the error range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0166] The term "mammal" refers to all mammals, including humans, livestock, and pets.

[0167] "Treatment" or "treatment" of a disease includes: (1) preventing the disease, e.g., causing clinical symptoms of the disease to not develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms, or (3) ameliorating the disease, e.g., causing regression of the disease or its clinical symptoms.

[0168] "Therapeutically effective amount" means that when administered to a mammal for treating a disease, the dosage of the compound is sufficient to effect such treatment of the disease."Therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal being treated.

[0169] In a specific embodiment, eq is the molar equivalent of the reactants.

[0170] Compounds disclosed herein are generally named according to the IUPAC or CAS nomenclature systems.

[0171] The following examples are further given to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the scope of protection of the present invention. The specific process parameters and the like in the following examples are only examples within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, and are not limited to the specific numerical values ​​exemplified below.

[0172] The abbreviations of solvents and their corresponding Chinese names are shown in Table A.

[0173] Table A. Comparison table of Chinese and English names of solvents used in the experiment

[0174] The test instruments and parameters in Example 11 are as follows:

[0175] The X-ray powder diffraction (XRPD) pattern in Example 11 was collected on an X-ray powder diffraction analyzer produced by PANalytacal, and the scanning parameters are shown in Table B.

[0176] Table B, XRPD test parameters

[0177] The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) patterns of Example 11 were acquired on a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. Table C lists the test parameters.

[0178] Table C, DSC and TGA test parameters

[0179] The liquid-state NMR spectra in Example 11 were collected on a Bruker 400M NMR spectrometer using DMSO-d6, deuterated chloroform or deuterated methanol as solvents.

[0180] The test instruments and parameters in Example 12 are shown in Table D below:

[0181] Table D. Test instruments and parameters in Example 12

[0182] Example 1 Compound of Formula I

[0183] Compound 1-1 (5.0 g, 1.0 eq) was dissolved in methyl tert-butyl ether (100 mL), and triethanolamine (17.21 g, 10.0 eq) and 4-dimethylaminopyridine (0.7 g, 0.5 eq) were added, followed by dropwise addition of isobutyric anhydride (18.25 g, 10.0 eq), and the reaction was allowed to proceed at room temperature overnight; post-treatment: water (50 mL) was added, the phases were separated, the organic phase was washed with 5% saline (50 mL), dried, concentrated, mixed, and passed through a column; the eluent was EA / PE (v / v) = 1 / 15; to obtain compound 1-2.

[0184] Compound 1-2 (2.0 g, 1.0 eq) was dissolved in MeOH (40 mL), and wet Pd / C (10%, 0.1 eq) was added. The atmosphere was purged with nitrogen three times, then hydrogen three times, and the hydrogen pressure was increased to 5 atm. The mixture was then heated to 50°C and reacted for 16 h. Post-treatment included filtration through a pad of diatomaceous earth (twice the amount of material added), concentration, column purification, and concentrating to obtain Form I, the free base of Formula I. XPRD results are shown in Figure 3 , TGA and DSC results are shown in Figures 4 and 5 , respectively, and 1H NMR results are shown in Figure 45 (DMSO-d6 was the solvent).

[0185] Example 2 Hydrochloride

[0186] To a solution of intermediate 1 (60 mg, 0.26 mmol, prepared as described in US2013165411) and pyridine (31 L, 0.33 mmol) in DCM (2 mL) was added Ac2O (32 L, 0.33 mmol) dropwise, and the mixture was stirred for 2 hours. After the reaction was completed, the solvent was removed by concentration, and the residue was purified on Pre-HPLC to give intermediate 2 (25 mg); MS (m / z): 438 [m + H]. At room temperature, intermediate 2 was dissolved in a solution of HCl (5 M) in dioxane, and the mixture was stirred for 1 hour. After completion of the reaction, the mixture was lyophilized to obtain compound 2 (16.9 mg) in the form of a light yellow powder. MS (m / z): 338 [m + H]. 1H NMR: (400MHz, D2O): 7.48 (t, J = 8.0 Hz, 1H); 7.01 (d, J = 7.6 Hz, 1H); 6.92 (dd, J = 12.0, 8.0 Hz, 1H); 5.35 (dd, J = 7.4, 3 .0Hz,1H); 4.35~4.17(m,5H); 3.73~3.60(m,1H); 3.56~3.51(m,2H); 3.08~3.01(m,1H); 1.99(s,3H),1.98(s,3H).

[0187] The following compounds were synthesized according to the procedure described in Example 2. The only difference was the starting materials.

[0188] Example 6

[0189] The compound of Example 6 was prepared according to the method described in US2013165411.

[0190] Example 7

[0191] The compound of Example 7 was prepared according to the method described in US2013165411.

[0192] Example 8

[0193] The compound of Example 8 was prepared according to the method described in US2013165411.

[0194] Example 9

[0195] The compound of Example 9 was prepared according to the method described in US2013165411.

[0196] Example 10 Activity Test of Formula I Compound

[0197] The compounds of the present invention are boron compounds and their prodrugs. The prodrugs are converted into the parent boron compounds in vivo to exert their antibacterial effects. Therefore, the antibacterial activity of the compounds of the present invention was tested using the parent boron compounds.

[0198] In one aspect, the in vitro activity of the parent boron compound is assessed by standard testing procedures, such as the minimum inhibitory concentration (MIC) assay as described in the Clinical and Laboratory Standards Institute (CLSI) document M24-A2. Low MIC values ​​indicate high antimicrobial activity, while high MIC values ​​indicate reduced antimicrobial activity. Generally, MIC values ​​of approximately <2 mg / L indicate good therapeutic (i.e., suitable for treatment) efficacy of the antimicrobial agent, while MIC values ​​>8 mg / L indicate a lack of effective therapeutic activity of the test compound.

[0199] The MIC data in Table 1 below illustrate the in vitro activity (potency) of representative compounds of the present invention against mycobacteria. As is apparent from the data in Table 1, the compound of Example 6 is highly active against a number of mycobacterial pathogens, including M. scrofulaceum, M. gordonae, M. avium, M. abscessus, M. intercelleulare, M. fortuitum, M. peregrinum, M. smegmatis, and M. massiliense (MIC range 0.063-2 mg / L).

[0200] GSK656 is a similar boron compound disclosed in WO / 2012 / 033858. Despite some structural similarities, the compounds of Example 6 and GSK656 exhibit very different antimicrobial spectra against non-tuberculous mycobacteria. For example, Example 6 is highly effective against Mycobacterium fortuitum, Mycobacterium exogenum, and Mycobacterium smegmatis, with an MIC of 0.125 mg / L, while the GSK656 MIC is >8 mg / L, a more than 64-fold reduction in activity. Similarly, the compound of Example 6 is more than four times more effective than GSK656 against Mycobacterium avium and Mycobacterium intracellulare. The huge differences in antimicrobial spectra and efficacy are surprising compared to the minor differences in structure. However, another boron compound disclosed in US2006 / 0234981, AN2690, has only moderate or no activity against all NTM species tested. Importantly, due to the complexity of NTM infections, a broad antimicrobial spectrum covering as many mycobacterial species as possible is beneficial and convenient for clinical use.

[0201] Table 1. In vitro antibacterial activity against mycobacterial pathogens

[0202] Alternatively, in vitro activity can be assessed by standard testing procedures, such as the determination of the minimum inhibitory concentration (MIC) as described in an approved standard. This standard is the "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically," 3rd edition, 1993, published by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA. Low MIC values ​​indicate high antimicrobial activity, while high MIC values ​​indicate reduced antimicrobial activity (in the latter case, higher drug concentrations are required to eradicate the pathogen). Generally, MIC values ​​of approximately <4-8 μg / mL indicate that the antimicrobial drug has therapeutic efficacy (i.e., suitable for treatment), while MIC values ​​of >16 μg / mL indicate a lack of therapeutically useful activity against the test compound.

[0203] Representative compounds of the present invention have potent in vitro activity (potency) against mycobacteria such as Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), Escherichia coli (E. coli), and Klebsiella pneumoniae (K. pneumoniae), as shown in the MIC data in Table 2 below.

[0204] As is apparent from the data in Table 2, the compound of Example 6 is highly active against a number of Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae (MIC range of 2-4 g / mL). The prodrugs of Example 6, such as the compounds of Examples 3 and 4, are not found to be active in vitro.

[0205] Table 2. In vitro antibacterial activity

[0206] To further characterize the antibacterial properties of the compounds of the present invention, the minimum bactericidal concentration (MBC) was also determined according to the Clinical and Laboratory Standards Institute (CLSI) document M24-A2. GSK656 and the compound of Example 6 were tested for MIC and MBC against 20 clinical isolates of the M. abscessus complex, including M. abscessus and M. massiliense. As shown in Table 3, GSK656 and the compound of Example 6 had similar MICs against the clinical isolates. However, surprisingly, the compound of Example 6 had a much lower MBC against all the strains tested. If the MBC / MIC ratio is ≤4, the antibiotic is considered bactericidal, and if the ratio is greater than 4, it is bacteriostatic. Therefore, the compound of Example 6 had a bactericidal effect against half of the isolates, while GSK656 had an antibacterial effect against all isolates. This is very surprising, given the similar structure and MIC distribution characteristics. In fact, bactericidal properties are very important for more effectively clearing bacterial infections. Bactericidal agents kill or completely eradicate pathogens, while bacteriostatic agents simply prevent bacterial growth. In the latter case, any remaining bacteria may develop bacterial resistance to the agent, rendering treatment ineffective or requiring restart of therapy.

[0207] Table 3. MICs and MBCs against clinical isolates of Bacillus abscessus complex

[0208] In order to determine the efficacy of the compounds of the present invention in vivo, a Mycobacterium abscessus mouse lung infection model was performed. BALB / c mice (randomly divided into groups of 6) were injected with cyclophosphamide one week before infection and inoculated intranasally with Mycobacterium abscessus CIP108297 (107 CFU / mouse). On the third day after infection, mice were subcutaneously injected with 10 mg / kg of the compound of Example 6 or GSK656 daily, or orally administered 100 mg / kg of linezolid (an approved antibiotic) or 200 mg / kg of clarithromycin (an approved antibiotic) daily. Mycobacterium abscessus CFU in the lungs was quantified 2 weeks after infection. As shown in Figure 1, the results showed that the compound of Example 6 caused a significant reduction in bacterial counts (~7.8 log10 CFU) compared to the untreated group. In addition, the bacteria in the lungs of the mice treated with the compound of Example 6 were significantly reduced compared to animals treated with GSK656. Considering the similar structure and MIC curve between GSK656 and the compound of Example 6, this significantly improved efficacy was unexpected. This can be attributed to the unexpectedly lower MBC found in the compound of Example 6. Furthermore, the compound of Example 6 also showed a higher potential to eliminate M. abscessus compared to linezolid or clarithromycin given at very high doses, further supporting its potential clinical application in humans.

[0209] As shown in Figure 2, H&E-stained tissue sections revealed that two weeks after infection, the alveolar walls of control mice were severely thickened, with inflammatory cell infiltration and erythrocyte exudation. In contrast, in the group treated with the compound of Example 6, pathological changes were rare, and lung lesions were negligible. These findings demonstrate the effectiveness of the compound of Example 6 in inhibiting the replication of Mycobacterium abscessus in a mouse model of pneumonia.

[0210] To further determine the efficacy of the compounds of the present invention in vivo, a Pseudomonas aeruginosa mouse lung infection model was used, similar to the method described by Andese in Antimicrobial Agents and Chemotherapy, 2002, 46(11), 3484-3489. In this model, a greater reduction in bacterial colony forming units (CFU) indicates a more beneficial therapeutic effect (more bacterial eradication), while a lower reduction in CFU indicates a lower effect (less bacterial eradication).

[0211] In the lung infection of Pseudomonas aeruginosa ICR mice (randomly divided into groups of 6), Example 6 was orally administered at a dose of 10 mg / kg once a day. As shown in Table 4, compared with the untreated control group, Example 6 showed weak antibacterial efficacy, with a result that the CFU in the lungs decreased by 0.53 log. As oral prodrugs, the compounds of Examples 3 and 9 were orally administered 10 mg / kg once a day, respectively. Although the prodrug itself does not have antibacterial efficacy, it shows good therapeutic effect in vivo. Surprisingly, the therapeutic effect of the compounds of Examples 3 and 9 is significantly better than that of Example 6, with the CFU in the lungs reduced by 1.77 and 0.82 log, respectively. The data strongly support that the prodrugs of Examples 3 and 9 are converted into Example 6 after oral administration to exert antibacterial activity, and the conversion rate is very high.

[0212] Table 4. Efficacy of Pseudomonas aeruginosa lung infection model in mice

[0213] In order to further illustrate the therapeutic potential of drug compounds, pharmacokinetic (PK) data are used to establish key parameters for predicting treatment outcomes, such as area under the curve (AUC), for monitoring changes in systemic drug concentration over time. Therefore, the higher the AUC value, the greater the risk of exposure to the drug, which is generally associated with greater therapeutic potential, because the amount of drug available for use in mammals to combat infection is greater. In contrast, lower AUC values ​​indicate that the exposure to the test drug is reduced, resulting in a reduction in the number of antibiotics available for combating bacterial infections. For this reason, the compounds of the present invention have been tested in an orally administered rat PK model, similar to the method described in the monograph "Current Protocols in Pharmacology", 2005, 7.1.1-71.26, John Wiley & Sons, Inc.

[0214] All compounds were administered to SD rats (randomly divided into groups of 3 per group) by intravenous or oral gavage. Since the prodrug is expected to be converted into the parent molecule in vivo, only the parent compound (Example 6) was tested for all samples. As shown in Table 5, the parent compound of Example 6 has a moderate oral bioavailability of 15%. The pharmacokinetic data of the prodrugs of the present invention show that at a dose of 5 mg / kg or 10 mg / kg, systemic exposure and Cmax are significantly improved. For example, the exposure (AUC) and Cmax shown by the compound of Example 3 are 2906 ng*h / ml and 870 ng / ml, respectively. This unexpected result indicates that the exposure and Cmax are increased by 3.4 times and 3 times, respectively, which is consistent with the improved efficacy described in Table 3. Due to the introduction of the prodrug substructure, the prodrug usually has a larger molecular weight, so the AUC is corrected by dose and molecular weight (MW) to obtain the AUC per mole to compare the efficiency between the prodrugs. Importantly, the compound of Example 3 also exhibited a significantly higher AUC per mole compared to the compound of Example 6 previously described in US2013 / 0165411.

[0215] Table 5. Pharmacokinetic studies in rats *AUC per mole is corrected for dose and molecular weight

[0216] In addition, in the lung distribution study conducted in Balb / C mice (3 mice each time), the exposure of Example 3 in the lung was much higher than that in the plasma (assessed by the area under the lung / plasma concentration-time curve (AUC)). As shown in Table 6, the compounds of Examples 6 and 3 were administered intravenously and orally at 10 mg / kg, respectively. In the analysis of Example 3, the concentrations of the parent compound (Example 6) and the prodrug (Example 3) in plasma and lung were determined. The prodrug (Example 3) was rapidly converted to Example 6, and the prodrug was almost undetectable in the plasma. Compared with the AUC of Example 6 administered intravenously, the oral bioavailability of Example 6 produced by Example 3 in mice was 83.95%. Despite the rapid conversion of the prodrug, it was surprising that more Example 6 was detected in the lungs, with a lung / plasma AUC ratio of 5.24, almost 2.2 times the AUC of Example 6 administered intravenously. The higher accumulation of the drug in the lungs is particularly useful for treating pneumonia, which is also consistent with the superior efficacy of Example 3 in the Pseudomonas aeruginosa mouse lung infection model (Table 4).

[0217] Table 6. Distribution of Examples 6 and 3 in mouse lungs and plasma

[0218] The above representative data show that the compounds of the present invention have surprisingly superior therapeutic potential, with unexpected advantages in potency, efficacy and exposure, which are completely unpredictable in any previous patents or publications on boron anti-infective drugs. The significant and surprising improvements in multiple distinct key parameters of the antibacterial compounds provided herein provide significant benefits for human or mammalian treatment, including but not limited to better bactericidal potential, better in vivo efficacy, convenient long-term oral administration, and reduced potential side effects.

[0219] Example 11 Salt screening and characterization

[0220] 11.1 Salt type screening

[0221] Using Form I of the free base of Formula I as the starting sample, a first batch of 27 salt forms was screened using nine ligand acids in three solvent systems (acetone, tetrahydrofuran, and ethanol). Approximately 20 mg of the starting sample was mixed with an equimolar ratio of the corresponding ligand in 0.5 mL of solvent and stirred at room temperature for approximately 3 hours. The mixture was then stirred at 5°C for 3 days. If a solid was obtained, the sample was centrifuged and characterized by XRPD. The results are summarized in Table 7. During the salt screening and subsequent experiments, three salt forms (fumarate, citrate Form I, and malate) and one new free base form were obtained. The screened salt forms were characterized by XRPD, TGA, and DSC.

[0222] Table 7. Summary of salt type screening test results *: The sample was stirred at room temperature for 3 hours to clarify, then stirred at 5°C for 3 days to precipitate solids. The sample was centrifuged, and the wet sample was vacuum dried at room temperature for 1 day to form a gel. #: The sample was stirred at room temperature for 3 hours to clarify, then stirred at 5°C for 3 days to clarify, then stirred at -20°C for 1 day to precipitate solids. The sample was centrifuged, and the wet sample was vacuum dried at room temperature for 1 day to form a gel. **: The sample was stirred at room temperature for 3 hours to clarify, then stirred at 5°C for 3 days to clarify, then stirred at -20°C for 1 day to clarify. 1.0 mL of heptane was added and stirred at -20°C for 1 day to precipitate solids. The sample was centrifuged, and the wet sample was vacuum dried at room temperature for 1 day to form a gel. ##: The sample was stirred at room temperature for 3 hours to clarify, then stirred at 5°C for 3 days to clarify, then stirred at -20°C for 1 day to clarify. 1.0 mL of heptane was added and stirred at -20°C for 1 day to form a gel or oil. The product was obtained by slowly evaporating at room temperature.

[0223] Based on the results of the first batch of salt screening, oil- and gel-forming phenomena were observed in most of the screened systems. Therefore, attempts were made to reduce solubility using mixed solvent systems to minimize this phenomenon. Samples obtained from the screening were also dried using nitrogen purging to obtain powder samples with better solid properties. In the second batch of salt screening, 12 salt-form screening experiments were conducted using free base Form I as the starting sample with six commonly used ligand acids in two mixed solvent systems: acetone / heptane (1:2, v / v) and tetrahydrofuran (THF) / heptane (1:2, v / v). Approximately 20 mg of the starting sample was mixed with an equimolar ratio of the corresponding ligand in 0.5 mL of solvent, stirred at room temperature for 1 hour, and then subjected to temperature cycling (50°C–5°C, 0.5°C / min). If a solid was obtained, the sample was centrifuged and characterized by XRPD. The results are summarized in Table 8. In the second batch of salt form screening tests, a total of four salt forms (hydrochloride form A, tartrate form I, fumarate form I and malate form I) were obtained. The screened salt forms and free base form II were characterized by XRPD, TGA and DSC.

[0224] Table 8. Summary of the results of the salt type screening test *: The sample was stirred at room temperature for 1 hour to form an oil. After temperature cycling (50°C to 5°C, 0.5°C / min, 2 cycles), a solid was obtained. #: The sample was stirred at room temperature for 1 hour to form a gel. After temperature cycling (50°C to 5°C, 0.5°C / min, 2 cycles), a gel was obtained. **: The sample was stirred at room temperature for 1 hour to form a suspension. After temperature cycling (50°C to 5°C, 0.5°C / min, 2 cycles), a solid was obtained. ##: The sample was stirred at room temperature for 1 hour to form a gel. After temperature cycling (50°C to 5°C, 0.5°C / min, 2 cycles), a solid was precipitated.

[0225] 11.2 Salt Form Characterization

[0226] 11.2.1 Fumarate

[0227] Because the sample in the first batch of screening tests was colloidal, an attempt was made to prepare the fumarate salt. In the second batch of salt screening tests, the fumarate salt Form I was prepared by mixing the starting sample (Form I free base of the compound of Formula I) with an equimolar ratio of fumaric acid in tetrahydrofuran (THF) / heptane (1:2, v / v). The sample was stirred at room temperature for 1 hour to form a suspension. After being subjected to a temperature cycle (50°C–5°C, 0.5°C / min, two cycles), the suspension was restored. The sample was centrifuged (10,000 rpm, 2 minutes), purged with nitrogen for approximately 1 hour, and dried under vacuum at room temperature overnight to form a powder. The XPRD results are shown in Figure 6, and the TGA and DSC results are shown in Figures 7 and 8, respectively. The results show that the sample exhibited an 8.59% weight loss upon heating to 150°C, with three endothermic peaks at 78.0°C, 84.9°C, and 102.6°C (peak temperatures), and one exothermic peak at 196.2°C (peak temperature). The 1H NMR results are shown in FIG46 .

[0228] 11.2.2 Malate

[0229] Because the sample in the first batch of screening tests was gelatinous, an attempt was made to prepare the malate salt. In the second batch of salt screening, malate salt Form I was prepared by mixing the starting sample (Form I free base of Formula I) with an equimolar ratio of malic acid in acetone / heptane (1:2, v / v). The sample was stirred at room temperature for 1 hour to form a gel. After temperature cycling (50°C–5°C, 0.5°C / min, 2 cycles), a solid precipitated. The sample was centrifuged (10,000 rpm, 2 minutes), purged with nitrogen for approximately 1 hour, and then vacuum-dried at room temperature overnight to form a powder. The XPRD results are shown in Figure 9, while the TGA and DSC results are shown in Figures 10 and 11, respectively. The results show a 9.44% weight loss upon heating the sample to 150°C, with two endothermic peaks at 67.4°C and 90.2°C (peak temperatures). The 1H NMR results are shown in Figure 47.

[0230] 11.2.3 Citrate

[0231] Citrate Form I was prepared by mixing the starting sample (Form I free base of Formula I) with citric acid in an equimolar ratio in ethanol. A small amount of solid precipitated after stirring the sample at room temperature for 3 hours. The sample was stirred at 5°C for 3 days, centrifuged (10,000 rpm, 2 minutes), and dried under vacuum at room temperature overnight. XPRD results are shown in Figure 12, while TGA and DSC results are shown in Figures 13-14, respectively. These results show an 8.32% weight loss upon heating the sample to 150°C, with two endothermic peaks at 142.4°C and 172.2°C (peak temperatures). 1H NMR results are shown in Figure 48.

[0232] 11.2.4 Hydrochloride

[0233] Hydrochloride Form A was prepared by mixing the starting sample (Form I, the free base of Formula I) with an equimolar solution of 1,4-dicyclohexyloxyhydrochloric acid in acetone / heptane (1:2, v / v). The sample was stirred at room temperature for 1 hour to form an oil. After temperature cycling (50°C–5°C, 0.5°C / min, 2 cycles), a solid precipitated. The sample was centrifuged (10,000 rpm, 2 minutes), purged with nitrogen for approximately 1 hour, and then vacuum-dried at room temperature overnight to obtain a powdered sample. XPRD results are shown in Figure 15. TGA and DSC results are shown in Figures 16 and 17, respectively. The results show a 4.93% weight loss upon heating the sample to 150°C, with an endothermic peak at 138.4°C (peak temperature) and an exothermic peak at 163.8°C (peak temperature). 1H NMR results are shown in Figure 49.

[0234] 11.2.5 Tartaric acid salts

[0235] Tartrate salt Form I was prepared by mixing the starting sample (Form I free base of Formula I) with an equimolar ratio of tartaric acid in acetone / heptane (1:2, v / v). The sample formed a gel after stirring at room temperature for 1 hour. After two cycles of temperature cycling (50°C to 5°C, 0.5°C / min), a solid precipitated, which also formed a slight gel. The sample was centrifuged (10,000 rpm for 2 minutes), purged with nitrogen for approximately 1 hour, and then vacuum-dried at room temperature overnight, resulting in a slightly gel-like consistency. XPRD results are shown in Figure 18, while TGA and DSC results are shown in Figures 19 and 20, respectively. The results show an 11.24% weight loss upon heating the sample to 150°C, with an endothermic peak at 67.6°C (peak temperature). 1H NMR results are shown in Figure 50.

[0236] 11.2.6 Free Base Form II

[0237] Free base Form II was obtained from the starting sample (Form I of the free base of Formula I) in ethanol. After stirring the sample at room temperature for 3 hours, a small amount of solid precipitated. The sample was then stirred at 5°C for 3 days, centrifuged (10,000 rpm, 2 minutes), the supernatant removed, and dried under vacuum at room temperature overnight. XPRD results are shown in Figure 21, while TGA and DSC results are shown in Figures 22 and 23, respectively. These results show a 6.25% weight loss upon heating the sample to 90°C and a 4.34% weight loss upon further heating to 150°C. Two endothermic peaks were observed at 78.3°C and 104.0°C (peak temperatures). 1H NMR results are shown in Figure 51.

[0238] 11.3 Repeated preparation of salt forms

[0239] Based on the salt form screening results, both citrate Form I and hydrochloride Form A were able to obtain powdered samples, and no obvious thermal signals were observed before 100°C on DSC, indicating that they were the dominant salt and crystal forms. Therefore, these were selected for repeated preparation. The steps for repeated salt form sample preparation are summarized in Table 9. The results show that citrate Form II and hydrochloride Form I were successfully prepared. The XPRD results of citrate Form II are shown in Figure 24, the TGA and DSC results are shown in Figures 25 and 26, respectively, and the 1H NMR results are shown in Figure 52 (deuterated methanol as the solvent). The XPRD results of hydrochloride Form I are shown in Figure 27, the TGA and DSC results are shown in Figures 28 and 29, respectively, and the 1H NMR results are shown in Figure 53.

[0240] Table 9. Salt type repeated preparation test steps

[0241] Example 12 Study on the Polymorphic Form of the Hydrochloride Compound

[0242] 12.1 Preparation and Characterization of Polymorphs of Hydrochloride Compounds

[0243] The hydrochloride of the compound of formula I was systematically studied for its crystal form using experimental methods such as solid-liquid suspension equilibrium at 25°C for 2 days and 14 days, solid-liquid suspension equilibrium at 5°C for 2 days, slow evaporation at 25°C, anti-solvent crystallization, hot saturated solution cooling crystallization, and high-pressure plate test. A total of five polymorphs were obtained. The experimental methods and characterization results are shown in Table 10 below: Table 10. Preparation and characterization of hydrochloride polymorphs

[0244] XRPD characterization results indicate that, of the five discovered crystalline forms, hydrochloride Forms II and VI exhibit high crystallinity, while the other forms exhibit moderate crystallinity. DSC characterization results indicate that hydrochloride Form II has the highest melting point and is the most thermodynamically stable form. Its TGA spectrum reveals a weight loss of only 0.961% before 140°C. Furthermore, hydrochloride Form II exhibits minimal residual solvent, making it the preferred form for subsequent studies.

[0245] 12.2 Test of factors affecting the stability of hydrochloride crystal form II

[0246] The specific experimental method for the stability test is as follows: 90 mg of hydrochloride Form II material was weighed into three glass dishes, which were placed under high temperature of 60°C (covered), high humidity of 92.5% ± 5% (uncovered), and light (4500 ± 500 Lux, with UV). Samples were taken on days 5 and 11 for XRPD and HPLC analysis, and the appearance color of the samples was recorded. The results are summarized in Table 11.

[0247] Table 11. Stability test results of hydrochloride crystal form II

[0248] As shown in Table 11, the hydrochloride crystal form II did not change in crystal form and appearance color under the conditions of high temperature, high humidity and strong light for 5 days and 11 days. Only under the strong light condition for 11 days did the chemical purity decrease by 2%.

[0249] The above contents are only basic descriptions of the concept of the present invention, and any equivalent transformations made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

[0250] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0251] The various aspects described above are a brief description of the present invention, and a person having ordinary skill in the art, after reading the foregoing description, will be able to make changes, equivalent substitutions, and other types of changes to the invention set forth herein. However, the present invention is not limited to the statements and examples described herein. Many modifications and variations of the crystals or crystalline compounds of the present invention and the methods for preparing the same can be implemented without departing from the spirit and scope thereof, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present invention, in addition to those listed here, will also be apparent to those skilled in the art based on the foregoing description. It will be understood that the present invention is not limited to specific methods, solvents, salts, operation sequences, process conditions, etc., which can of course vary. It will also be understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting. Therefore, the description should be viewed as illustrative.

Claims

1. A compound of formula I or a pharmaceutically acceptable acid addition salt thereof, provided that the compound is not the free base in amorphous form and the acid addition salt is not the hydrochloride in amorphous form, 2. The compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is an inorganic acid salt or an organic acid salt.

3. The compound according to claim 2 or a pharmaceutically acceptable acid addition salt thereof, wherein, The inorganic acid salt is a hydrochloride, a sulfate, a bisulfate, a nitrate, a hydrobromide, a hydroiodide, a carbonate, a bicarbonate, a sulfite, a bisulfite, a pyrosulfate, a monohydrogen phosphate, a dihydrogen phosphate, a perchlorate, a persulfate, a hemisulfate, a bisulfate, a thiocyanate, a phosphate, a pyrophosphate, a metaphosphate, or any combination thereof; the organic acid salt is a formate, an acetate, a propionate, a butyrate, a benzoate, a malonate, a succinate, a pyruvate, a mesylate, an esylate, a propanesulfonate, a citrate, a 4-nitrobenzoate, a benzenesulfonate, a p-toluenesulfonate, a malate, a propiolate, a 2-butynoate, a 2-hydroxyethanesulfonate, a vinyl acetate, a tartrate, an L-tartrate, a fumarate, a hydroxyethanesulfonate, a maleate, a lactate, a lactobionate, a pamoate, a salicylate, a galactarate, a glucoheptonate, a mandelate, a 1,2-ethanedisulfonate, a naphthalenesulfonate, an oxalate, a trifluoroacetate, a trifluoromethanesulfonate, an adipate, a suberate, a sebacate, a butyne-1,4-dioate, a hexyne-1,6-dioate, a glycolate, an alginate, an ascorbate, an isoascorbate, an aspartate, an L-aspartate, a glutamate, an L-glutamate, a 2-phenoxybenzoate, a 2-(4-hydroxybenzoyl)benzoate, an acetoacetate, a 2-hydroxyethanesulfonate, a benzenesulfonate, a borate, a chlorobenzoate, a camphorate, an itaconate, a camphorsulfonate, a levocamphorsulfonate, a methylbenzoate, a dinitrobenzoate, a sulfamate, a lactobionate, a galactobionate, a cyclopentanepropionate, a dodecyl sulfate, an acrylate, a cyclopentanepropionate, a glycerophosphate, a methoxybenzoate, a digluconate, a gluconate, a heptanoate, a hexanoate, a 2-hydroxyethanesulfonate, a pivalate, a nicotinate, a cinnamate, an oleate, a palmitate, a pimelate, a pectinate, a phthalate, a phenylacetate, a lauryl sulfate, a 2-acetoxybenzoate, a nicotinate, a cinnamate, an oleate, a palmitate, a pimelate, a pectinate, a phthalate, a glutarate, a hydroxymaleate, a hydroxybenzoate, a 3-hydroxy-2-naphthoate, a 3-phenylpropionate, an isobutyrate, a pivalate, a picrate, a stearate, a 2,2-dichloroacetate, an acylated amino acid salt, an alginate, a 4-acetamidobenzenesulfonate, a caprate, a cholate, a caprylate, a nonanoate, a cyclamate, a phthalate, a cysteine hydrochloride, a sorbate, a pamoate, a mucate, a glycine hydrochloride, a naphthalenedisulfonate, a xylenesulfonate, a cystine dihydrochloride, an undecanoate, a polyvinylsulfate, a sulfosalicylic acid salt, a phenylbutyrate, a 4-hydroxybutyrate, a polyvinyl sulfate, a naphthalene-1-sulfonate, a naphthalene-2-sulfonate, a valerate, or any combination thereof.

4. The compound or its pharmaceutically acceptable acid addition salt according to any one of claims 1-3, which is in crystalline form.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The compound represented by the formula (I) is its free base crystalline form I, and the X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77±0.20°, 9.91±0.20°, 10.10±0.20°, 11.68±0.20°, 15.09±0.20°, 21.46±0.20°, 23.25±0.20°.

6. The compound according to claim 5 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77±0.20°, 9.22±0.20°, 9.91±0.20°, 10.10±0.20°, 11.68±0.20°, 15.09±0.20°, 17.98±0.20°, 18.35±0.20°, 18.53±0.20°, 19.55±0.20°, 19.89±0.20°, 20.24±0.20°, 21.16±0.20°, 21.46±0.20°, 23.01±0.20°, 23.25±0.20°, 23.57±0.20°, 25.10±0.20°, 25.53±0.20°, 26.74±0.20°, 29.28±0.20°.

7. The compound according to claim 6 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the free base crystalline form I has diffraction peaks at the following 2θ angles: 7.77°, 9.22°, 9.91°, 10.10°, 11.68°, 11.95°, 15.09°, 15.61°, 17.98°, 18.35°, 18.53°, 18.85°, 19.26°, 19.55°, 19.89°, 20.24°, 21.16°, 21.46°, 21.87°, 22.21°, 23.01°, 23.25°, 23.57°, 24.05°, 25.10°, 25.53°, 25.88°, 26.4°, 26.74°, 27.50°, 28.12°, 29.28°, 31.20°, 31.62°, 32.80°, 34.08°, 36.47°, 37.74°.

8. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The compound represented by the formula (I) is its free base crystalline form II, and the X-ray powder diffraction pattern of the free base crystalline form II has diffraction peaks at the following 2θ angles: 3.93±0.20°, 7.82±0.20°, 11.72±0.20°, 15.13±0.20°, 21.50±0.20°.

9. The compound according to claim 8 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the free base crystalline form II has diffraction peaks at the following 2θ angles: 3.93±0.20°, 7.82±0.20°, 10.15±0.20°, 11.72±0.20°, 15.13±0.20°, 15.64±0.20°, 18.01±0.20°, 19.60±0.20°, 21.50±0.20°, 23.28±0.20°, 25.14±0.20°, 29.32±0.20°.

10. The compound according to claim 9 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the free base crystalline form II has diffraction peaks at the following 2θ angles: 3.93°, 7.82°, 9.11°, 10.15°, 11.72°, 15.13°, 15.64°, 18.01°, 18.40°, 19.60°, 21.50°, 23.28°, 25.14°, 26.78°, 27.56°, 29.32, 32.87°, 37.57°.

11. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is fumarate crystalline form I of the compound represented by formula (I). The X-ray powder diffraction pattern of the fumaric acid crystalline form I has diffraction peaks at the following 2θ angles: 3.22 ± 0.20°, 9.51 ± 0.20°, 13.00 ± 0.20°, 15.86 ± 0.20°, 20.19 ± 0.20°.

12. The compound according to claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the fumaric acid crystalline form I has diffraction peaks at the following 2θ angles: 3.22 ± 0.20°, 9.51 ± 0.20°, 11.52 ± 0.20°, 13.00 ± 0.20°, 15.86 ± 0.20°, 19.61 ± 0.20°, 20.19 ± 0.20°, 21.65 ± 0.20°, 22.41 ± 0.20°, 24.58 ± 0.20°, 26.34 ± 0.20°.

13. The compound according to claim 12 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the fumaric acid crystalline form I has diffraction peaks at the following 2θ angles: 3.22°, 9.51°, 10.13°, 11.52°, 13.00°, 13.63°, 14.76°, 15.86°, 16.69°, 18.75°, 19.61°, 20.19°, 21.19°, 21.65°, 22.41°, 24.58°, 26.34°, 28.75°, 29.83°, 35.27°.

14. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is malate crystalline form I of the compound represented by formula (I). The X-ray powder diffraction pattern of the malate crystalline form I has diffraction peaks at the following 2θ angles: 7.31 ± 0.20°, 11.75 ± 0.20°.

15. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is citrate crystalline form I of the compound represented by formula (I). The X-ray powder diffraction pattern of the citrate crystalline form I has diffraction peaks at the following 2θ angles: 6.30 ± 0.20°, 6.74 ± 0.20°, 9.04 ± 0.20°, 12.10 ± 0.20°, 18.55 ± 0.20°.

16. The compound according to claim 15 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the citrate crystalline form I has diffraction peaks at the following 2θ angles: 6.30 ± 0.20°, 6.74 ± 0.20°, 9.04 ± 0.20°, 12.10 ± 0.20°, 13.35 ± 0.20°, 17.28 ± 0.20°, 18.55 ± 0.20°, 20.11 ± 0.20°, 21.02 ± 0.20°.

17. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is citrate crystal form II of the compound shown by formula (I), and the X-ray powder diffraction pattern of the citrate crystal form II has diffraction peaks at the following 2θ angles: 6.72 ± 0.20°, 9.04 ± 0.20°, 15.11 ± 0.20°, 18.59 ± 0.20°, 21.51 ± 0.20°, 24.03 ± 0.20°, 24.62 ± 0.20°.

18. The compound according to claim 17 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the citrate crystal form II has diffraction peaks at the following 2θ angles: 6.72 ± 0.20°, 9.04 ± 0.20°, 13.97 ± 0.20°, 15.11 ± 0.20°, 18.59 ± 0.20°, 20.17 ± 0.20°, 21.09 ± 0.20°, 21.51 ± 0.20°, 24.03 ± 0.20°, 24.62 ± 0.20°, 28.11 ± 0.20°.

19. The compound according to claim 17 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the citrate crystal form II is substantially as shown in Figure 24.

20. The compound according to any one of claims 17-19 or a pharmaceutically acceptable acid addition salt thereof, wherein, The thermogravimetric analysis curve of the citrate crystal form II has a weight loss of about 8.79% at 150.00 °C ± 3.00 °C, and the differential scanning calorimetry curve of the citrate crystal form II contains an endothermic peak at 138.20 °C ± 3.00 °C.

21. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is tartrate crystal form I of the compound shown by formula (I), and the X-ray powder diffraction pattern of the tartrate crystal form I has diffraction peaks at the following 2θ angles: 3.87 ± 0.20°, 7.66 ± 0.20°.

22. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is hydrochloride crystal form I of the compound shown by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form I has diffraction peaks at the following 2θ angles: 5.04 ± 0.20°, 10.05 ± 0.20°, 14.38 ± 0.20°, 15.88 ± 0.20°, 25.53 ± 0.20°.

23. The compound according to claim 22 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form I has diffraction peaks at the following 2θ angles: 5.04 ± 0.20°, 8.59 ± 0.20°, 10.05 ± 0.20°, 14.38 ± 0.20°, 15.88 ± 0.20°, 18.81 ± 0.20°, 22.79 ± 0.20°, 23.81 ± 0.20°, 25.53 ± 0.20°, 26.45 ± 0.20°, 28.34 ± 0.20°.

24. The compound according to claim 23 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form I has diffraction peaks at the following 2θ angles: 5.04°, 8.59°, 10.05°, 12.24°, 14.38°, 15.88°, 16.64°, 17.12°, 18.81°, 21.07°, 22.79°, 23.81°, 25.53°, 25.95°, 26.45°, 26.81, 28.34°, 31.38°.

25. The compound according to any one of claims 1-4 or a pharmaceutically acceptable acid addition salt thereof, wherein, The acid addition salt is hydrochloride crystal form II of the compound represented by formula (I), and the X-ray powder diffraction pattern of the hydrochloride crystal form II has diffraction peaks at the following 2θ angles: 4.96 ± 0.20°, 9.88 ± 0.20°, 14.23 ± 0.20°, 16.43 ± 0.20°, 23.46 ± 0.20°.

26. The compound according to claim 25 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form II has diffraction peaks at the following 2θ angles: 4.96 ± 0.20°, 9.88 ± 0.20°, 14.23 ± 0.20°, 14.83 ± 0.20°, 16.43 ± 0.20°, 18.78 ± 0.20°, 23.46 ± 0.20°, 25.58 ± 0.20°, 26.41 ± 0.20°, 29.94 ± 0.20°, 30.79 ± 0.20°.

27. The compound according to claim 26 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form II has diffraction peaks at the following 2θ angles: 4.96 ± 0.20°, 8.60 ± 0.20°, 9.88 ± 0.20°, 10.23 ± 0.20°, 12.12 ± 0.20°, 14.23 ± 0.20°, 14.83 ± 0.20°, 15.94 ± 0.20°, 16.43 ± 0.20°, 17.39 ± 0.20°, 18.78 ± 0.20°, 19.83 ± 0.20°, 21.06 ± 0.20°, 22.43 ± 0.20°, 22.83 ± 0.20°, 23.46 ± 0.20°, 23.92 ± 0.20°, 24.53 ± 0.20°, 24.85 ± 0.20°, 25.58 ± 0.20°, 26.02 ± 0.20°, 26.41 ± 0.20°, 28.36 ± 0.20°, 28.66 ± 0.20°, 29.27 ± 0.20°, 29.94 ± 0.20°, 30.79 ± 0.20°, 31.26 ± 0.20°, 31.79 ± 0.20°, 32.54 ± 0.20°, 33.26 ± 0.20°, 33.66 ± 0.20°, 34.93 ± 0.20°, 35.55 ± 0.20°, 37.02 ± 0.20°, 37.72 ± 0.20°, 38.37 ± 0.20°, 39.16 ± 0.20°, 39.90 ± 0.20°.

28. The compound according to claim 25 or a pharmaceutically acceptable acid addition salt thereof, wherein, The X-ray powder diffraction pattern of the hydrochloride crystal form II is substantially as shown in Figure 30.

29. The compound according to any one of claims 25 - 28 or a pharmaceutically acceptable acid addition salt thereof, wherein, In the thermogravimetric analysis curve of the hydrochloride crystal form II, the weight loss is about 0.96% at 140.00°C ± 3.00°C, and the differential scanning calorimetry curve of the hydrochloride crystal form II contains an endothermic peak at 148.90°C ± 3.00°C.

30. A pharmaceutical composition, wherein, It contains the compound of formula I or a pharmaceutically acceptable acid addition salt thereof as described in any one of claims 1-29, and also contains a combination of one or more of a pharmaceutically acceptable carrier, excipient, diluent, and adjuvant.

31. The pharmaceutical composition according to claim 30, wherein, The pharmaceutical composition is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, by inhalation, vaginally, by topical administration, subcutaneous injection, lipid injection, intra-articular injection, intraperitoneal or intrathecal injection; optionally, the pharmaceutical composition is administered orally.

32. Use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof according to any one of 1-29, or a pharmaceutical composition according to claim 30, in the manufacture of a medicament, wherein, The drug is used for treating microbial infections in mammals.

33. The use according to claim 32, wherein, The microbial infection is a Gram-negative bacterial infection.

34. The use according to claim 33, wherein, The Gram-negative bacteria are selected from one or more of Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae).

35. The use according to claim 32, wherein The microbial infection is a non-tuberculous mycobacterial infection.

36. The use according to claim 35, wherein The non-tuberculous mycobacteria are selected from one or more of Mycobacterium scrofulaceum (M. scrofulaceum), Mycobacterium gordonae (M. gordonae), Mycobacterium avium (M. avium), Mycobacterium abscessus (M. abscessus), Mycobacterium intracellulare (M. intercelleulare), Mycobacterium fortuitum (M. fortuitum), Mycobacterium peregrinum (M. peregrinum), Mycobacterium smegmatis (M. smegmatis) and Mycobacterium massiliense (M. massiliense).

37. Use according to any one of claims 32 - 36, wherein, The microbial infection is a microbial infection of the skin, soft tissue, respiratory tract, blood, peritoneal cavity, urinary tract or eye.

38. The use according to any one of claims 32 - 37, wherein, The mammal is a human.

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