Salts of aromatic ring-containing derivative antagonists, their preparation method and applications

Abstract

This application relates to salts and crystalline forms of aromatic ring-containing derivative antagonists, and their preparation methods and applications. Specifically, this application relates to salts and crystalline forms of the compound of formula (I), preparation methods, pharmaceutical compositions containing therapeutically effective amounts of the salts or crystalline forms, and their use as dual-acting protease inhibitors in the manufacture of medicaments for treating or preventing angiotensin-dependent and endothelin-dependent diseases.

Description

[Technical Field]

[0001] The present application relates to the field of biopharmaceuticals, and in particular to salts and crystalline forms of dual-acting pharmaceutical preparations for treating or preventing angiotensin-dependent and endothelin-dependent diseases, as well as methods for preparing and applying the same. [Background technology]

[0002] Focal segmental glomerulosclerosis (FSGS) is a phenotype of nephrotic syndrome and a major cause of end-stage renal disease. Its pathogenesis is complex and not yet fully understood. Current drug treatments, primarily glucocorticoids and immunosuppressants, have shown poor response rates, failed to effectively control the onset and progression of FSGS, and have significant side effects. Currently, there are no approved treatments for FSGS. The complete remission rate for FSGS treatment is less than 30%. One-third of patients progress to chronic renal failure within five years, requiring long-term dialysis or kidney transplantation to survive. This creates a significant economic burden on families and society, making the search for new treatment strategies a priority.

[0003] In addition to FSGS, other kidney diseases or conditions characterized by glomerular damage include IgA nephropathy and idiopathic membranous nephropathy. IgA nephropathy, also known as Berger's disease, is caused by the accumulation of immunoglobulin A (IgA) in the kidney. The presence of IgA in the kidney can cause renal dysfunction, including inflammation, glomerular damage, and proteinuria. In some cases, patients with IgA nephropathy progress to ESRD. IgA nephropathy is the most common glomerulonephritis worldwide. Approximately 30% of patients experience a 50% decline in glomerular filtration rate over a 10-year period. Patients with IgA nephropathy form IgG autoantibodies to counteract galactose-deficient IgA1 antibodies. These antibodies then deposit in the mesangium and activate complement. Primary treatment for patients with IgA nephropathy involves eliminating risk factors, particularly hypertension, by blocking the renin-angiotensin-aldosterone system (RAAS). Although immunosuppression has also been extensively studied, no significant advantages have been observed. Common side effects of hormone therapy include elevated blood glucose levels, osteoporosis, and infections. Therefore, there remains a need for compositions and methods for treating various kidney diseases or conditions (e.g., FSGS, IgA nephropathy, and IMN).

[0004] Angiotensin II (Ang II) and endothelin-1 (ET-1), two potent and effective endogenous vasoactive peptides, are thought to play a role in regulating vascular tone and pathological tissue remodeling in various diseases, including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid, and sodium balance. Excessive activation of the RAAS promotes systemic and local glomerular capillary hypertension, causes glomerular hemodynamic damage, and can lead to kidney injury and fibrosis via profibrotic and proinflammatory pathways. RAAS-dependent drugs, such as angiotensin receptor blockers (ARBs), are used to treat diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. Furthermore, the potential benefits of ETA receptor antagonists (ERAs) in the treatment of hypertension and diabetic nephropathy have been demonstrated by a growing body of data.

[0005] Studies have shown that the combination of an ARB and an ERA produces a synergistic effect, with Ang II and ET-1 acting cooperatively in blood pressure control and pathological tissue remodeling. Elevated Ang II levels promote the synthesis and vasoconstriction of ET-1, and ET receptor blockade with an ETA can attenuate Ang II-induced vasoconstriction and reduce plasma aldosterone. ARBs not only block the action of Ang II on its AT1 receptor but also limit ET-1 production. Therefore, simultaneous blockade of both Ang II and ET-1 activity may provide superior efficacy compared with blocking either agent alone. While ARBs are the standard treatment for patients with diabetic nephropathy, phase II clinical trials have shown that dual antagonists (ARBs and ERAs) can improve proteinuria in patients with FSGS. Therefore, drugs with an AT1 / ETA dual target antagonism mechanism have potential therapeutic potential for renal disease and are of interest for drug development. Summary of the Invention [Problem to be solved by the invention]

[0006] WO 2023 / 025277 (Application No. PCT / CN2022 / 115068) discloses the structures of a series of aromatic ring-containing biological antagonists. In subsequent research, the present invention has conducted comprehensive research on the salts and crystalline forms of the above substances to obtain the optimal crystalline form, in order to facilitate product handling, filtration, drying, and storage, and to achieve long-term product stability and high bioavailability. [Means for solving the problem]

[0007] The entire contents of International Patent Application PCT / CN2022 / 115068 are incorporated herein by reference.

[0008] An object of the present invention is to provide an acid salt of a compound represented by general formula (I): [ka] where: L1 is -CH2 or -CD2-, X1 is N or CR 1 and X2 is N or CR 2 and X3 is N or CR 3 and R 1 , R 2 and R 3 are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 N, O or S atoms, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-3Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 further substituted with one or more substituents selected from the group consisting of an aryl group and a 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; R1 is hydrogen, C 1-3 Alkyl group or -(CH2) n1 O(CH2) n2 R A2 wherein C is selected from 1-3 The alkyl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-6 further substituted with one or more substituents of a cycloalkyl group; R A2 is C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 3-6 Cycloalkyl groups, 4- to 7-membered heterocyclyl groups, C 3-6 Cycloalkyl C 1-3 Alkyl group or 4- to 7-membered heterocyclyl C 1-3 alkyl groups, R2 and R3 each independently represent hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 N, O or S atoms, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-10 further substituted with one or more substituents selected from the group consisting of an aryl group and a 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; Or, R2 and R3 are bonded to the connecting atom to form C 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocyclyl group, R7 and R8 each independently represent hydrogen, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, or C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Haloalkoxy group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; When L1 is -CH2-, and R2 and R3 are both hydrogen, R7 and R8 are not both -CH3, When L1 is -CH2- and R2 and R3 are both hydrogen, R1 is not hydrogen, n1 and n2 each independently represent 0, 1, 2, or 3; Acids that can be used for acid salts include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, geraniol, methylparaben ... The acid may be selected from antiseptic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid, and is preferably methanesulfonic acid, benzenesulfonic acid, isethionic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, phosphoric acid or hydrobromic acid.

[0009] In a preferred embodiment of the present invention, R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, methyl, ethyl, or propyl; R1 is hydrogen, -CH3, -CH2CH3, [ka] is selected from R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, and a propyl group; or R2 and R3 are bonded to the connecting atom to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group; R7 is selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, deuterated methyl, dideuteromethyl, or trideuteromethyl; R8 is selected from a methyl group, an ethyl group, or a propyl group.

[0010] In a preferred embodiment of the invention, the compound is 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide, 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide, 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, The acid in the acid salt is selected from methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid or hydrobromic acid.

[0011] In a further preferred embodiment of the present invention, the number of acids is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0012] In a further preferred embodiment of the present invention, the acid salt is a hydrate or anhydrous. When the acid salt is a hydrate, the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 0.5, 1, 2 or 3.

[0013] In a further preferred embodiment of the present invention, the acid salt is in crystalline form, Preferably, the acid salt crystalline form of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, an acid salt crystalline form of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide; an acid salt crystalline form of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide; an acid salt crystalline form of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide; an acid salt crystalline form of 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, More preferred are methanesulfonate crystalline form, ethanesulfonate crystalline form, hydrochloride crystalline form, sulfate crystalline form, p-toluenesulfonate crystalline form, benzenesulfonate crystalline form, isethionate crystalline form, and hydrobromide crystalline form.

[0014] In a further preferred embodiment of the present invention, the acid salt crystalline form of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is as follows: Hydrochloride crystalline form A, whose powder X-ray diffraction pattern has a diffraction peak at 2θ of 9.2±0.2°, or a diffraction peak at 9.0±0.2°, or a diffraction peak at 8.2±0.2°, or a diffraction peak at 10.8±0.2°, or a diffraction peak at 16.8±0.2°, or a diffraction peak at 18.8±0.2°, or a diffraction peak at 20.2±0.2°, or a diffraction peak at 20.6±0.2°. or has a diffraction peak at a position at 20.9±0.2°, or has a diffraction peak at a position at 23.2±0.2°, or has a diffraction peak at a position at 25.3±0.2°, or has a diffraction peak at a position at 24.0±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Hydrochloride crystalline form B, whose powder X-ray diffraction pattern has a diffraction peak at 2θ of 10.4±0.2°, or a diffraction peak at 7.3±0.2°, or a diffraction peak at 14.1±0.2°, or a diffraction peak at 14.6±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 19.3±0.2°, or a diffraction peak at 21.9±0.2°, or a diffraction peak at 24.8±0.2°. or has a diffraction peak at a position of 11.0±0.2°, or has a diffraction peak at a position of 13.1±0.2°, or has a diffraction peak at a position of 20.3±0.2°, or has a diffraction peak at a position of 22.1±0.2°, or has a diffraction peak at a position of 24.1±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Hydrochloride crystalline form C, whose powder X-ray diffraction pattern has a diffraction peak at 8.6±0.2 degrees 2θ, or a diffraction peak at 7.9±0.2 degrees 2θ, or a diffraction peak at 14.7±0.2 degrees 2θ, or a diffraction peak at 14.9±0.2 degrees 2θ, or a diffraction peak at 6.3±0.2 degrees 2θ, or a diffraction peak at 17.4±0.2 degrees 2θ, or a diffraction peak at 10.3±0.2 degrees 2θ, or a diffraction peak at 12.4±0.2 degrees 2θ, or has a diffraction peak at a certain position, or has a diffraction peak at a position of 23.8±0.2°, or has a diffraction peak at a position of 24.8±0.2°, or has a diffraction peak at a position of 16.0±0.2°, or has a diffraction peak at a position of 18.2±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Crystalline form A of the ethanesulfonate salt, which has an X-ray powder diffraction pattern having a diffraction peak at 2θ of 8.7±0.2°, or a diffraction peak at 7.4±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 17.5±0.2°, or a diffraction peak at 19.4±0.2°, or a diffraction peak at 22.7±0.2°, or a diffraction peak at 26.4±0.2°, or a diffraction peak at 28.8±0.2°. or has a diffraction peak at a position where the angle is 20.1±0.2°, or has a diffraction peak at a position where the angle is 35.1±0.2°, or has a diffraction peak at a position where the angle is 35.4±0.2°, or has a diffraction peak at a position where the angle is 15.5±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Crystalline form B of the ethanesulfonate salt, which has an X-ray powder diffraction pattern having a diffraction peak at a 2θ angle of 8.8±0.2°, or a diffraction peak at a 2θ angle of 8.3±0.2°, or a diffraction peak at a 2θ angle of 7.9±0.2°, or a diffraction peak at a 2θ angle of 17.0±0.2°, or a diffraction peak at a 2θ angle of 16.2±0.2°, or a diffraction peak at a 2θ angle of 18.4±0.2°, or a diffraction peak at a 2θ angle of 20.6±0.2°, or a diffraction peak at a 2θ angle of 24.1±0.2°. or a diffraction peak at a position where the angle is 26.4±0.2°, or a diffraction peak at a position where the angle is 10.8±0.2°, or a diffraction peak at a position where the angle is 12.6±0.2°, or a diffraction peak at a position where the angle is 19.9±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, p-Toluenesulfonate Crystalline Form A, whose powder X-ray diffraction pattern has a diffraction peak at 2θ of 5.8±0.2°, or 6.2±0.2°, or 18.6±0.2°, or 23.2±0.2°, or 29.1±0.2°, preferably including any one, or 1 to 2, or 2 to 3 of the above diffraction peaks, more preferably any one, 2, 3, 4, or 5 of the above diffraction peaks; Crystalline form A of the methanesulfonate salt, the powder X-ray diffraction pattern of which has a diffraction peak at 2θ of 8.1±0.2°, or at 8.4±0.2°, or at 4.1±0.2°, or at 20.8±0.2°, or at 22.3±0.2°, or at 18.9±0.2°, or at 24.5±0.2°, or at 20.0±0.2°. or a diffraction peak at a position where the angle is 24.3±0.2°, or a diffraction peak at a position where the angle is 11.1±0.2°, or a diffraction peak at a position where the angle is 12.6±0.2°, or a diffraction peak at a position where the angle is 16.5±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Sulfate crystalline form A, having an X-ray powder diffraction pattern having a diffraction peak at 2θ of 8.3±0.2°, or a diffraction peak at 20.9±0.2°, or a diffraction peak at 18.5±0.2°, or a diffraction peak at 24.4±0.2°, or a diffraction peak at 10.0±0.2°, or a diffraction peak at 11.0±0.2°, or a diffraction peak at 12.6±0.2°, or a diffraction peak at 16.3±0.2° or a diffraction peak at 19.9±0.2°, or a diffraction peak at 20.4±0.2°, or a diffraction peak at 21.9±0.2°, or a diffraction peak at 26.7±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them, Crystalline Form A of benzenesulfonate salt, the powder X-ray diffraction pattern of which has a diffraction peak at 2θ of 5.9±0.2°, or a diffraction peak at 23.8±0.2°, or a diffraction peak at 17.8±0.2°, or a diffraction peak at 29.9±0.2°, preferably including any one to three, or any two to four, of the above diffraction peaks, more preferably including any one, two, three, or four of the above diffraction peaks; isethionate crystalline form A, the powder X-ray diffraction pattern of which has a diffraction peak at 2θ of 9.9±0.2°, or a diffraction peak at 19.9±0.2°, or a diffraction peak at 8.3±0.2°, or a diffraction peak at 20.5±0.2°, or a diffraction peak at 18.2±0.2°, or a diffraction peak at 23.9±0.2°, or a diffraction peak at 10.6±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7 of the above diffraction peaks, more preferably any 2, 3, 4, or 5 of the above diffraction peaks; Crystalline form A of the hydrobromide salt, which has an X-ray powder diffraction pattern having a diffraction peak at 2θ of 30.0±0.2°, or a diffraction peak at 22.3±0.2°, or a diffraction peak at 25.9±0.2°, or a diffraction peak at 29.7±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 35.7±0.2°, or a diffraction peak at 33.3±0.2°, or a diffraction peak at 23.4±0.2°. The diffraction peak may have a diffraction peak at a position where the angle is 28.6±0.2°, or a diffraction peak at a position where the angle is 28.8±0.2°, or a diffraction peak at a position where the angle is 18.1±0.2°, or a diffraction peak at a position where the angle is 26.6±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them.

[0015] In a further preferred embodiment of the present invention, The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A comprises at least one or more diffraction peaks at 9.2±0.2°, 9.0±0.2°, and 8.2±0.2° 2θ, preferably two of these, more preferably three of these, and optionally further comprises at least one peak at 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, and 23.2±0.2° 2θ, preferably two, three, four, or five of these, for example: 9.2±0.2°, 9.0±0.2°, 9.2±0.2°, 8.2±0.2°, 9.0±0.2°, 8.2±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.6±0.2°, 20.9±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.9±0.2°, 23.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.9±0.2°, and 23.2±0.2°. The powder X-ray diffraction pattern of the hydrochloride salt crystalline form B comprises at least one or more diffraction peaks at 10.4±0.2°, 7.3±0.2°, and 14.1±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one further peak at 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, and 13.1±0.2° 2θ, preferably two, three, four, or five of these, for example 10.4±0.2°, 7.3±0.2°, 10.4±0.2°、14.1±0.2°、 7.3±0.2°、14.1±0.2°、 10.4±0.2°、7.3±0.2°、14.1±0.2°、 10.4±0.2°、14.1±0.2°、14.6±0.2°、 7.3±0.2°、14.1±0.2°、14.6±0.2°、 10.4±0.2°、7.3±0.2°、14.1±0.2°、14.6±0.2°、 10.4±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、 7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、 10.4±0.2°、7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、 10.4±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、 7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、 10.4±0.2°、7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、 10.4±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、21.9±0.2°、 7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、21.9±0.2°、 10.4±0.2°、7.3±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、21.9±0.2°、24.8±0.2°、 10.4±0.2°、14.1±0.2°、14.6±0.2°、17.0±0.2°、19.3±0.2°、21.9±0.2°、24.8±0.2°、11.0±0.2°、 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 10.4±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 24.8±0.2°, 11.0±0.2°, 10.4±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, 13.1±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, and 13.1±0.2°. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form C comprises at least one or more diffraction peaks at 8.6±0.2°, 7.9±0.2°, and 14.7±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one further peak at 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, and 24.8±0.2° 2θ, preferably two, three, four, or five of these, for example: 8.6±0.2°, 7.9±0.2°, 8.6±0.2°, 14.7±0.2°, 7.9±0.2°, 14.7±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, and 23.8±0.2°. The powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form A comprises at least one or more diffraction peaks at 8.7±0.2°, 7.4±0.2°, and 17.0±0.2° 2θ, preferably two of these, more preferably three of these, and optionally further comprises at least one peak at 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, and 35.1±0.2° 2θ, preferably two, three, four, or five of these, for example: 8.7±0.2°、7.4±0.2°、 8.7±0.2°、17.0±0.2°、 7.4±0.2°、17.0±0.2°、 8.7±0.2°、7.4±0.2°、17.0±0.2°、 8.7±0.2°、17.0±0.2°、17.5±0.2°、 7.4±0.2°、17.0±0.2°、17.5±0.2°、 8.7±0.2°、7.4±0.2°、17.0±0.2°、17.5±0.2°、 8.7±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、 7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、 8.7±0.2°、7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、 8.7±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、 7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、 8.7±0.2°、7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、 8.7±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、26.4±0.2°、 7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、26.4±0.2°、 8.7±0.2°、7.4±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、26.4±0.2°、28.8±0.2°、 8.7±0.2°、17.0±0.2°、17.5±0.2°、19.4±0.2°、22.7±0.2°、26.4±0.2°、28.8±0.2°、20.1±0.2°、 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 8.7±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 28.8±0.2°, 20.1±0.2°, 8.7±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 20.1±0.2°, 35.1±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 20.1±0.2°, and 35.1±0.2°. The powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B comprises at least one or more diffraction peaks at 8.8±0.2°, 8.3±0.2°, and 7.9±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one further peak at 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, and 10.8±0.2° 2θ, preferably two, three, four, or five of these, for example: 8.8±0.2°, 8.3±0.2°, 8.8±0.2°, 7.9±0.2°, 8.3±0.2°, 7.9±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2° 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 24.1±0.2°, 26.4±0.2°, 8.8±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 26.4±0.2°, 10.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 26.4±0.2°, and 10.8±0.2°. The powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A contains at least a diffraction peak located at 5.8±0.2 degrees 2θ, and optionally further contains at least one peak located at 6.2±0.2 degrees, 18.6±0.2 degrees, 23.2±0.2 degrees, or 29.1±0.2 degrees 2θ, preferably one, two, three, or four of these peaks, such as 5.8±0.2°, 5.8±0.2°, 6.2±0.2°, 5.8±0.2°, 18.6±0.2°, 5.8±0.2°, 23.2±0.2°, 5.8±0.2°, 29.1±0.2°, 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 5.8±0.2°, 18.6±0.2°, 23.2±0.2°, 5.8±0.2°, 23.2±0.2°, 29.1±0.2°, 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 23.2±0.2°, 5.8±0.2°, 18.6±0.2°, 23.2±0.2°, 29.1±0.2°, 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 23.2±0.2°, and 29.1±0.2°. The powder X-ray diffraction pattern of methanesulfonate crystalline Form A comprises at least one or more diffraction peaks at 8.1±0.2°, 8.4±0.2°, and 4.1±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one further peak at 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, and 11.1±0.2° 2θ, preferably two, three, four, or five of these, for example: 8.1±0.2°, 8.4±0.2°, 8.1±0.2°, 4.1±0.2°, 8.4±0.2°, 4.1±0.2°, 8.1±0.2°、8.4±0.2°、4.1±0.2°、 8.1±0.2°、4.1±0.2°、20.8±0.2°、 8.4±0.2°、4.1±0.2°、20.8±0.2°、 8.1±0.2°、8.4±0.2°、4.1±0.2°、20.8±0.2°、 8.1±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、 8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、 8.1±0.2°、8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、 8.1±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、 8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、 8.1±0.2°、8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、 8.1±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、24.5±0.2°、 8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、24.5±0.2°、 8.1±0.2°、8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、24.5±0.2°、20.0±0.2°、 8.1±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、24.5±0.2°、20.0±0.2°、24.3±0.2°、 8.4±0.2°、4.1±0.2°、20.8±0.2°、22.3±0.2°、18.9±0.2°、24.5±0.2°、20.0±0.2°、24.3±0.2°、 8.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 20.0±0.2°, 24.3±0.2°, 8.1±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 24.3±0.2°, 11.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 24.3±0.2°, and 11.1±0.2°. The X-ray powder diffraction pattern of the sulfate salt crystalline form A comprises at least one or more diffraction peaks at 8.3±0.2°, 20.9±0.2°, and 18.5±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one peak at 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, and 20.4±0.2° 2θ, preferably two, three, four, or five of these, for example: 8.3±0.2°, 20.9±0.2°, 8.3±0.2°, 18.5±0.2°, 20.9±0.2°, 18.5±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 16.3±0.2°, 19.9±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 19.9±0.2°, 20.4±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 19.9±0.2°, and 20.4±0.2°. The powder X-ray diffraction pattern of benzenesulfonate crystalline form A contains at least one diffraction peak located at one or more of the positions where 2θ is 5.9±0.2°, 23.8±0.2°, 17.8±0.2°, and 29.9±0.2°, preferably two of these, more preferably three of these, and even more preferably four of these, for example: 5.9±0.2°, 5.9±0.2°, 23.8±0.2°, 5.9±0.2°, 17.8±0.2°, 5.9±0.2°, 29.9±0.2°, 5.9±0.2°, 23.8±0.2°, 17.8±0.2°, 5.9±0.2°, 17.8±0.2°, 29.9±0.2°, 5.9±0.2°, 23.8±0.2°, 17.8±0.2°, and 29.9±0.2°. The powder X-ray diffraction pattern of isethionate crystalline Form A comprises at least one or more diffraction peaks at 9.9±0.2°, 19.9±0.2°, and 8.3±0.2° 2θ, preferably two of these, more preferably three of these, and optionally further comprises at least one peak at 20.4±0.2°, 18.3±0.2°, 23.9±0.2°, and 10.6±0.2° 2θ, preferably two, three, or four of these, for example: 9.9±0.2°, 19.9±0.2°, 9.9±0.2°, 8.3±0.2°, 19.9±0.2°, 8.3±0.2°, 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 9.9±0.2°, 8.3±0.2°, 20.4±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 9.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 9.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 9.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 10.6±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 10.6±0.2°, 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, and 10.6±0.2°. The X-ray powder diffraction pattern of the hydrobromide salt crystalline form A comprises at least one or more diffraction peaks at 30.0±0.2°, 22.3±0.2°, and 25.9±0.2° 2θ, preferably two of these, more preferably three of these, and optionally at least one further peak at 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, and 28.8±0.2° 2θ, preferably two, three, four, or five of these, for example 30.0±0.2°, 22.3±0.2°, 30.0±0.2°, 25.9±0.2°, 22.3±0.2°, 25.9±0.2°, 30.0±0.2°, 22.3±0.2°, 25.9±0.2°, 30.0±0.2°, 25.9±0.2°, 29.7±0.2°, 22.3±0.2°、25.9±0.2°、29.7±0.2°、 30.0±0.2°、22.3±0.2°、25.9±0.2°、29.7±0.2°、 30.0±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、 22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、 30.0±0.2°、22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、 30.0±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、 22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、 30.0±0.2°、22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、 30.0±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、33.3±0.2°、 22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、33.3±0.2°、 30.0±0.2°、22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、33.3±0.2°、23.4±0.2°、 30.0±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、33.3±0.2°、23.4±0.2°、28.6±0.2°、 22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、33.3±0.2°、23.4±0.2°、28.6±0.2°、 30.0±0.2°、22.3±0.2°、25.9±0.2°、29.7±0.2°、17.0±0.2°、35.7±0.2°、23.4±0.2°、28.6±0.2°、 30.0±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 28.6±0.2°, 28.8±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 28.6±0.2°, and 28.8±0.2°.

[0016] In a further preferred embodiment of the present invention, The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A comprises diffraction peaks at one or more of the following positions where 2θ is 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, and 24.0±0.2°, preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 9.2±0.2°, 9.0±0.2°, 16.8±0.2°, 18.8±0.2°, 9.2±0.2°, 8.2±0.2°, 16.8±0.2°, 18.8±0.2°, 9.2±0.2°, 9.0±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 9.2±0.2°, 8.2±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 9.2±0.2°, 9.0±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 9.2±0.2°, 8.2±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 9.2±0.2°, 9.0±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 24.0±0.2°, 9.2±0.2°, 8.2±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 24.0±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 9.2±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 24.0±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, and 24.0±0.2°. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form B comprises diffraction peaks at one or more of the following positions where 2θ is 10.4±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, and 24.1±0.2°, preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 10.4±0.2°, 7.3±0.2°, 17.0±0.2°, 19.3±0.2°, 10.4±0.2°, 14.1±0.2°, 17.0±0.2°, 19.3±0.2°, 10.4±0.2°, 7.3±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 10.4±0.2°, 14.1±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 10.4±0.2°, 7.3±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 10.4±0.2°, 14.1±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 10.4±0.2°, 7.3±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, 10.4±0.2°, 14.1±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, 10.4±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 10.4±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 10.4±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 10.4±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, and 22.1±0.2°. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form C comprises diffraction peaks at one or more of the following positions where 2θ is 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 18.2±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 6.3±0.2°, 8.6±0.2°, 7.9±0.2°, 17.4±0.2°, 10.3±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 8.6±0.2°, 7.9±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 8.6±0.2°, 7.9±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 8.6±0.2°, 7.9±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 18.2±0.2°, 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 8.6±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, and 16.0±0.2°. The powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions where 2θ is 8.7±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, and 15.5±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 8.7±0.2°, 7.4±0.2°, 19.4±0.2°, 22.7±0.2°, 8.7±0.2°, 17.0±0.2°, 19.4±0.2°, 22.7±0.2°, 8.7±0.2°, 7.4±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 8.7±0.2°, 17.0±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 8.7±0.2°, 7.4±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 8.7±0.2°, 17.0±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 8.7±0.2°, 7.4±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 15.5±0.2°, 8.7±0.2°, 17.0±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 15.5±0.2°, 8.7±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 8.7±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 8.7±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 8.7±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 15.5±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, and 15.5±0.2°. The powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B comprises diffraction peaks at one or more of the following positions where 2θ is 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, 10.8±0.2°, 12.6±0.2°, and 19.9±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 8.8±0.2°, 8.3±0.2°, 16.2±0.2°, 18.4±0.2°, 8.8±0.2°, 7.9±0.2°, 16.2±0.2°, 18.4±0.2°, 8.8±0.2°, 8.3±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 8.8±0.2°、7.9±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、 8.8±0.2°、8.3±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、 8.8±0.2°、7.9±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、 8.8±0.2°、8.3±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、12.6±0.2°、19.9±0.2°、 8.8±0.2°、7.9±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、12.6±0.2°、19.9±0.2°、 8.8±0.2°、8.3±0.2°、7.9±0.2°、17.0±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、 8.8±0.2°、7.9±0.2°、17.0±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、 8.3±0.2°、7.9±0.2°、17.0±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、12.6±0.2°、 8.8±0.2°、8.3±0.2°、7.9±0.2°、17.0±0.2°、16.2±0.2°、18.4±0.2°、24.1±0.2°、26.4±0.2°、10.8±0.2°、12.6±0.2°、 8.8±0.2°、7.9±0.2°、17.0±0.2°、16.2±0.2°、18.4±0.2°、20.6±0.2°、26.4±0.2°、10.8±0.2°、12.6±0.2°、19.9±0.2°、 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 26.4±0.2°, 10.8±0.2°, 12.6±0.2°, and 19.9±0.2°. The powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A contains diffraction peaks at one or more of the positions where 2θ is 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 23.2±0.2°, and 29.1±0.2°, and preferably contains diffraction peaks at any of four, five, or six of these positions, for example: 5.8±0.2°, 6.2±0.2°, 23.2±0.2°, 29.1±0.2°, 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, and 29.1±0.2°. The X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions where 2θ is 8.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, or 16.5±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 8.1±0.2°, 8.4±0.2°, 22.3±0.2°, 18.9±0.2°, 8.1±0.2°, 4.1±0.2°, 22.3±0.2°, 18.9±0.2°, 8.1±0.2°, 8.4±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 8.1±0.2°, 4.1±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 8.1±0.2°, 8.4±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 8.1±0.2°, 4.1±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 8.1±0.2°, 8.4±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 16.5±0.2°, 8.1±0.2°, 4.1±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 16.5±0.2°, 8.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 8.1±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 8.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 8.1±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 16.5±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, and 16.5±0.2°. The X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A comprises diffraction peaks at one or more of the following positions where 2θ is 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, and 26.7±0.2°, preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: 8.3±0.2°, 20.9±0.2°, 10.0±0.2°, 11.0±0.2°, 8.3±0.2°, 18.5±0.2°, 10.0±0.2°, 11.0±0.2°, 8.3±0.2°, 20.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 8.3±0.2°, 18.5±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 8.3±0.2°, 20.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 8.3±0.2°, 18.5±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 8.3±0.2°, 20.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 26.7±0.2°, 8.3±0.2°, 18.5±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 26.7±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 8.3±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 26.7±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, and 26.7±0.2°. The powder X-ray diffraction pattern of isethionate crystalline Form A comprises diffraction peaks at one or more of the following positions where 2θ is 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.5±0.2°, 18.2±0.2°, 23.9±0.2°, and 10.6±0.2°, and preferably at any of four, five, or six of these positions, for example: 9.9±0.2°, 19.9±0.2°, 20.4±0.2°, 18.2±0.2°, 9.9±0.2°, 8.3±0.2°, 20.5±0.2°, 18.2±0.2°, 9.9±0.2°, 19.9±0.2°, 20.5±0.2°, 18.2±0.2°, 23.9±0.2°, 10.6±0.2°, 9.9±0.2°, 8.3±0.2°, 20.5±0.2°, 18.2±0.2°, 23.9±0.2°, and 10.6±0.2°. The X-ray powder diffraction pattern of the hydrobromide salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 30.0±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, and preferably at any of four, five, six, eight, or ten of these positions, for example: 30.0±0.2°, 22.3±0.2°, 17.0±0.2°, 35.7±0.2°, 30.0±0.2°, 25.9±0.2°, 17.0±0.2°, 35.7±0.2°, 30.0±0.2°, 22.3±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 30.0±0.2°, 25.9±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 30.0±0.2°, 22.3±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 30.0±0.2°, 25.9±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 30.0±0.2°, 22.3±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, 30.0±0.2°, 25.9±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, 30.0±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 30.0±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 30.0±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 30.0±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, and 26.6±0.2°.

[0017] In a further preferred embodiment of the present invention, The melting point of the hydrochloride salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is 155 to 176°C. The melting point of the hydrochloride salt crystalline form B of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is 169.4 to 174.9; The melting point of the methanesulfonate salt of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, crystalline form A, is 209 to 217°C. The melting point of the sulfate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is 195 to 209°C. The melting point of the hydrobromide salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is 158-165°C.

[0018] In a further preferred embodiment of the present invention, The characteristic X-ray diffraction peaks of the hydrochloride salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, measured using Cu-Kα irradiation, are shown in Table 1, and are expressed as 2θ angles and d-spacings.

[0019] [Table 1]

[0020] The compound of the present invention, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form A, has an X-ray powder diffraction pattern substantially as shown in FIG. 1 and a DSC pattern substantially as shown in FIG. 2.

[0021] The characteristic X-ray diffraction peaks of the hydrochloride salt crystalline form B of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, as measured using Cu-Kα irradiation, are shown in Table 2, which are expressed as 2θ angles and d-spacings.

[0022] [Table 2]

[0023] The compound of the present invention, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B, has an X-ray powder diffraction pattern substantially as shown in FIG. 3 and a DSC pattern substantially as shown in FIG. 4.

[0024] The characteristic X-ray diffraction peaks of the ethanesulfonate salt of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, crystalline form A, obtained using Cu-Kα irradiation, are shown in Table 3, which are expressed as 2θ angles and d-spacings.

[0025] [Table 3]

[0026] The powder X-ray diffraction pattern of the ethanesulfonate salt of the compound of the present invention, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, crystalline form A, is substantially as shown in FIG. 5.

[0027] The characteristic X-ray diffraction peaks of the ethanesulfonate crystalline form B of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, measured using Cu-Kα irradiation, are shown in Table 4, and are expressed as 2θ angles and d-spacings.

[0028] [Table 4]

[0029] The powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B of the compound of the present invention, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, is substantially as shown in FIG. 6.

[0030] The characteristic X-ray diffraction peaks of the p-toluenesulfonate crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, measured using Cu-Kα irradiation, are shown in Table 5, and are expressed as 2θ angles and d-spacings.

[0031] [Table 5]

[0032] The powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A of the compound of the present invention, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, is substantially as shown in FIG. 7.

[0033] The characteristic X-ray diffraction peaks of the methanesulfonate salt of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, crystalline form A, obtained using Cu-Kα irradiation, are shown in Table 6, and are expressed as 2θ angles and d-spacings.

[0034] [Table 6]

[0035] The powder X-ray diffraction pattern of methanesulfonate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide according to the present invention is substantially as shown in FIG. 8, and the DSC pattern thereof is substantially as shown in FIG. 9.

[0036] The characteristic X-ray diffraction peaks of the sulfate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide using Cu-Kα irradiation, expressed as 2θ angles and d-spacings, are shown in Table 7.

[0037] [Table 7]

[0038] The powder X-ray diffraction pattern of the sulfate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide according to the present invention is substantially as shown in FIG. 10 and its DSC pattern is substantially as shown in FIG. 11.

[0039] The characteristic X-ray diffraction peaks of the crystalline form A of the benzenesulfonate salt of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, measured using Cu-Kα irradiation, are shown in Table 8, which are expressed as 2θ angles and d-spacings.

[0040] [Table 8]

[0041] The powder X-ray diffraction pattern of the benzenesulfonate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide described in the present invention is substantially as shown in FIG. 12.

[0042] The characteristic X-ray diffraction peaks of the isethionate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, expressed as 2θ angles and d-spacings, using Cu-Kα irradiation, are shown in Table 9.

[0043] [Table 9]

[0044] The powder X-ray diffraction pattern of the isethionate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide according to the present invention is substantially as shown in FIG. 13 and its DSC pattern is substantially as shown in FIG. 14.

[0045] The characteristic X-ray diffraction peaks of the hydrobromide salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, measured using Cu-Kα irradiation, are shown in Table 10, which are expressed as 2θ angles and d-spacings.

[0046] [Table 10]

[0047] The powder X-ray diffraction pattern of the hydrobromide salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide according to the present invention is substantially as shown in Figure 15.

[0048] The powder X-ray diffraction pattern of the hydrochloride salt crystalline form C of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide according to the present invention is substantially as shown in Figure 16.

[0049] In a further preferred embodiment of the present invention, the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Hydrochloride Crystalline Form A and the positions of the corresponding diffraction peaks in FIG. 1 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Hydrochloride Crystalline Form B and the positions of the corresponding diffraction peaks in FIG. 3 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of ethanesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 5 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of ethanesulfonate crystalline form B and the positions of the corresponding diffraction peaks in FIG. 6 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the six diffraction peaks with the highest relative peak intensities in the powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A and the positions of the corresponding diffraction peaks in Figure 7 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the four diffraction peaks with the highest relative peak intensities in the powder X-ray diffraction pattern of methanesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 8 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Sulfate Crystalline Form A and the positions of the corresponding diffraction peaks in Figure 10 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; The 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of benzenesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 12 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the seven highest relative peak intensities in the powder X-ray diffraction pattern of isethionate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 13 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the five diffraction peaks with the highest relative peak intensity in the powder X-ray diffraction pattern of crystalline Form A of the hydrobromide salt and the positions of the corresponding diffraction peaks in Figure 15 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; The 2θ error between the positions of the five diffraction peaks with the highest relative peak intensities in the powder X-ray diffraction pattern of Hydrochloride Crystalline Form C and the positions of the corresponding diffraction peaks in FIG. 16 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0050] In a further preferred embodiment of the present invention, the acid salt crystalline form is a hydrate or anhydrous, and when the acid salt crystalline form is a hydrate, the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and further, the water in the hydrate is channel water or crystal water or a combination of both.

[0051] The present invention provides a method for preparing an acid salt of a compound, the method comprising: 1) Weighing an appropriate amount of free base and dissolving it in a good solvent; 2) weighing an appropriate amount of counter ion acid and dissolving it in an organic solvent, the amount of the counter ion acid being preferably 1.0 to 1.5 equivalents; 3) combining the two solutions and stirring to precipitate, or adding an anti-solvent dropwise and then stirring to precipitate; 4) quickly centrifuging or allowing to stand and blow dry to obtain the desired product; where: The good solvent is selected from one or more of acetone, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, or tert-butanol, and is preferably one or more of 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, acetone, or ethyl formate; The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably one or more of methanol, ethanol, and acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the anti-solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate, preferably one or more of water, methyl tert-butyl ether or isopropyl ether; The counter ion acid may be hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, isethionic acid, formic acid, fumanic acid, guar ... The acid may be selected from the group consisting of carboxylic acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, and L-malic acid, and is preferably methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, or hydrobromic acid.

[0052] The present invention provides a method for preparing an acid salt of a compound, the method comprising: 1) weighing an appropriate amount of free base and suspending it in an anti-solvent; 2) weighing an appropriate amount of counter ion acid and dissolving it in an organic solvent, the amount of the counter ion acid being preferably 1.0 to 1.5 equivalents; 3) adding the solution to the suspension and stirring for 2 hours; 4) rapidly centrifuging or allowing to stand and blow dry to obtain the salt of the compound of general formula (I), where: The anti-solvent is selected from one or more of ethanol, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, dichloromethane, methanol, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol or 3-pentanone, preferably one or more of ethanol, ethyl acetate, isopropanol or isopropyl acetate.

[0053] The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably one or more of methanol, ethanol, and acetonitrile. The good solvent and the organic solution must be compatible with each other when used. The counter ion acid may be hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, isethionic acid, formic acid, fumanic acid, guar ... The acid may be selected from the group consisting of carboxylic acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, and L-malic acid, and is preferably methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, or hydrobromic acid.

[0054] The present invention further relates to pharmaceutical compositions, which comprise a therapeutically effective amount of an acid salt or crystalline form of a compound of general formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0055] The pharmaceutical composition according to the present invention is suitable for oral administration and injection administration, preferably oral administration. The dosage form includes tablets, capsules, dispersions and suspensions, preferably tablets.

[0056] In some embodiments of the present invention, the weight percentage of the compound represented by general formula (I) in the pharmaceutical composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15 to 40%, even more preferably 20 to 30%, and most preferably 20 to 25%.

[0057] In some embodiments of the present invention, the weight percentage of the compound represented by general formula (I) in the pharmaceutical composition based on the free base is 0.1 to 99%, 0.2 to 98.5%, 0.3 to 98%, 0.4 to 97.5%, 0.5 to 97%, 0.6 to 96.5%, 0.7 to 96%, 0.8 to 95.5%, 0.9 to 95%, 1 to 94.5%, 1.1 to 94%, 1.2 to 93.5%, 1.3 to 93%, 1.4 to 92.5%, 1.5 to 92%, 1.6 to 91.5%, 1.7 to 91%, 1.8 to 90.5%, 1.9 to 90%, 2 to 89.5%, 2.1 to 89%, 2.2 to 88%, 2.3 to 88%, 2.4 to 88%, 2.5 to 98%, 2.6 to 98%, 2.7 to 98%, 2.8 to 98%, 2.9 to 98%, 3.1 to 3.1%, 3.2 to 3.2%, 3.3 to 3.3%, 3.4 to 3.4%, 3.5 to 3.5%, 3.6 to 3.6%, 3.7 to 3.7%, 3.8 to 3.8%, 3.9 to 3.9 ...9 to 3.9%, 3.1 to 3.1%, 3. 0.5%, 2.3~88%, 2.4~87.5%, 2.5~87%, 2.6~86.5%, 2.7~86%, 2.8~85.5%, 2.9~85%, 3~84.5%, 3.1~84%, 3.2~83.5%, 3.3~83%, 3.4~82.5%, 3.5~82%, 3.6~81 0.5%, 3.7-81%, 3.8-80.5%, 3.9-80%, 4-79.5%, 4.1-79%, 4.2-78.5%, 4.3-78%, 4.4-77.5%, 4.5-77%, 4.6-76.5%, 4.7-76%, 4.8-75.5%, 4.9-75%, 5-74.5% , 5.1~74%, 5.2~73.5%, 5.3~73%, 5.4~72.5%, 5.5~72%, 5.6~71.5%, 5.7~71%, 5.8~70.5%, 5.9~70%, 6~69.5%, 6.1~69%, 6.2~68.5%, 6.3~68%, 6.4~67.5% ,6.5~67%,6.6~66.5%,6.7~66%,6.8~65.5%,6.9~65%,7~64.5%,7.1~64%,7.2~63.5%,7.3~63%,7.4~62.5%,7.5~62%,7.6~61.5%,7.7~61%,7.8~60.5%, 7.9~60%, 8~59.5%, 8.1~59%, 8.2~58.5%, 8.3~58%, 8.4~57.5%, 8.5~57%, 8.6~56.5%, 8.7~56%, 8.8~55.5%, 8.9~55%, 9~54.5%, 9.1~54%, 9.2~53.5%, 9.3 ~53%, 9.4~52.5%, 9.5~52%, 9.6~51.5%, 9.7~51%, 9.8~50.5%, 9.9~50%, 10~49.5%, 10.1~49%, 10.2~48.5%, 10.3~48%, 10.4~47.5%, 10.5~47%, 10.6~46.5%, 10.7-46%, 10.8-45.5%, 10.9-45%, 11-44.5%, 11.1-44%, 11.2-43.5%, 11.3-43%, 11.4-42.5%, 11.5-42%, 11.6-41.5%, 11.7-41%, 11.8-40.5%, 11.9-40%, 12-39.5%, 12.1-39 %, 12.2~38.5%, 12.3~38%, 12.4~37.5%, 12.5~37%, 12.6~36.5%, 12.7~36%, 12.8~35.5%, 12.9~35%, 13~34.5%, 13.1~34%, 13.2~33.5%, 13.3~33%, 13.4~32.5%, 13.5~32%, 13.6~3 1.5%, 13.7-31%, 13.8-30.5%, 13.9-30%, 14-29.5%, 14.1-29%, 14.2-28.5%, 14.3-28%, 14.4-27.5%, 14.5-27%, 14.6-26.5%, 14.7-26%, 14.8-25.5%, 14.9-25%, 15-24.5%, 15.1- 24%, 15.2-23.5%, 15.3-23%, 15.4-22.5%, 15.5-22%, 15.6-21.5%, 15.7-21%, 15.8-20.5%, 15.9-20%, 16-19.5%, 16.1-19%, 16.2-18.5%, 16.3-18%, 16.4-17.5% or 16.5-17%.

[0058] In some embodiments of the present invention, the weight percentage of the compound represented by general formula (I) in the pharmaceutical composition based on the free base is 15-30%, 15.1-29.9%, 15.2-29.8%, 15.3-29.7%, 15.4-29.6%, 15.5-29.5%, 15.6-29.4%, 15.7-29.3%, 15.8-29.2%, 15.9-29.1%, 16-29%, 16.1-28.9%, 16.2-28.8%, 16.3-28.7%, 16.4-28.6%, %, 16.5~28.5%, 16.6~28.4%, 16.7~28.3%, 16.8~28.2%, 16.9~28.1%, 17~28%, 17.1~27.9%, 17.2~27.8%, 17.3~27.7%, 17.4~27.6%, 17.5~27.5%, 17.6~27.4%, 17.7~27.3%, 17.8~27.2%, 17.9~27.1%, 18~27%, 18.1~26.9%, 18.2~26.8%, 18.3~26.7%, 18.4~26.6%, 18.5~26.5%, 18.6~26.4%, 18.7~26.3%, 18.8~26.2%, 18.9~26.1%, 19~26%, 19.1~25.9%, 19.2~25.8%, 19.3~25.7%, 19.4~25.6%, 19.5~25.5%, 19.6~25.4%, 19.7~25.3%, 19.8~25.2%, 19.9~25.1%, 20~25%, 20.1~24.9%, 20.2~24.8%, 20.3~24.7%, 20.4~24.6%, 20 0.5-24.5%, 20.6-24.4%, 20.7-24.3%, 20.8-24.2%, 20.9-24.1%, 21-24%, 21.1-23.9%, 21.2-23.8%, 21.3-23.7%, 21.4-23.6%, 21.5-23.5%, 21.6-23.4%, 21.7-23.3%, 21.8-23.2%, 21.9-23.1%, 22-23%, 22.1-22.9%, 22.2-22.8%, 22.3-22.7% or 22.4-22.6%.

[0059] In another aspect, the object of the present invention is to further provide angiotensin II (AT) dependence of an acid salt or crystalline form comprising a compound according to general formula (I), or a pharmaceutical composition thereof.

[0060] In another aspect, the object of the present invention is further to provide the use of an acid salt or crystalline form comprising a compound according to general formula (I), or a pharmaceutical composition thereof, in the manufacture of a medicament for treating and / or preventing an endothelin (ET)-dependent disease.

[0061] In another aspect, the object of the present invention is further to provide the use of an acid salt or crystalline form comprising a compound according to general formula (I), or a pharmaceutical composition thereof, in the manufacture of a medicament for treating and / or preventing dual-acting angiotensin-dependent and endothelin (DARA)-dependent diseases.

[0062] In another aspect, the object of the present invention is further to provide the use of an acid salt or crystalline form comprising a compound according to general formula (I), or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and / or prevention of pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0063] The present invention further relates to methods for treating and / or preventing pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0064] In another aspect, it is a further object of the present invention to provide the use of an acid salt or crystalline form comprising a compound according to general formula (I), or a pharmaceutical composition thereof, in the treatment and / or prevention of pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or related diseases such as kidney diseases.

[0065] In the above technical solutions, the kidney-related disease is selected from diseases or conditions related to the function of the kidney, glomerulus or glomerular system mesangial cells, and more preferably focal segmental glomerulosclerosis or IgA nephropathy.

[0066] Unless otherwise specified, reference herein to a "compound of formula (I)" or a "compound of the invention" also covers any single stereoisomer of that compound.

[0067] Unless otherwise specified, references herein to "compounds of formula (I)" or "compounds of the invention" also encompass isotopically labeled compounds obtained by replacing any single atom in the compound with its isotope. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I), in which one or more atoms are replaced with atoms having the same atomic number as the atom normally found in nature, but a different atomic mass or mass number.

[0068] Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen such as 2H(D) and 3H(T); isotopes of carbon such as 11C, 13C, and 14C; isotopes of chlorine such as 36Cl; isotopes of fluorine such as 18F; isotopes of iodine such as 123I and 125I; isotopes of nitrogen such as 13N and 15N; isotopes of oxygen such as 15O, 17O, and 18O; and isotopes of sulfur such as 35S.

[0069] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, by substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0070] The drawings are intended to provide a further understanding of the invention, constitute a part of the specification, and are used to interpret the invention in conjunction with the following specific embodiments, but are not intended to be limiting of the invention. [Brief explanation of the drawings]

[0071] [Figure 1]1 is an XRPD pattern of the hydrochloride salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 2] 1 is a DSC pattern of the hydrochloride salt crystalline form A of the compound (4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 3] 1 is an XRPD pattern of the hydrochloride salt crystalline form B of the compound (4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 4] 1 is a DSC pattern of the hydrochloride salt crystalline form B of the compound (4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 5] FIG. 1 is an XRPD pattern of the ethanesulfonate salt crystalline form A of the compound (4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 6] FIG. 1 is an XRPD pattern of the ethanesulfonate salt crystalline form B of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 7] FIG. 1 is an XRPD pattern of the p-toluenesulfonate salt crystalline form A of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 8] FIG. 1 is an XRPD pattern of the methanesulfonate salt crystalline form A of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 9] FIG. 1 is a DSC pattern of the methanesulfonate salt crystalline form A of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 10] 1 is an XRPD pattern of the sulfate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 11] 1 is a DSC pattern of the sulfate salt crystalline form A of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. [Figure 12]FIG. 1 is an XRPD pattern of the benzenesulfonate salt crystalline form A of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 13] FIG. 1 is an XRPD pattern of the isethionate salt crystalline form A of 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 14] FIG. 1 is a DSC pattern of the isethionate salt crystalline form A of 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 15] FIG. 1 is an XRPD pattern of the hydrobromide salt crystalline form A of the compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide. [Figure 16] 1 is an XRPD pattern of the hydrochloride salt crystalline form C of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide. DETAILED DESCRIPTION OF THE INVENTION

[0072] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0073] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 8 carbon atoms, even more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, Examples include 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available linkage site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups, and in the present invention, is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a haloalkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, or an alkyl group substituted with a hydroxy group.

[0074] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0075] The ring of a cycloalkyl group can be fused onto the ring of an aryl group, heteroaryl group, or heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples include indanyl group, tetrahydronaphthyl group, benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group, or carboxylate group.

[0076] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, C(O), or S(O). m(where m is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 3 to 8-membered heterocyclyl groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, and nitrogen-containing fused heterocyclyl groups.

[0077] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, or tetrahydrothiopyran dioxide groups, and preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, or tetrahydropyranyl. Examples of the alkyl group include tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepanyl, 1,4-diazacycloheptyl, and piperazinyl, and more preferably piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azetidinyl, dihydrotetrazolyl, pyrimidin-4(3H)-one, 1,2,4-oxadiazol-5(2H)-one, and 5,6-dihydro-4H-cyclopenta[d]isoxazole. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, where such spirocyclic, fused-ring, and bridged-ring heterocyclyl groups are optionally linked to other groups via a single bond or further tandemly linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0078] Heterocyclyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0079] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as a phenyl group or a naphthyl group. A phenyl group is more preferred.

[0080] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0081] The term "heteroaryl group" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 12-membered, and more preferably 5- or 6-membered, and examples thereof include an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, and a pyrazinyl group. Preferred are a pyridyl group, a pyrazinyl group, an oxadiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyrimidinyl group, and a thiazolyl group. More preferred are a pyridyl group, an oxadiazolyl group, a pyrazolyl group, a pyrazinyl group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, a pyrrolyl group, a thiazolyl group, and an oxazolyl group.

[0082] Heteroaryl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0083] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, or cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0084] "Haloalkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0085] A "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0086] "Hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where alkyl group is as defined above.

[0087] "Hydroxy" refers to an -OH group.

[0088] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0089] An "amino group" refers to -NH2.

[0090] A "cyano group" refers to -CN.

[0091] "DMF" refers to N,N-dimethylformamide.

[0092] "TFA" refers to trifluoroacetic acid.

[0093] "MeCN" refers to acetonitrile.

[0094] "DCM" refers to dichloromethane;

[0095] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be one or more of A, B, and C.

[0096] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0097] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0098] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and a person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0099] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0100] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity.

[0101] X-ray powder diffraction pattern (XRPD) refers to an experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak positions (abscissa) and peak intensities (ordinate). As those skilled in the art will appreciate, experimental error therein is due to instrument conditions, sample preparation, and sample purity. In particular, as those skilled in the art will appreciate, X-ray diffraction patterns typically vary depending on instrument conditions. As those skilled in the art will appreciate, suitable error limits for XRPD may be 2θ±0.5°, 2θ±0.4°, 2θ±0.3°, or 2θ±0.2°. It should be noted that the relative intensities of an X-ray diffraction pattern may also vary depending on experimental conditions, and therefore the order of peak intensities is not the only or decisive factor. Furthermore, experimental factors such as sample height may affect the overall peak angle, and a certain deviation is usually acceptable. Therefore, as those skilled in the art will appreciate, any crystalline form having characteristic peaks that are the same as or similar to those of the patterns of the present invention is within the scope of the present invention.

[0102] "DSC" refers to differential scanning calorimetry (DSC) experiments. [Example]

[0103] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0104] Example The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). The internal standard was tetramethylsilane (TMS).

[0105] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C). 18 A 150 x 4.6 mm chromatography column is used.

[0106] Thin-layer chromatography silica gel plates used were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with 0.15mm to 0.20mm specifications for TLC and 0.4mm to 0.5mm specifications for product separation and purification by thin-layer chromatography. Column chromatography generally used Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0107] The starting materials in the examples of the present invention are either known and commercially available, or can be synthesized using or according to methods known in the art.

[0108] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0109] Intermediate 1 2-Bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka]

[0110] Step 1 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)benzenesulfonamide 4-Chloro-5-methylisoxazol-3-amine (5.0 g, 37.8 mmol) was dissolved in tetrahydrofuran (50 mL) and the reaction mixture was cooled to -78 °C. Potassium tert-butoxide (8.43 g, 75.3 mmol) was then added to the reaction mixture, and the mixture was stirred at -78 °C for 0.5 h. Intermediate 1a (10.0 g, 39.4 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. Water and dichloromethane (3 × 20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, Intermediate 1b (12.5 g, 88.5% yield). MS m / z (ESI): 351.2[M+1] + .

[0111] Step 2 Preparation of 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide Intermediate 1b (12.5 g, 35.7 mmol) and potassium carbonate (9.8 g, 71.4 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(trimethylsilyl)ethoxymethyl chloride (8.9 g, 53.6 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Water and dichloromethane (3 x 20 mL) were added for extraction. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate system) to give the desired product, Intermediate 1 (17.2 g, yield: 98.5%).

[0112] Example 1 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0113] Step 1 Preparation of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((hydroxy-d)-methyl-d2)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-1 (80 mg, 0.17 mmol) (see International Publication No. 2010 / 114801 for the preparation method) and lithium aluminum deuteride (11 mg, 0.26 mmol) were dissolved in tetrahydrofuran (5 mL), the reaction mixture was cooled to 0°C, and the mixture was stirred for 2 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel chromatography column (petroleum ether / ethyl acetate system) to obtain Example 1-2 (50 mg, 70%). MS m / z (ESI): 464.2[M+1] + .

[0114] Step 2 Preparation of (2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl-d2 methanesulfonic acid Methanesulfonyl chloride (14.8 mg, 0.13 mmol) and diisopropylethylamine (41.8 mg, 0.32 mmol) were added to a solution of Example 1-2 (50 mg, 0.11 mmol) in dichloromethane (4 mL) under ice bath conditions, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to give crude Example 1-3 (60 mg, 98%), which was used directly in the next step. MS m / z (ESI): 541.2[M+1] + .

[0115] Step 3 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-3 (60 mg, 0.11 mmol) was dissolved in DMF (4 mL), and potassium carbonate (30.7 mg, 0.24 mmol) and 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one (25.8 mg, 0.13 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the crude product was purified by HPLC to give Example 1-4 (42 mg, 72%). MS m / z (ESI): 639.3[M+1] + .

[0116] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 1-4 (42 mg, 0.07 mmol) was dissolved in ethanol (2 mL), 6N hydrochloric acid was added, heated to reflux for 1 h, adjusted to pH 8 with sodium carbonate, and then adjusted to pH 5 and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase HPLC to give Example 1 (10 mg, 26%). MS m / z (ESI): 595.3[M+1] + .

[0117] Example 2 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0118] Method 1: The synthesis method of Example 2 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-chloro-5-methylisoxazolamine to obtain Example 2 (51 mg), with a yield of 50.3%. Method 2: [ka]

[0119] Step 1 Preparation of (4-bromo-3-(ethoxymethyl)phenyl)-d2methanol Example 2-1 (1.0 g, 3.48 mmol) (see International Publication No. 2010 / 114801 for the preparation method) and lithium aluminum deuteride (219.3 mg, 5.22 mmol) were dissolved in tetrahydrofuran (20 mL), the reaction mixture was cooled to 0°C, and the mixture was stirred for 2 hours. Saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel chromatography column (petroleum ether / ethyl acetate system) to obtain Example 2-2 (850 mg, 98%). MS m / z (ESI): 248.1[M+1] + .

[0120] Step 2 Preparation of 4-bromo-3-(ethoxymethyl)benzyl-d2 methanesulfonate Methanesulfonyl chloride (433.4 mg, 3.78 mmol) and diisopropylethylamine (1.33 g, 10.32 mmol) were added to a solution of Example 2-2 (50 mg, 3.44 mmol) in dichloromethane (20 mL) under ice bath conditions, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to give crude Example 2-3 (1.1 g, 98%), which was used directly in the next step. MS m / z (ESI): 326.2[M+1] + .

[0121] Step 3 Preparation of 3-(4-bromo-3-(ethoxymethyl)phenyl)methyl-d2)-2-butyl-1,3-diazaaspirin[4.4]non-1-en-4-one Example 2-3 (1.1 g, 3.38 mmol) was dissolved in DMF (15 mL), and potassium carbonate (1.03 g, 7.44 mmol) and 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one (858.4 mg, 3.72 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the crude product was purified by HPLC to give Example 2-4 (1.2 g, 86%). MS m / z (ESI): 424.4[M+1] + .

[0122] Step 4 Preparation of 2-butyl-3-((3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl-d2)-1,3-diazaspiro[4.4]non-1-en-4-one Compound 2-4 (1.2 g, 2.86 mmol) was dissolved in 15 mL of 1,4-dioxane, and bis(pinacolato)diboron (0.87 g, 3.4 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (102.9 mg, 0.14 mmol), and potassium acetate (0.84 g, 8.56 mmol) were added. Under nitrogen gas protection, the mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using an eluent system (ethyl acetate / petroleum ether = 10-50%) to give Example 2-5 (1.0 g, 80.0%). MS m / z (ESI): 471.5[M+1] + .

[0123] Step 5 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl-d2)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-n-(2-trimethylsilylethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 2-5 (0.5 g, 1.07 mmol) was dissolved in 20 mL of 1,4-dioxane and water (2 mL), and Intermediate 1 (0.4 g, 1.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.039 g, 0.053 mmol), and potassium carbonate (0.3 g, 3.2 mmol) were added. Under nitrogen gas protection, the mixture was heated to 90 °C and reacted with stirring for 16 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using an eluent system (ethyl acetate / petroleum ether = 10-50%) to give Example 2-6 (0.45 g) in 66.0% yield. MS m / z (ESI): 746.4[M+1] + .

[0124] Step 6 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl-d2)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 2-6 (0.45 g, 0.7 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the mixture was heated to 70 °C and reacted with stirring for 2 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Example 2 (0.2 g, 50.0%) was obtained from the residue using silica gel chromatography and eluent system p-HPLC (FA).

[0125] MS m / z (ESI): 615.2[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.05-7.97(m,1H),7.54(s,2H),7.22-7.12(m,2H),6.99(s,2H),4.08(d,J=13. 1Hz,1H),3.99(d,J=13.1Hz,1H),3.21(ddd,J=9.4,7.0,3.6Hz,2H),2.35(t,J=7 .5Hz,2H),2.25(s,3H),1.85(d,J=8.5Hz,6H),1.69(d,J=8.8Hz,2H),1.50(q,J= 7.7Hz,2H),1.28(d,J=7.6Hz,2H),1.01(t,J=6.9Hz,3H),0.82(t,J=7.3Hz,3H).

[0126] Example 3 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0127] The synthesis method of Example 3 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-fluoro-5-methylisoxazoleamine to obtain Example 3 (11 mg, solid), with a yield of 40.3%.

[0128] MS m / z (ESI): 599.3[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.05-7.97(m,1H),7.54(s,2H),7.22-7.12(m,2H),6.99(s,2H),4.08(d,J=13. 1Hz,1H),3.99(d,J=13.1Hz,1H),3.21(ddd,J=9.4,7.0,3.6Hz,2H),2.35(t,J=7 .5Hz,2H),2.25(s,3H),1.85(d,J=8.5Hz,6H),1.69(d,J=8.8Hz,2H),1.50(q,J= 7.7Hz,2H),1.28(d,J=7.6Hz,2H),1.01(t,J=6.9Hz,3H),0.82(t,J=7.3Hz,3H).

[0129] Example 4 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0130] Step 1 Preparation of methyl 2-bromo-5-(bromomethyl)benzoate N-Bromosuccinimide (854.68 mg, 4.80 mmol) and Example 4-1 (1.0 g, 4.37 mmol) were dissolved in carbon tetrachloride (5 mL). Benzoyl peroxide (105.74 mg, 436.55 μmol) was then added to the reaction mixture. The reaction mixture was then stirred at 80°C for 16 hours, saturated sodium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 4-2 (1.1 g, 3.57 mmol, 81.82% yield).

[0131] Step 2 Preparation of (2-bromo-5-(bromomethyl)phenyl)deuteromethane-ol Lithium aluminum deuteride (104.72 mg, 2.44 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of Example 4-2 (500 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 1 h, and then water (0.1 mL), 15% sodium hydroxide solution (0.1 mL), and water (0.3 mL) were added sequentially to the reaction mixture. After stirring for 0.5 h, the mixture was filtered. The filter cake was washed with dichloromethane (10 mL x 3). The filtrate was dried and concentrated to give the target molecule of Example 4-3 (310 mg, 1.10 mmol, 67.72% yield).

[0132] Step 3 Preparation of 3-(4-bromo-3-(hydroxymethyl-2)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one 2-Butyl-1,3-diazaspiro[4.4]non-1-en-4-one (62.01 mg, 319.18 μmol) and Example 4-3 were dissolved in acetonitrile (2 mL), followed by the addition of potassium carbonate (29.36 mg, 212.79 μmol). The reaction mixture was stirred at 80 ° C for 3 hours. After the reaction was completed, saturated sodium chloride (10 mL) solution was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 4-4 (18 mg, 45.53 μmol, 21.40% yield). MS m / z (ESI): 395.2[M+1] + .

[0133] Step 4 Preparation of 3-(4-bromo-3-(ethoxymethyl-D2)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one Example 4-4 (500 mg, 1.26 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of sodium hydride (151.76 mg, 3.79 mmol, 60% purity). The reaction mixture was stirred at room temperature for 0.5 h, followed by the addition of ethyl iodide (986.30 mg, 6.32 mmol). The reaction mixture was stirred at room temperature for 1.5 h. After the reaction was completed, saturated sodium chloride (10 mL) solution was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the target molecule of Example 4-5 (210 mg, 496.01 μmol, 39.22% yield). MS m / z (ESI): 423.2[M+1] + .

[0134] Step 5 Preparation of 2-butyl-3-(3-(ethoxymethyl-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-11-en-4-one Example 4-5 (100 mg, 236.19 μmol), bis(pinacolato)diboron (71.97 mg, 283.43 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (19.27 mg, 23.62 μmol), and potassium acetate (45.35 mg, 472.39 μmol) were dissolved in dioxane (5 mL), and the reaction mixture was stirred at 90 °C for 16 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated to give the crude target molecule of Example 4-6 (105 mg, 223.19 μmol, 94.50% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 471.2[M+1] + .

[0135] Step 6 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl-d2)-N-(((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Intermediate 1 (93 mg, 235.05 μmol), Example 4-6 (110.58 mg, 235.05 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (21.53 mg, 23.51 μmol), and cesium carbonate (229.88 mg, 705.16 μmol) were dissolved in dioxane and water (2.5 mL, 4:1), and the reaction mixture was stirred at 100 °C for 1 h. Saturated aqueous sodium chloride (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to give the target molecule of Example 4-7 (106 mg, 160.79 μmol, 68.41% yield). MS m / z (ESI): 745.3[M+1] + .

[0136] Step 7 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 4 was carried out in accordance with the synthesis method of Example 2, and the title compound of Example 4 (32 mg, 33.5%) was obtained using Example 4-7 as the starting material.

[0137] MS m / z (ESI): 615.2[M+1] + . 1 H NMR (400MHz,DMSO) δ 8.01(dd,J=16.0,14.4Hz,1H),7.60(t,J=29.2Hz,2H),7.15(d,J=11.1Hz,2 H),7.00(s,2H),4.83-4.66(m,2H),3.28-3.13(m,2H),2.36(t,J=7.5Hz,2H ),2.28(s,3H),1.86(d,J=6.4Hz,6H),1.71(d,J=8.0Hz,2H),1.52(dt,J=15 .2,7.5Hz,2H),1.34-1.25(m,2H),1.01(t,J=7.0Hz,3H),0.88-0.75(m,3H).

[0138] Example 5 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(((methoxy-d3)methyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0139] Step 1 Preparation of methyl 2-bromo-5-(bromomethyl)benzoate Under nitrogen gas protection, bromosuccinimide (8.16 g, 45.84 mmol) was added to a solution of Example 5-1 (10 g, 43.65 mmol) in MeCN (80 mL), and the mixture was stirred overnight at 25° C. for 12 hours. The reaction mixture was concentrated, diluted with 100 mL of ethyl acetate, and washed three times with 50 mL of water. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to obtain Example 5-2 (10 g) in a yield of 74.3%. 1 H NMR (400MHz,Chloroform-d) δ 7.82(d,J=2.3Hz,1H),7.64(d,J=8.3Hz,1H),7.36(dd,J=8.3,2.4Hz,1H),4.44(s,2H),3.94(s,3H).

[0140] Step 2 Preparation of (2-bromo-5-(bromomethyl)phenyl)methanol Under nitrogen gas protection, diisobutylaluminum hydride (1M, 62.11 mL) was added to a DCM solution of Example 5-2 (10 g, 31.06 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding ice water (200 mL) and extracted with dichloromethane (100 mL*3). The organic phases were combined, dried, and concentrated to give Example 5-3 (6.0 g, solid), which was used directly in the next step.

[0141] Step 3 Preparation of 3-(4-bromo-3-(hydroxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one To a solution of Example 5-3 (1.25 g, 4.46 mmol) and 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride (1.03 g, 4.46 mmol) in MeCN (15 mL) was added potassium carbonate (1.23 g, 8.93 mmol), and the mixture was stirred at 80° C. for 12 hours. The reaction was quenched by adding water (10 mL) and extracted with dichloromethane (10 mL*3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give Example 5-4 (1.0 g, solid) in a yield of 56.9%. MS m / z (ESI): 493.0[M+1] + .

[0142] Step 4 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(hydroxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide A reactor was charged with Example 5-4 (400 mg, 1.05 mmol), (2-(N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)boronic acid (380 mg, 1.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (85 mg, 105.1 μmol), KCO (285 mg, 2.10 mmol), 1',4-dioxane (5 mL), and HO (1 mL). The mixture was stirred at 100 °C for 12 hours under nitrogen gas protection. After the reaction mixture was cooled, 8 mL of water was added to quench it, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give Example 5-5 (500 mg, solid) in a yield of 75.3%. MS m / z (ESI): 715.3[M+1] + .

[0143] Step 5 Preparation of 2'-(bromomethyl)-4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Under nitrogen gas protection, carbon tetrabromide (525 mg, 1.58 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added to a solution of Example 5-5 (500 mg, 0.79 mmol) in DCM (10 mL) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with dichloromethane (10 mL*3). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give Example 5-6 (520 mg, solid) in a yield of 95.3%. MS m / z (ESI): 778.2[M+1] + .

[0144] Step 6 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(((trifluoromethoxy)methyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Deuterated methanol (11.6 mg, 0.33 mmol) and silver fluoride (48 mg, 0.33 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was cooled to -30°C and stirred for 2 hours. Then, Example 5-6 (125 mg, 0.16 mmol) dissolved in 5 mL of acetonitrile was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried, concentrated, and purified using a column (petroleum ether / ethyl acetate system) to give Example 5-7 (85 mg, 69.1%). MS m / z (ESI): 783.2[M+1] + .

[0145] Step 7 Preparation of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide The synthesis method of Example 5 was carried out in accordance with the synthesis method of Example 2, and the title compound of Example 5 (26 mg, yield: 56.3%) was obtained using Example 5-7 as the starting material.

[0146] MS m / z (ESI): 602.2[M+1] + . 1 H NMR (400MHz,DMSO) δ 8.09-7.93(m,1H),7.53(s,2H),7.14(d,J=21.2Hz,2H),6.98(dd,J=16.8 ,7.7Hz,2H),4.73(s,2H),4.00(dd,J=31.4,13.0Hz,2H),2.36(t,J=7.5Hz ,2H),2.25(s,3H),1.85(d,J=7.1Hz,6H),1.69(d,J=7.5Hz,2H),1.52(dt ,J=15.2,7.6Hz,2H),1.29(dt,J=22.4,7.5Hz,2H),0.82(t,J=7.3Hz,3H).

[0147] Example 6 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-(ethoxymethyl)-N-(5-methyl-4-(methyl-d3)isoxazol-3-yl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0148] The synthesis method of Example 6 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 5-methyl-4-(deuterated methyl)isoxazol-3-amine to obtain Example 6 (6.8 mg, yield: 14.0%). MS m / z (ESI): 596.3[M+1] + .

[0149] Example 7 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-2-(ethoxymethyl)phenyl)-N-(4-fluoro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide [ka]

[0150] The synthesis method of Example 7 was the same as that of Example 1, except that 4,5-dimethylisoxazolamine was replaced with 4-fluoro-5-methylisoxazolamine to obtain Example 7 (19 mg, yield: 50.3%).

[0151] MS m / z (ESI): 600.3[M+1] 1 H NMR (400MHz,DMSO) δ 8.79(t,J=9.8Hz,1H),8.41(d,J=8.1Hz,1H),7.64(dd,J=8.0,4.8Hz,1H),7.22(s ,1H),7.05(dt,J=42.2,21.0Hz,3H),4.09(s,2H),3.22(dd,J=13.9,7.0Hz,2H),2. 36(t,J=7.5Hz,2H),2.28(s,3H),1.87(s,6H),1.71(s,2H),1.52(dt,J=15.2,7.5H z,2H),1.30(dt,J=14.7,7.4Hz,2H),0.99(t,J=7.0Hz,3H),0.83(t,J=7.3Hz,3H).

[0152] Example 8 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide [ka]

[0153] Method 1: The synthesis method of Example 8 was the same as that of Example 1, except that 4,5-dimethylisoxazoleamine was replaced with 4-chloro-5-methylisoxazoleamine to obtain Example 8 (56.6 mg, white solid), with a yield of 45.8%. Method 2: [ka]

[0154] Step 1 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-n-(2-trimethylsilylethoxy)methyl)-[1,1'-biphenyl]-2-sulfonamide Example 8-1 (0.3 g, 0.64 mmol) (see International Publication No. WO 2010 / 114801 for the preparation method) was dissolved in 10 mL of 1,4-dioxane and water (1 mL), and Intermediate 1 (0.24 g, 0.64 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.023 g, 0.032 mmol), and potassium carbonate (0.18 g, 1.9 mmol) were added. Under nitrogen gas protection, the mixture was heated to 90°C and reacted with stirring for 16 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography with an eluent system (ethyl acetate / petroleum ether=10-50%) to obtain Example 8-2 (0.27 g, solid), with a yield of 66.0%. MS m / z (ESI): 744.4[M+1] + .

[0155] Step 2 Preparation of 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)-n-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide Example 8-2 (0.27 g, 0.7 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Example 8 (0.12 g, 54.5%) was obtained from the residue using silica gel chromatography and eluent system p-HPLC (FA).

[0156] MS m / z (ESI): 612.8[M+1] + . 1H NMR (400MHz,DMSO-d6) δ 7.97-7.95(m,1H),7.37-7.31(m,2H),7.09(s,1H),6.97(d,J=7.6Hz,1H),6.93-6.88(m, 2H),4.70(s,2H),4.08(d,J=13.2Hz,1H),3.93(d,J=13.2Hz,1H),3.24-3.15(m,2H),2.36 (t,J=7.6Hz,2H),2.12(s,3H),1.88-1.81(m,6H),1.72-1.65(m,2H),1.57-1 .49(m,2H),1.33-1.27(m,2H),1.01(t,J=6.8Hz,3H),0.83(t,J=7.2Hz,3H).

[0157] Example 9 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide [ka]

[0158] The synthesis method of Example 9 was similar to that of Example 1, except that 2-butyl-1,3-diazaspiro-[4,4]non-1-en-4-one was replaced with 2'-butylspiro[bicyclo[3.1.0]hexane-3,4'-imidazol]-5'(1'H)-one, and lithium aluminum deuteride was replaced with lithium aluminum hydride to synthesize Example 9 (11 mg, yield 36%).

[0159] MS m / z (ESI): 605.2[M+1] + . 1H NMR (400MHz,DMSO) δ 8.06(dd,J=7.4,1.9Hz,1H),7.66-7.57(m,2H),7.21-7.14(m,2H),7.03-6.92(m ,2H),4.68(s,2H),4.00(s,2H),3.21(d,J=6.8Hz,2H),2.32(d,J=7.5Hz,2H),2. 20(s,4H),1.86(d,J=13.5Hz,2H),1.66(s,3H),1.50(dq,J=9.2,5.5Hz,5H),1.3 3-1.26(m,2H),1.08-0.98(m,4H),0.82(t,J=7.3Hz,3H),0.56(q,J=4.0Hz,1H).

[0160] Biological Test Evaluation The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0161] 1. Cell function experiments Test Example 1. Measurement of the effect of the compounds of the present invention on calcium flux in cells stably expressing the AT1 receptor 1. Purpose of the experiment: Test the antagonistic effect of compounds on HEK293-AT1 cell activity 2. Laboratory equipment and reagents: 2.1 Instruments: 384-well test plate (Corning: 3764), 384-well Echo Compound Plate (Labcyte: LP-0200), 384-well compound plate (PE:6008590), Bravo Tip (Agilent:10734-202), FLIPR Tip (Molecular Device:9000-0764), Plate reader FLIPR Tetra (Molecular Device), Pipetting workstation Bravo (Agilent), ECHO 550 (LABCYTE), Liquid pipette Multidrop Combi (ThermoFisher).

[0162] 2.2 Reagents: DMEM, high glucose (Gibco:12100), Fetal bovine serum (Biosera: FB-1058 / 500), P / S(Biosera:XC-A4122), 5X Matrigel (Corning:354230), HBSS (Sigma: H1387), HEPES (Invitrogen: 15630080), Fluo-8 AM (AAT Bioquest:21080), Probenecid (Sigma: P8761), Pluronic F-127(Sigma:P2443-250G), Angiotensin III TFA (MCE:HY-113035A), Irbesartan (MCE:HY-B0202), 1000X Fluo-8 AM (2 mM): Fluo-8 AM was dissolved in DMSO, shaken for 1-2 minutes, aliquoted, and stored at -20°C. Complete medium: DMEM+10% FBS+1X P / S, Cell inoculation medium: DMEM+10% FBS+1X PS, Experimental buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025% Pluronic F-127, Experimental Buffer 2: 1X HBSS + 20mM HEPES + 0.075% Pluronic F-127, 1X Matrigel: Dilute 5X Matrigel in DMEM Cell line: HDB HEK293-AT1.

[0163] 3. Experimental Method: 1) HEK293-AT1 cells were cultured in complete medium at 37°C and 5% CO2 until they reached 70%-90% conjugation.

[0164] 2) Coat a 384-well cell plate with 1X Matrigel, 5 μL per well, and coat for 10-30 minutes at room temperature.

[0165] 3) The cells were digested, resuspended in cell seeding medium, and seeded into a 384-well cell culture plate at 8,000 cells / well / 20 μL, and cultured at 37°C, 5% CO2 for 24 hours.

[0166] 4) The cell culture plate was removed from the CO2 incubator and equilibrated at room temperature for 10 minutes.

[0167] 5) 1000X Fluo-8 AM was taken and diluted to a concentration of 2 μM 1X Fluo-8 AM with Experimental Buffer 1 equilibrated to room temperature.

[0168] 6) The medium was removed from the cell culture plate, and 20 μL of 1× Fluo-8 AM was added to each well. The plate was centrifuged at 300 rpm for 60 seconds at room temperature, and then incubated at room temperature in the dark for 1 hour.

[0169] 7) Preparation of positive control compound and test compound working solution (3X): (1) Using the Bravo instrument, dilute the compound concentration to 11% on a 384-well Echo compound plate (LABCYTE: LP-0200); (2) Transfer 90 nL of compound (compound stock concentration, e.g., percent highest concentration 10 mM) from each well to a 384-well compound plate (PE:6008590) using an instrument ECHO; (3) Using a Multidrop Combi, 30 μL of experimental buffer 2 was added to a 384-well compound plate (PE:6008590), and the positive control compound and test compound were diluted to 30 μM (3X), and the plate was left at room temperature for use.

[0170] 8) 10 μL of diluted 3X compound was added to the corresponding experimental wells of the 384-well cell plate on the FLIPR Tetra, the compound and cells were incubated at room temperature for 10 minutes, then 10 μL of diluted 4X agonist was added and data was read and collected.

[0171] 4. Experimental data processing method: The fluorescence signal values ​​(RFU) were read and collected using FLIPR Tetra, and the maximum RFU value was taken. Based on the readings of the low control (DMSO control) and high control (100 nM positive compound) experimental groups, the activation percentage data was calculated {% activation rate = (RFU sample - RFU low control) / (RFU high control - RFU low control) × 100}. The concentrations of the test compounds were diluted 3-fold in the reaction system, resulting in 11 concentrations ranging from 10 μM to 0.17 nM. The activation percentage and the 11 concentration data were fitted to a parameter nonlinear logistic equation using XLFit to calculate the IC of the compounds. 50 values ​​were calculated. 5. Experimental Results:

[0172] [Table 11]

[0173] 6. Experimental Conclusion: As can be seen from the data in the table, the compounds of the examples shown in the present invention exhibited good antagonistic activity in the experiment of the effect on calcium flux in cells stably expressing the AT1 receptor.

[0174] Test Example 2. Measurement of the effect of the compounds of the present invention on calcium flux in cells stably expressing ETA receptors 1. Purpose of the experiment: The antagonistic effect of compounds on HEK293-ETA cell activity is tested.

[0175] 2. Laboratory equipment and reagents: 2.1 Instruments: 384-well test plate (Corning: 3764), 384-well Echo Compound Plate (Labcyte: LP-0200), 384-well compound plate (PE:6008590), Bravo Tip (Agilent:10734-202), FLIPR Tip(Molecular Device:9000-0764) Plate reader FLIPR Tetra (Molecular Device), Pipetting workstation Bravo (Agilent) and ECHO 550 (LABCYTE), Liquid pipette Multidrop Combi (ThermoFisher).

[0176] 2.2 Reagents: DMEM, high glucose (Gibco:12100), Fetal bovine serum (Biosera: FB-1058 / 500), P / S(Biosera:XC-A4122), 5X Matrigel (Corning:354230), HBSS (Sigma: H1387), HEPES (Invitrogen: 15630080), Fluo-8 AM (AAT Bioquest:21080), Probenecid (Sigma: P8761), Pluronic F-127(Sigma:P2443-250G), Endothelin 1 (MCE:HY-P0202), Zibotentan (MCE: HY-10088), 1000X Fluo-8 AM (2 mM): Dissolve Fluo-8 AM in DMSO, shake for 1-2 minutes, dispense, and store at -20°C. Complete medium: DMEM+10% FBS+1X P / S, Cell inoculation medium: DMEM+10% FBS+1X PS, Experimental buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025% Pluronic F-127, Experimental Buffer 2: 1X HBSS + 20mM HEPES + 0.075% Pluronic F-127, 1X Matrigel: Dilute 5X Matrigel in DMEM Cell line: HDB HEK293- ETA.

[0177] 3. Experimental Method: 1) HEK293-ETA cells were cultured in complete medium at 37°C and 5% CO2 until they reached 70%-90% confluence.

[0178] 2) Coat a 384-well cell plate with 1X Matrigel, 5 μL per well, and coat for 10-30 minutes at room temperature.

[0179] 3) The cells were digested, resuspended in cell seeding medium, and seeded into a 384-well cell culture plate at 8,000 cells / well / 20 μL, and cultured at 37°C, 5% CO2 for 24 hours.

[0180] 4) The cell culture plate was removed from the CO2 incubator and equilibrated at room temperature for 10 minutes.

[0181] 5) 1000X Fluo-8 AM was taken and diluted to a concentration of 2 μM 1X Fluo-8 AM with Experimental Buffer 1 equilibrated to room temperature.

[0182] 6) The medium was removed from the cell culture plate, and 20 μL of 1× Fluo-8 AM was added to each well. The plate was centrifuged at 300 rpm for 60 seconds at room temperature, and then incubated at room temperature in the dark for 1 hour.

[0183] 7) Preparation of positive control compound and test compound working solution (3X): (1) Using the Bravo instrument, dilute the compound concentration to 11% on a 384-well Echo compound plate (LABCYTE: LP-0200); (2) Transfer 90 nL of compound (compound stock concentration, e.g., percent highest concentration 10 mM) from each well to a 384-well compound plate (PE:6008590) using an instrument ECHO; (3) Using a Multidrop Combi, 30 μL of experimental buffer 2 was added to a 384-well compound plate (PE:6008590), and the positive control compound and test compound were diluted to 30 μM (3X), and the plate was left at room temperature for use.

[0184] 8) 10 μL of diluted 3X compound was added to the corresponding experimental wells of the 384-well cell plate on the FLIPR Tetra, the compound and cells were incubated at room temperature for 10 minutes, then 10 μL of diluted 4X agonist was added and data was read and collected.

[0185] 4. Experimental data processing method: The fluorescence signal values ​​(RFU) were read and collected using FLIPR Tetra, and the maximum RFU value was taken. Based on the readings of the low control (DMSO control) and high control (100 nM positive compound) experimental groups, the activation percentage data was calculated {% activation rate = (RFU sample - RFU low control) / (RFU high control - RFU low control) × 100}. The concentrations of the test compounds were diluted 3-fold in the reaction system, resulting in 11 concentrations ranging from 10 μM to 0.17 nM. The activation percentage and the 11 concentration data were fitted to a parameter nonlinear logistic equation using XLFit to calculate the IC of the compounds. 50 values ​​were calculated. 5. Experimental Results:

[0186] [Table 12]

[0187] 6. Experimental Conclusion: As can be seen from the data in the table, the compounds of the examples shown in the present invention exhibited good antagonistic activity in the experiment of their effect on calcium flux in cells stably expressing ETA receptors.

[0188] 2. Pharmacokinetic evaluation test in rats 1. Research purpose: Using SD rats as test animals, the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma) when orally administered at a dose of 5 mg / kg was examined.

[0189] 2. Experimental plan: 2.1 Experimental Chemicals: Compounds of the present invention examples, self-prepared.

[0190] 2.2 Experimental animals: SD rats, 3 male rats per group, Shanghai Jie Sijie Laboratory Animal Co., Ltd., Animal Production Permit Number (SCXK(Shanghai)2013-0006 N0.311620400001794).

[0191] 2.3 Pharmaceutical Formulation: 0.5% CMC-Na (1% Tween 80) was dissolved by ultrasonication and prepared as a clear solution or a uniform suspension.

[0192] 2.4 Administration: After overnight fasting, rats were administered po The po dose was 5 mg / kg and the administration volume was 10 mL / kg.

[0193] 2.5 Sample Collection: After oral administration to rats, 0.2 mL of blood was collected from the jugular vein at 0.25 h, 0.5 h, 1.0 h, 2.0 h, and 4.0 h, placed in an EDTA-2K test tube, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, stored at -80°C, and fed 4 h after administration.

[0194] 2.6 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile to precipitate, mixed, and then centrifuged at 3500 × g for 5 to 20 minutes.

[0195] 2) The treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS, and the LC / MS / MS analysis instrument was AB Sciex API 4000 Qtrap.

[0196] 2.7 Liquid phase analysis: ● Liquid phase conditions: Shimadzu LC-20AD pump ● Chromatography column: Agilent ZORBAX XDB-C18 (50 × 2.1 mm, 3.5 μm) Mobile phase: Solution A was 0.1% formic acid in water, and solution B was acetonitrile. ● Flow rate: 0.4mL / min The elution time was 0 to 4.0 minutes, and the eluent was as follows:

[0197] [Table 13]

[0198] 3. Test Results and Analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the rat drug experiment results are shown in Table 13 below:

[0199] [Table 14]

[0200] 3.4 Experimental conclusions: The data in the table show that in pharmacokinetic evaluation experiments in rats, the compounds of the examples of the present invention showed high exposure after oral administration.

[0201] 3. In vitro ADMET evaluation test Test Example 1: Metabolic stability test in liver microsomes 1. Purpose of the experiment: The purpose of this experiment is to determine the stability of the compounds of the examples in rat, dog and human liver microsomes.

[0202] 2. Experimental steps: 2.1 Preparation of compound working solution Preparation of compound working solution: Add phosphate buffer to compound stock solution to a final concentration of 20 μM.

[0203] 2.2 Preparation of liver microsomal working solution The solution was diluted with 100 mM phosphate buffer to a final concentration of 0.625 mg / mL.

[0204] 2.3 Preparation of NADPH and UDPGA NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronic acid) were weighed out and added to 100 mM phosphate buffer, with the final concentrations of both being 20 mM.

[0205] 2.4 Preparation of the drilling agent 1 mg of Alamethicin was weighed out and added to 200 μL of DMSO to prepare a 5 mg / mL solution, which was then diluted with phosphate buffer to a final concentration of 50 μg / mL.

[0206] 2.5 Preparation of reaction stop solution Stop solution: cold acetonitrile containing 100 ng / mL labetalol hydrochloride and 400 ng / mL tolbutamide as internal standards.

[0207] 2.6 Incubation process 400 μL of the prepared liver microsomes, 25 μL of the compound working solution, and 25 μL of Alamethicin were added sequentially to a 96-well plate and pre-incubated at 37°C for 10 minutes. Then, 50 μL of the prepared NADPH / UDPGA was added to initiate the reaction, and the mixture was incubated at 37°C. The total volume of the reaction system was 500 μL, and the final contents of each component were as follows:

[0208] [Table 15]

[0209] 2.7 Sample analysis 2.7.1 Chromatography conditions: Instrument: Shimadzu LC-30 AD, Chromatography column: XBridge™ C18 (50*4.6 mm, 5 μm particle size), Mobile phase: A: 0.1% formic acid solution, B: methanol Flash gradient: 0.2-1.6 min 5%A-95%A, 3.0-3.1 min 95%A-5%A Run time: 4.0 min.

[0210] 2.7.2 Mass spectrometry conditions: Instrument: API5500 liquid chromatography mass spectrometer, AB Sciex, Ion source: electrospray ionization (ESI), Drying gas: N2, temperature 500℃, Electrospray voltage: 5000V, Detection method: cation detection, Scanning method: Multiple Reaction Monitoring (MRM) method. 3. Experimental Results:

[0211] [Table 16]

[0212] 4. Experimental Conclusion: The above data indicate that the compounds of the examples of the present invention have good metabolic stability in liver microsomes of rats, dogs and humans.

[0213] Test Example 3: Single-point CYP enzyme inhibition test 1. Purpose of the experiment Using a human liver microsome incubation system, the inhibition of compounds against CYP450 enzyme subtypes (1A2, 2C19, 2D6, 3A4-M, 3A4-T) was rapidly predicted using a single-point method.

[0214] 2. Experimental steps 2.1 Solution formulation For 2.5 mM NADPH, 4.165 mg of reduced nicotinamide adenine dinucleotide phosphate (NADPH) was weighed and added with 100 mM phosphate buffer up to 2 mL. For 0.25 mg / mL microsomes, 4 mL of 100 mM phosphate buffer was added to 50 μL of 20 mg / mL microsomes and mixed uniformly.

[0215] Preparation of test compound reaction mixture: The compounds of the examples to be tested were weighed and diluted to 10 mM in DMSO, then diluted to 100 μM in 100 mM phosphate buffer.

[0216] 2.2 Experimental procedure: 1. 40 μL of liver microsomes, 10 μL of substrate, and 10 μL of test compound were added to a 96-well plate and pre-incubated for 3 minutes.

[0217] 2. 40 μL of NADPH was added.

[0218] 3. At 20 min, 300 μL of acetonitrile stop solution containing the internal standard was added.

[0219] 4. Centrifuge and add sample. 3. Experimental Results:

[0220] [Table 17] Note: Strong inhibition: IC 50 <1 μM, moderate inhibition: 1 μM <IC 50 <10 μM, weak inhibition: IC 50 >10 μM

[0221] 4. Experimental Conclusion: The above data indicate that the compounds of the examples of the present invention do not exhibit strong inhibition against each CYP enzyme subtype, but rather only weak inhibition, and therefore have a low risk of DDI.

[0222] 4. Evaluation of the efficacy of compounds on blood pressure in spontaneously hypertensive rat models 1. Purpose of the experiment: In this experiment, the pharmacological effects of the test compounds on blood pressure and heart rate were evaluated using spontaneously hypertensive rat (SHR) models.

[0223] 2. Main instruments and materials used in the experiment Kent Scientific CODA Non-Invasive Blood Pressure System.

[0224] 3. Experimental animals: Spontaneously hypertensive rats (SHRs), male, 150-200 g, 13-15 weeks old, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., 50 rats.

[0225] 4. Experimental Method: 4.1 Acclimatization Period: After the animals arrived at the experimental facility, they were allowed to acclimate to the animal facility for 5-7 days. 4.2 After the acclimation period, the animals were tail-cuffed for 3 days, twice daily. After the final tail-cuff acclimation, basal blood pressure was measured and the animals were randomly grouped according to their basal blood pressure. There was no significant difference between the mean systolic blood pressures of the animals in each group, and the number of animals in each group met the requirements of statistical testing and pharmacodynamic guidelines. 4.3 The day after grouping, the animals were administered 5 mL / kg PO according to the experimental design and grouping. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were measured by the tail-cuff method before administration and at 1, 2, 4, 6, 8, and 24 hours after administration.

[0226] 5. Data Processing and Analysis Statistical analysis of differences between groups was performed by two-way ANOVA test, where P<0.05 indicated a significant difference and P<0.01 indicated an extremely significant difference.

[0227] 6. Experimental Results The results showed that in a spontaneous hypertension model, compared to the vehicle, the groups administered with compounds 44, 45, 49, and 30mpk of the present invention in the examples showed a significant decrease in blood pressure (systolic blood pressure, diastolic blood pressure, mean arterial pressure) 1 to 8 hours after administration (P<0.05), and no significant effect on heart rate was observed in the administered groups, demonstrating good safety.

[0228] Research into salts of compounds and their crystalline forms As is well known to those skilled in the art, the compounds in the above examples have been proven to have good antagonistic effects on cells stably expressing ETA receptors, and their pharmaceutically acceptable salts often have similar pharmacological activity.In addition, the inventors have further studied the physicochemical properties of the salt forms and crystalline forms of the corresponding compounds.The preparation and characterization of the specific salt forms or crystalline forms below do not imply any limitation on the scope of protection of the present invention.Those skilled in the art can obtain more salt forms and crystalline forms of the compounds of the present invention based on the present invention through conventional salt formation or crystallization means, and all of these salt forms and crystalline forms are included in the scope of protection of the present invention.Specifically, as follows:

[0229] 1. Experimental Instruments 1.1 Some parameters of physicochemical detection instruments

[0230] [Table 18]

[0231] 1.2 Instruments and liquid phase analysis conditions 1.2.1 Instruments and Equipment

[0232] [Table 19] 1.2.2 Chromatography conditions

[0233] [Table 20]

[0234] 2. Study of compound salt forms 2.1 Screening of Salt Forms of the Compound of Example 2 2.1.1 Experimental Objective: Salt forms of the compounds were screened.

[0235] 2.1.2 Experimental steps: 1) Operation procedure (1) Salt screening by evaporation drying method 0.1748 g of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base was weighed out and added to 3500 μL of ethanol, dissolved by ultrasound, and filtered to obtain a stock solution. 200 μL of the stock solution was taken and mixed with the counterion acid solution in a molar ratio of 1:1.2. The mixture was mixed uniformly and the reaction was observed and recorded. The mixture was then slowly evaporated to dryness to obtain a solid.

[0236] [Table 21]

[0237] (2) Salt formation by solvent beating 0.1748 g of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base was weighed out and added to 3500 μL of ethanol. The mixture was dissolved using ultrasound and filtered to prepare a stock solution. 200 μL of the stock solution was taken and mixed with the counterion acid solution in a molar ratio of 1:1.2. The mixture was mixed uniformly and the reaction was observed and recorded. The mixture was then slowly evaporated to dryness, and the anti-solvent ethyl acetate and MTBE were added and the mixture was stirred at room temperature.

[0238] [Table 22]

[0239] 2.1.3 Experimental Results: According to the salt screening experiment, the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base could form salts with hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, isethionic acid, phosphoric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, ethanesulfonic acid or fumaric acid.

[0240] As described above, those skilled in the art can obtain many more pharmaceutically acceptable salts in accordance with the present invention by conventional methods.

[0241] 3. Research into the crystalline forms of compounds and their salts 3.1 Study of the crystalline form of compounds 3.1.1 Experimental Objective: The crystalline form of the compound of Example 2 is screened.

[0242] 3.1.2 Experimental steps: 1) Operation procedure (1) Preparation of salt crystals by evaporation drying method 0.1748 g of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base was weighed out, added to 3500 μL of ethanol, dissolved by ultrasound, and filtered to obtain a stock solution. 200 μL of the stock solution was taken and added to the counterion acid solution in a molar ratio of 1:1.2. The mixture was mixed uniformly and the reaction was observed and recorded. The mixture was then slowly evaporated to dryness to obtain a solid, which was then vacuum dried and characterized by XRD and DSC.

[0243] [Table 23]

[0244] (2) Formation of salt crystals by solvent beating 0.1748 g of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base was weighed out, added to 3500 μL of ethanol, dissolved by ultrasound, and filtered to prepare a stock solution. 200 μL of the stock solution was taken and the counterion acid solution was added in a molar ratio of 1:1.2. The mixture was mixed uniformly and the reaction mixture was observed and recorded. The mixture was then slowly evaporated to dryness. The anti-solvent ethyl acetate and MTBE were added and the mixture was stirred at room temperature. After the solid precipitated, it was dried under vacuum and subjected to XRD and DSC characterization.

[0245] [Table 24]

[0246] 3.1.3 Experimental results According to the research experiments on the crystalline form of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide salt, the hydrobromide, sulfate, p-toluenesulfonate, methanesulfonate, ethanesulfonate and benzenesulfonate of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide can form crystalline forms.

[0247] 3.2 Preparation of Crystalline Forms of Compounds 3.2.1 Experimental Objective: Crystalline forms of the compounds and their salts are prepared.

[0248] 3.2.2 Experimental steps: 1) Operation procedure I. Preparation of Hydrochloride Crystalline Form A 20.48 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B was weighed, and 0.2 mL of ethanol was added and dissolved at 40°C. 600 μL of anti-solvent n-heptane was added to precipitate the solid, and the solution was stirred at room temperature for 1 hour. The mixture was placed in a metal bath, magnetically stirred, and maintained at room temperature overnight. The mixture was then rapidly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40°C to a constant weight to obtain compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form A.

[0249] Upon detection analysis, it had an XRPD pattern substantially as shown in FIG. 1 and a DSC pattern substantially as shown in FIG.

[0250] II. Preparation of Hydrochloride Crystalline Form B Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of dichloromethane, dissolve, filter, add hydrochloric acid solution in a molar ratio of 1:1.2, and slowly evaporate to dryness at room temperature. 0.4 mL of ethanol was added to precipitate the solid, which was then centrifuged, the supernatant removed, and the solid dried under vacuum at 40°C until it reached a constant weight, yielding compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B.

[0251] Upon detection analysis, it had an XRPD pattern substantially as shown in FIG. 3 and a DSC pattern substantially as shown in FIG.

[0252] III. Preparation of ethanesulfonate crystalline form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasound, filter, add ethanesulfonic acid solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide ethanesulfonate crystalline form A.

[0253] Upon detection analysis, it had an XRPD pattern substantially as shown in FIG.

[0254] IV. Preparation of ethanesulfonate crystalline form B Weigh 20 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 100 μL of ethyl acetate, stir at room temperature, add ethanesulfonic acid solution in a molar ratio of 1:1.2, and if no solid precipitates, add isopropyl ether. After that, an oily substance gradually adhered to the wall and transformed into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40°C until it reached a constant weight to obtain compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide ethanesulfonate crystalline form B.

[0255] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG.

[0256] V. Preparation of p-toluenesulfonic acid salt crystalline form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasonication, filter, add p-toluenesulfonic acid solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide p-toluenesulfonate crystalline form A.

[0257] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG.

[0258] VI. Preparation of methanesulfonate crystalline form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasound, filter, add methanesulfonic acid solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide methanesulfonate crystalline form A.

[0259] Upon detection analysis, it had an XRPD pattern substantially as shown in FIG. 8 and a DSC pattern substantially as shown in FIG.

[0260] VII. Preparation of sulfate crystalline form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasonication, filter, add sulfuric acid aqueous solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide sulfate crystalline form A.

[0261] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG. 10 and a DSC pattern substantially as shown in FIG.

[0262] VIII. Preparation of benzenesulfonate crystalline form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasound, filter, add benzenesulfonic acid solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide benzenesulfonate crystalline form A.

[0263] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG.

[0264] IX. Preparation of Isethionate Crystalline Form A Weigh 20 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 100 μL of ethyl acetate, stir at room temperature, add isethionic acid solution in a molar ratio of 1:1.2, and if no solid precipitates, add isopropyl ether. After that, an oily substance gradually adhered to the wall and transformed into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40°C until it reached a constant weight to obtain compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide isethionate crystalline form A.

[0265] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG. 13 and a DSC pattern substantially as shown in FIG.

[0266] X. Preparation of Hydrobromide Crystal Form A Weigh out 11 mg of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base, add 0.2 mL of ethanol, dissolve by ultrasonication, filter, add hydrobromic acid solution in a molar ratio of 1:1.2, and slowly evaporate and dry at room temperature to obtain a glassy solid. The resulting mixture was added with 100 μL of ethyl acetate and continued beating to convert it into a solid. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40° C. until it reached a constant weight, thereby obtaining compound 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide hydrobromide crystalline form A.

[0267] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG.

[0268] XI. Preparation of Hydrochloride Crystalline Form C 1 g of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide free base was weighed, ethanol (2 mL) was added, and n-heptane (4 mL) was added. The mixture was stirred at room temperature for 2 hours, filtered, and the solid was rinsed with n-heptane to obtain 600 mg of a white solid, i.e., the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form C.

[0269] Detection analysis showed that it had an XRPD pattern substantially as shown in FIG.

[0270] 4. Solid-state stability experiments 4.1 Solid-state stability experiments of different salt crystalline forms of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0271] 4.1.1 Experimental Objective: The physicochemical stability of the crystalline forms of the compounds under high temperature, high humidity, high temperature, high humidity and light irradiation conditions was examined, providing a basis for screening and storing the crystalline forms. 4.1.2 Instruments and liquid phase analysis conditions

[0272] [Table 25]

[0273] 4.1.3 Experimental plan 4.1.3.1 Appropriate amounts of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B, methanesulfonate crystalline form A, sulfate crystalline form A, and hydrobromide crystalline form A were weighed and treated under conditions of light irradiation (5000±500 lux), high humidity (25°C, 92.5%), high temperature (60°C), and 50°C±2°C / RH75%±5% for a certain period of time, and then their XRPD, purity, and impurity content data were measured. 4.1.4.1 Experimental Results:

[0274] [Table 26]

[0275] The largest single impurity in the hydrochloride salt crystalline form B, the methanesulfonate salt crystalline form A, and the sulfate salt crystalline form A showed an increase on day 20 compared to day 0, and the largest single impurity in the hydrobromide salt crystalline form A showed an increase on day 10 compared to day 0. The results showed that the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride salt crystalline form B, the methanesulfonate salt crystalline form A, the sulfate salt crystalline form A, and the hydrobromide salt crystalline form A were relatively stable.

[0276] 5. Hygroscopicity experiment 5.1 Experimental Objectives The hygroscopicity of the hydrochloride crystalline form B of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide under different relative humidity conditions was investigated to provide a basis for screening and storing the compound's crystalline form.

[0277] 5.2 Experimental plan: The compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B was placed in saturated water vapor at different relative humidities to dynamically equilibrate the compound with the water vapor, and the percentage of weight increase due to moisture absorption of the compound after equilibration was calculated.

[0278] [Table 27]

[0279] 5.3 Experimental results: 5.3.1 Hygroscopicity of Compound Hydrochloride Crystalline Form B. The compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride crystalline form B showed a slight hygroscopicity, increasing its weight by 0.378% upon moisture absorption under 80% RH. Furthermore, after two cycles of moisture absorption and desorption under 0-95% RH conditions, the XRPD pattern of the hydrochloride crystalline form B remained unchanged, i.e., the crystalline form did not change.

Claims

1. An acid salt of a compound represented by general formula (I), 【Chemistry 1】 L １ is -CH ２ or -CD ２ - and X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and R １ , R ２ and R ３ are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ aryl groups or 5-10 membered heteroaryl groups containing 1-3 N, O or S atoms, １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ The aryl group or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ further substituted with one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; R １ is hydrogen, C １－３ Alkyl group or -(CH ２ ) ｎ１ O (CH ２ ) ｎ２ R Ａ２ and C is selected from １－３ The alkyl group may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ haloalkoxy group or C ３－６ further substituted with one or more substituents of a cycloalkyl group; R Ａ２ is C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C ３－６ Cycloalkyl group, 4- to 7-membered heterocyclyl group, C ３－６ Cycloalkyl C １－３ Alkyl group or 4- to 7-membered heterocyclyl C １－３ alkyl groups, R ２ , R ３ are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ aryl groups or 5-10 membered heteroaryl groups containing 1-3 N, O or S atoms, １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ The aryl group or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ cycloalkyl groups, 3-8 membered heterocyclyl groups containing 1-3 N, O or S atoms, C ６－１０ further substituted with one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; Or, R ２ , R ３ is bonded to the connecting atom and C ３－８ forming a cycloalkyl group or a 3- to 8-membered heterocyclyl group, R ７ or R ８ are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Haloalkoxy group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; n1 and n2 each independently represent 0, 1, 2, or 3; L １ Ga-CH ２ - and R ２ and R ３ are simultaneously hydrogen, R ７ and R ８ At the same time, -CH ３ Instead, L １ Ga-CH ２ - and R ２ and R ３ are simultaneously hydrogen, R １ is not hydrogen, Acids for acid salts include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, and caprylic acid. Acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, gluta carboxylic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid, and preferably methanesulfonic acid, benzenesulfonic acid, isethionic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, phosphoric acid or hydrobromic acid.

2. R １ , R ２ and R ３ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, methyl, ethyl, or propyl; R １ is hydrogen, -CH ３ , -CH ２ CH ３ , 【Chemistry 2】 is selected from R ２ or R ３ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, or a propyl group; Or, R ２ , R ３ is bonded to the linking atom to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; R ７ is selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, deuterated methyl, dideuteromethyl or trideuteromethyl; R ８ 2. The acid salt of a compound of formula (I) according to claim 1, characterized in that is selected from the group consisting of a methyl group, an ethyl group and a propyl group.

3. The compound is 【Transformation 3】 2. The acid salt of the compound of formula (I) according to claim 1, which is selected from:

4. The compound is 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxydeuteromethyl)-[1,1'-biphenyl]-2-sulfonamide, 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide, 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazole]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide; 2. The acid salt of the compound of formula (I) according to claim 1, wherein the acid in the acid salt is selected from methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, and hydrobromic acid.

5. the number of acids is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1; The acid salt of the compound of formula (I) according to claim 1, characterized in that the acid salt is preferably a hydrate or anhydrous, and when the acid salt is a hydrate, the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

6. the acid salt is in crystalline form; Preferably, the acid salt crystalline form of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, an acid salt crystalline form of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide; an acid salt crystalline form of 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-fluoro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide; an acid salt crystalline form of 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-N-(4-chloro-5-methyl-isoxazol-3-yl)benzenesulfonamide; an acid salt crystalline form of 4'-((2'-butyl-5'-oxyspiro[bicyclo[3.1.0]hexane-3,4'-imidazole]-1'(5'H)-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide, The acid salt of the compound of formula (I) according to claim 1, characterized in that it is more preferably in the form of a methanesulfonate crystal, an ethanesulfonate crystal, a hydrochloride crystal, a sulfate crystal, a p-toluenesulfonate crystal, a benzenesulfonate crystal, an isethionate crystal, or a hydrobromide crystal.

7. The acid salt crystalline form of the compound 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-d2)-N-(4-chloro-5-methylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide is as follows: Hydrochloride crystalline form A, having a powder X-ray diffraction pattern having a diffraction peak at 2θ of 9.2±0.2°, or a diffraction peak at 9.0±0.2°, or a diffraction peak at 8.2±0.2°, or a diffraction peak at 10.8±0.2°, or a diffraction peak at 16.8±0.2°, or a diffraction peak at 18.8±0.2°, or a diffraction peak at 20.2±0.2°, or a diffraction peak at 20.6±0.2°. has a diffraction peak at a certain position, or has a diffraction peak at a position of 20.9±0.2°, or has a diffraction peak at a position of 23.2±0.2°, or has a diffraction peak at a position of 25.3±0.2°, or has a diffraction peak at a position of 24.0±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form A comprises at least one or more diffraction peaks at 2θ of 9.2±0.2°, 9.0±0.2°, and 8.2±0.2°, preferably two of these, more preferably three of these, and optionally further comprises at least one peak at 2θ of 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, and 23.2±0.2°, preferably two, three, four, or five of these, for example ９．２±０．２°、９．０±０．２°、 ９．２±０．２°、８．２±０．２°、 ９．０±０．２°、８．２±０．２°、 ９．２±０．２°、９．０±０．２°、８．２±０．２°、 ９．２±０．２°、８．２±０．２°、１０．８±０．２°、 ９．０±０．２°、８．２±０．２°、１０．８±０．２°、 ９．２±０．２°、９．０±０．２°、８．２±０．２°、１０．８±０．２°、 ９．２±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、 ９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、 ９．２±０．２°、９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、 ９．２±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、 ９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、 ９．２±０．２°、９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、 ９．２±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、 ９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、 ９．２±０．２°、９．０±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、 ９．２±０．２°、８．２±０．２°、１０．８±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、２０．９±０．２°、 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form A comprises diffraction peaks at one or more of the following positions where 2θ is 9.2±0.2°, 9.0±0.2°, 8.2±0.2°, 10.8±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 24.0±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: ９．２±０．２°、９．０±０．２°、１６．８±０．２°、１８．８±０．２°、 ９．２±０．２°、８．２±０．２°、１６．８±０．２°、１８．８±０．２°、 ９．２±０．２°、９．０±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、 ９．２±０．２°、８．２±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、 ９．２±０．２°、９．０±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、２０．９±０．２°、２３．２±０．２°、 ９．２±０．２°、８．２±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、２０．９±０．２°、２３．２±０．２°、 ９．２±０．２°、９．０±０．２°、１６．８±０．２°、１８．８±０．２°、２０．２±０．２°、２０．６±０．２°、２０．９±０．２°、２３．２±０．２°、２５．３±０．２°、２４．０±０．２°、 9.2±0.2°, 8.2±0.2°, 16.8±0.2°, 18.8±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 23.2±0.2°, 25.3±0.2°, 24.0±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form A is substantially as shown in Figure 1; More preferably, the hydrochloride salt crystalline form A has a DSC pattern as shown in FIG. 2 , Hydrochloride crystalline form B, whose powder X-ray diffraction pattern has a diffraction peak at 2θ of 10.4±0.2°, or a diffraction peak at 7.3±0.2°, or a diffraction peak at 14.1±0.2°, or a diffraction peak at 14.6±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 19.3±0.2°, or a diffraction peak at 21.9±0.2°, or a diffraction peak at 24.8±0.2°. or has a diffraction peak at a position of 11.0±0.2°, or has a diffraction peak at a position of 13.1±0.2°, or has a diffraction peak at a position of 20.3±0.2°, or has a diffraction peak at a position of 22.1±0.2°, or has a diffraction peak at a position of 24.1±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form B contains at least diffraction peaks located at one or more of the positions where 2θ is 10.4±0.2°, 7.3±0.2°, and 14.1±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak located at the position where 2θ is 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, and 13.1±0.2°, preferably two, three, four, or five of these, for example １０．４±０．２°、７．３±０．２°、 １０．４±０．２°、１４．１±０．２°、 ７．３±０．２°、１４．１±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２４．８±０．２°、１１．０±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、１１．０±０．２°、１３．１±０．２°、 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, 13.1±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form B comprises diffraction peaks located at one or more of the following positions in 2θ: 10.4±0.2°, 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 24.8±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, 24.1±0.2°, and preferably at any of 4, 5, 6, 8, or 10 positions therein, for example: １０．４±０．２°、７．３±０．２°、１７．０±０．２°、１９．３±０．２°、 １０．４±０．２°、１４．１±０．２°、１７．０±０．２°、１９．３±０．２°、 １０．４±０．２°、７．３±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、 １０．４±０．２°、１４．１±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、 １０．４±０．２°、７．３±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、 １０．４±０．２°、１４．１±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、 １０．４±０．２°、７．３±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、２２．１±０．２°、 １０．４±０．２°、１４．１±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、２２．１±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、 ７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、 １０．４±０．２°、７．３±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２４．８±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、 １０．４±０．２°、１４．１±０．２°、１４．６±０．２°、１７．０±０．２°、１９．３±０．２°、２１．９±０．２°、１１．０±０．２°、１３．１±０．２°、２０．３±０．２°、２２．１±０．２°、 7.3±0.2°, 14.1±0.2°, 14.6±0.2°, 17.0±0.2°, 19.3±0.2°, 21.9±0.2°, 11.0±0.2°, 13.1±0.2°, 20.3±0.2°, 22.1±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form B is substantially as shown in Figure 3; More preferably, the hydrochloride salt crystalline form B has a DSC pattern as shown in Figure 4, Hydrochloride crystalline form C, having an X-ray powder diffraction pattern having a diffraction peak at 8.6±0.2° 2θ, or a diffraction peak at 7.9±0.2°, or a diffraction peak at 14.7±0.2°, or a diffraction peak at 14.9±0.2°, or a diffraction peak at 6.3±0.2°, or a diffraction peak at 17.4±0.2°, or a diffraction peak at 10.3±0.2°, or a diffraction peak at 12.4±0.2°. has a diffraction peak at a certain position, or has a diffraction peak at a position of 23.8±0.2°, or has a diffraction peak at a position of 24.8±0.2°, or has a diffraction peak at a position of 16.0±0.2°, or has a diffraction peak at a position of 18.2±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form C contains at least one or more diffraction peaks at 8.6±0.2°, 7.9±0.2°, and 14.7±0.2° 2θ, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, and 24.8±0.2° 2θ, preferably two, three, four, or five of these, for example ８．６±０．２°、７．９±０．２°、 ８．６±０．２°、１４．７±０．２°、 ７．９±０．２°、１４．７±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、 ８．６±０．２°、１４．７±０．２°、１４．９±０．２°、 ７．９±０．２°、１４．７±０．２°、１４．９±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、１４．９±０．２°、 ８．６±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、 ７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、 ８．６±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、 ７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、 ８．６±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、 ７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、 ８．６±０．２°、１４．７±０．２°、１４．９±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、２３．８±０．２°、 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form C comprises diffraction peaks at one or more of the following positions in 2θ: 8.6±0.2°, 7.9±0.2°, 14.7±0.2°, 14.9±0.2°, 6.3±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 18.2±0.2°, and preferably at any of 4, 5, 6, 8, or 10 positions therein, for example: ８．６±０．２°、７．９±０．２°、１４．７±０．２°、６．３±０．２°、 ８．６±０．２°、７．９±０．２°、１７．４±０．２°、１０．３±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、 ８．６±０．２°、７．９±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、２３．８±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、２３．８±０．２°、 ８．６±０．２°、７．９±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、２３．８±０．２°、２４．８±０．２°、１６．０±０．２°、 ８．６±０．２°、７．９±０．２°、１４．７±０．２°、６．３±０．２°、１７．４±０．２°、１０．３±０．２°、１２．４±０．２°、２３．８±０．２°、２４．８±０．２°、１６．０±０．２°、 8.6±0.2°, 7.9±0.2°, 17.4±0.2°, 10.3±0.2°, 12.4±0.2°, 23.8±0.2°, 24.8±0.2°, 16.0±0.2°, 18.2±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrochloride salt crystalline form C is substantially as shown in Figure 16; Ethanesulfonate crystalline form A, having a powder X-ray diffraction pattern having a diffraction peak at 2θ of 8.7±0.2°, or a diffraction peak at 7.4±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 17.5±0.2°, or a diffraction peak at 19.4±0.2°, or a diffraction peak at 22.7±0.2°, or a diffraction peak at 26.4±0.2°, or a diffraction peak at 28.8±0.2°. or has a diffraction peak at a position where the angle is 20.1±0.2°, or has a diffraction peak at a position where the angle is 35.1±0.2°, or has a diffraction peak at a position where the angle is 35.4±0.2°, or has a diffraction peak at a position where the angle is 15.5±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form A contains at least one or more diffraction peaks at 2θ of 8.7±0.2°, 7.4±0.2°, and 17.0±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 2θ of 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, and 35.1±0.2°, preferably two, three, four, or five of these, for example: ８．７±０．２°、７．４±０．２°、 ８．７±０．２°、１７．０±０．２°、 ７．４±０．２°、１７．０±０．２°、 ８．７±０．２°、７．４±０．２°、１７．０±０．２°、 ８．７±０．２°、１７．０±０．２°、１７．５±０．２°、 ７．４±０．２°、１７．０±０．２°、１７．５±０．２°、 ８．７±０．２°、７．４±０．２°、１７．０±０．２°、１７．５±０．２°、 ８．７±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、 ７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、 ８．７±０．２°、７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、 ８．７±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、 ７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、 ８．７±０．２°、７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、 ８．７±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、 ７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、 ８．７±０．２°、７．４±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、 ８．７±０．２°、１７．０±０．２°、１７．５±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、２０．１±０．２°、 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, More preferably, the powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions in 2θ: 8.7±0.2°, 7.4±0.2°, 17.0±0.2°, 17.5±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, and 15.5±0.2°, preferably at any of 4, 5, 6, 8, or 10 positions therein, for example: ８．７±０．２°、７．４±０．２°、１９．４±０．２°、２２．７±０．２°、 ８．７±０．２°、１７．０±０．２°、１９．４±０．２°、２２．７±０．２°、 ８．７±０．２°、７．４±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、 ８．７±０．２°、１７．０±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、 ８．７±０．２°、７．４±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、２０．１±０．２°、３５．１±０．２°、 ８．７±０．２°、１７．０±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、２０．１±０．２°、３５．１±０．２°、 ８．７±０．２°、７．４±０．２°、１９．４±０．２°、２２．７±０．２°、２６．４±０．２°、２８．８±０．２°、２０．１±０．２°、３５．１±０．２°、３５．４±０．２°、１５．５±０．２°、 8.7±0.2°, 17.0±0.2°, 19.4±0.2°, 22.7±0.2°, 26.4±0.2°, 28.8±0.2°, 20.1±0.2°, 35.1±0.2°, 35.4±0.2°, 15.5±0.2°, More preferably, the powder X-ray diffraction pattern of ethanesulfonate salt crystalline form A is substantially as shown in FIG. 5 ; Ethanesulfonate crystalline form B, having a powder X-ray diffraction pattern having a diffraction peak at 2θ of 8.8±0.2°, or a diffraction peak at 8.3±0.2°, or a diffraction peak at 7.9±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 16.2±0.2°, or a diffraction peak at 18.4±0.2°, or a diffraction peak at 20.6±0.2°, or a diffraction peak at 24.1±0.2°. or has a diffraction peak at a position where the angle is 26.4±0.2°, or has a diffraction peak at a position where the angle is 10.8±0.2°, or has a diffraction peak at a position where the angle is 12.6±0.2°, or has a diffraction peak at a position where the angle is 19.9±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B contains at least one or more diffraction peaks at 2θ of 8.8±0.2°, 8.3±0.2°, and 7.9±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 2θ of 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, and 10.8±0.2°, preferably two, three, four, or five of these, for example: ８．８±０．２°、８．３±０．２°、 ８．８±０．２°、７．９±０．２°、 ８．３±０．２°、７．９±０．２°、 ８．８±０．２°、８．３±０．２°、７．９±０．２° ８．８±０．２°、７．９±０．２°、１７．０±０．２°、 ８．３±０．２°、７．９±０．２°、１７．０±０．２°、 ８．８±０．２°、８．３±０．２°、７．９±０．２°、１７．０±０．２°、 ８．８±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、 ８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、 ８．８±０．２°、８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、 ８．８±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、 ８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、 ８．８±０．２°、８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、 ８．８±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、 ８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、 ８．８±０．２°、８．３±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、 ８．８±０．２°、７．９±０．２°、１７．０±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、２６．４±０．２°、 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, More preferably, the powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B comprises diffraction peaks at one or more of the following positions in 2θ: 8.8±0.2°, 8.3±0.2°, 7.9±0.2°, 17.0±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, 10.8±0.2°, 12.6±0.2°, and 19.9±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: ８．８±０．２°、８．３±０．２°、１６．２±０．２°、１８．４±０．２°、 ８．８±０．２°、７．９±０．２°、１６．２±０．２°、１８．４±０．２°、 ８．８±０．２°、８．３±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、 ８．８±０．２°、７．９±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、 ８．８±０．２°、８．３±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、２６．４±０．２°、１０．８±０．２°、 ８．８±０．２°、７．９±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、２６．４±０．２°、１０．８±０．２°、 ８．８±０．２°、８．３±０．２°、１６．２±０．２°、１８．４±０．２°、２０．６±０．２°、２４．１±０．２°、２６．４±０．２°、１０．８±０．２°、１２．６±０．２°、１９．９±０．２°、 8.8±0.2°, 7.9±0.2°, 16.2±0.2°, 18.4±0.2°, 20.6±0.2°, 24.1±0.2°, 26.4±0.2°, 10.8±0.2°, 12.6±0.2°, 19.9±0.2°, More preferably, the powder X-ray diffraction pattern of the ethanesulfonate salt crystalline form B is substantially as shown in FIG. 6 ; p-Toluenesulfonate crystalline form A, having a powder X-ray diffraction pattern having a diffraction peak at 2θ of 5.8±0.2°, or 6.2±0.2°, or 18.6±0.2°, or 23.2±0.2°, or 29.1±0.2°, preferably including any one, or 1 to 2, or 2 to 3 of the above diffraction peaks, more preferably any one, 2, 3, 4, or 5 of the above diffraction peaks; Preferably, the powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A contains at least a diffraction peak located at a position where 2θ is 5.8±0.2 degrees, and optionally further contains at least one peak located at a position where 2θ is 6.2±0.2 degrees, 18.6±0.2 degrees, 23.2±0.2 degrees, or 29.1±0.2 degrees, and preferably contains one, two, three, or four of these peaks, for example: ５．８±０．２°、 ５．８±０．２°、６．２±０．２°、 ５．８±０．２°、１８．６±０．２°、 ５．８±０．２°、２３．２±０．２°、 ５．８±０．２°、２９．１±０．２°、 ５．８±０．２°、６．２±０．２°、１８．６±０．２°、 ５．８±０．２°、１８．６±０．２°、２３．２±０．２°、 ５．８±０．２°、２３．２±０．２°、２９．１±０．２°、 ５．８±０．２°、６．２±０．２°、１８．６±０．２°、２３．２±０．２°、 ５．８±０．２°、１８．６±０．２°、２３．２±０．２°、２９．１±０．２°、 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 23.2±0.2°, 29.1±0.2°, More preferably, the powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A comprises diffraction peaks at one or more of the positions where 2θ is 5.8±0.2°, 6.2±0.2°, 18.6±0.2°, 23.2±0.2°, and 29.1±0.2°, and preferably at any of 4, 5, or 6 of these positions, for example: ５．８±０．２°、６．２±０．２°、２３．２±０．２°、２９．１±０．２°、 ５．８±０．２°、６．２±０．２°、１８．６±０．２°、２９．１±０．２°、 More preferably, the powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A is substantially as shown in FIG. 7; Crystalline form A of the methanesulfonate salt, wherein the powder X-ray diffraction pattern has a diffraction peak at 2θ of 8.1±0.2°, or a diffraction peak at 8.4±0.2°, or a diffraction peak at 4.1±0.2°, or a diffraction peak at 20.8±0.2°, or a diffraction peak at 22.3±0.2°, or a diffraction peak at 18.9±0.2°, or a diffraction peak at 24.5±0.2°, or a diffraction peak at 20.0±0.2°. or has a diffraction peak at a position where the angle is 24.3±0.2°, or has a diffraction peak at a position where the angle is 11.1±0.2°, or has a diffraction peak at a position where the angle is 12.6±0.2°, or has a diffraction peak at a position where the angle is 16.5±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of methanesulfonate crystalline form A contains at least one or more diffraction peaks at 2θ of 8.1±0.2°, 8.4±0.2°, and 4.1±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 2θ of 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, and 11.1±0.2°, preferably two, three, four, or five of these, for example: ８．１±０．２°、８．４±０．２°、 ８．１±０．２°、４．１±０．２°、 ８．４±０．２°、４．１±０．２°、 ８．１±０．２°、８．４±０．２°、４．１±０．２°、 ８．１±０．２°、４．１±０．２°、２０．８±０．２°、 ８．４±０．２°、４．１±０．２°、２０．８±０．２°、 ８．１±０．２°、８．４±０．２°、４．１±０．２°、２０．８±０．２°、 ８．１±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、 ８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、 ８．１±０．２°、８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、 ８．１±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、 ８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、 ８．１±０．２°、８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、 ８．１±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、 ８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、 ８．１±０．２°、８．４±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、 ８．１±０．２°、４．１±０．２°、２０．８±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、２４．３±０．２°、 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, More preferably, the powder X-ray diffraction pattern of methanesulfonate crystalline form A comprises diffraction peaks at one or more of the following positions in 2θ: 8.1±0.2°, 8.4±0.2°, 4.1±0.2°, 20.8±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 16.5±0.2°, and preferably at any of 4, 5, 6, 8, or 10 positions therein, for example: ８．１±０．２°、８．４±０．２°、２２．３±０．２°、１８．９±０．２°、 ８．１±０．２°、４．１±０．２°、２２．３±０．２°、１８．９±０．２°、 ８．１±０．２°、８．４±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、 ８．１±０．２°、４．１±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、 ８．１±０．２°、８．４±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、２４．３±０．２°、１１．１±０．２°、 ８．１±０．２°、４．１±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、２４．３±０．２°、１１．１±０．２°、 ８．１±０．２°、８．４±０．２°、２２．３±０．２°、１８．９±０．２°、２４．５±０．２°、２０．０±０．２°、２４．３±０．２°、１１．１±０．２°、１２．６±０．２°、１６．５±０．２°、 8.1±0.2°, 4.1±0.2°, 22.3±0.2°, 18.9±0.2°, 24.5±0.2°, 20.0±0.2°, 24.3±0.2°, 11.1±0.2°, 12.6±0.2°, 16.5±0.2°, More preferably, the powder X-ray diffraction pattern of methanesulfonate crystalline form A is substantially as shown in Figure 8; More preferably, methanesulfonate salt crystalline form A has a DSC pattern as shown in FIG. 9 : Sulfate crystalline form A, having an X-ray powder diffraction pattern having a diffraction peak at 2θ of 8.3±0.2°, or a diffraction peak at 20.9±0.2°, or a diffraction peak at 18.5±0.2°, or a diffraction peak at 24.4±0.2°, or a diffraction peak at 10.0±0.2°, or a diffraction peak at 11.0±0.2°, or a diffraction peak at 12.6±0.2°, or a diffraction peak at 16.3±0.2° or has a diffraction peak at a position where the angle is 19.9±0.2°, or has a diffraction peak at a position where the angle is 20.4±0.2°, or has a diffraction peak at a position where the angle is 21.9±0.2°, or has a diffraction peak at a position where the angle is 26.7±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of Sulfate Crystalline Form A contains at least one or more diffraction peaks at 2θ of 8.3±0.2°, 20.9±0.2°, and 18.5±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 2θ of 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, and 20.4±0.2°, preferably two, three, four, or five of these, for example: ８．３±０．２°、２０．９±０．２°、 ８．３±０．２°、１８．５±０．２°、 ２０．９±０．２°、１８．５±０．２°、 ８．３±０．２°、２０．９±０．２°、１８．５±０．２°、 ８．３±０．２°、１８．５±０．２°、２４．４±０．２°、 ２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、 ８．３±０．２°、２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、 ８．３±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、 ２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、 ８．３±０．２°、２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、 ８．３±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、 ２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、 ８．３±０．２°、２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、 ８．３±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、 ２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、 ８．３±０．２°、２０．９±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、 ８．３±０．２°、１８．５±０．２°、２４．４±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、１９．９±０．２°、 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, More preferably, the powder X-ray diffraction pattern of Sulfate Crystalline Form A comprises diffraction peaks at one or more of the following positions in 2θ: 8.3±0.2°, 20.9±0.2°, 18.5±0.2°, 24.4±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 26.7±0.2°, and preferably at any of 4, 5, 6, 8, or 10 positions therein, for example: ８．３±０．２°、２０．９±０．２°、１０．０±０．２°、１１．０±０．２°、 ８．３±０．２°、１８．５±０．２°、１０．０±０．２°、１１．０±０．２°、 ８．３±０．２°、２０．９±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、 ８．３±０．２°、１８．５±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、 ８．３±０．２°、２０．９±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、１９．９±０．２°、２０．４±０．２°、 ８．３±０．２°、１８．５±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、１９．９±０．２°、２０．４±０．２°、 ８．３±０．２°、２０．９±０．２°、１０．０±０．２°、１１．０±０．２°、１２．６±０．２°、１６．３±０．２°、１９．９±０．２°、２０．４±０．２°、２１．９±０．２°、２６．７±０．２°、 8.3±0.2°, 18.5±0.2°, 10.0±0.2°, 11.0±0.2°, 12.6±0.2°, 16.3±0.2°, 19.9±0.2°, 20.4±0.2°, 21.9±0.2°, 26.7±0.2°, More preferably, the powder X-ray diffraction pattern of Sulfate Crystalline Form A is substantially as shown in Figure 10; More preferably, Sulfate Salt Crystalline Form A has a DSC pattern as shown in Figure 11 : Crystalline form A of benzenesulfonate salt, the powder X-ray diffraction pattern of which has a diffraction peak at a 2θ of 5.9±0.2°, or a diffraction peak at a 23.8±0.2°, or a diffraction peak at a 2θ of 17.8±0.2°, or a diffraction peak at a 29.9±0.2°, preferably including any one to three, or any two to four, of the above diffraction peaks, more preferably including any one, two, three, or four of the above diffraction peaks; Preferably, the powder X-ray diffraction pattern of benzenesulfonate crystalline form A contains at least one diffraction peak located at one or more of the positions where 2θ is 5.9±0.2°, 23.8±0.2°, 17.8±0.2°, and 29.9±0.2°, preferably two of these, more preferably three, and even more preferably four, for example: ５．９±０．２°、 ５．９±０．２°、２３．８±０．２°、 ５．９±０．２°、１７．８±０．２°、 ５．９±０．２°、２９．９±０．２°、 ５．９±０．２°、２３．８±０．２°、１７．８±０．２°、 ５．９±０．２°、１７．８±０．２°、２９．９±０．２°、 5.9±0.2°, 23.8±0.2°, 17.8±0.2°, and 29.9±0.2°, More preferably, the powder X-ray diffraction pattern of crystalline form A of the benzenesulfonate salt is substantially as shown in FIG. 12 ; isethionate crystalline form A, having a powder X-ray diffraction pattern having a diffraction peak at 2θ of 9.9±0.2°, or a diffraction peak at 19.9±0.2°, or a diffraction peak at 8.3±0.2°, or a diffraction peak at 20.5±0.2°, or a diffraction peak at 18.2±0.2°, or a diffraction peak at 23.9±0.2°, or a diffraction peak at 10.6±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7 of the above diffraction peaks, more preferably any 2, 3, 4, or 5 of the above diffraction peaks; Preferably, the powder X-ray diffraction pattern of isethionate crystalline form A contains at least one or more diffraction peaks at 2θ of 9.9±0.2°, 19.9±0.2°, and 8.3±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one peak at 2θ of 20.4±0.2°, 18.3±0.2°, 23.9±0.2°, and 10.6±0.2°, preferably two, three, or four of these, for example: ９．９±０．２°、１９．９±０．２°、 ９．９±０．２°、８．３±０．２°、 １９．９±０．２°、８．３±０．２°、 ９．９±０．２°、１９．９±０．２°、８．３±０．２°、 ９．９±０．２°、８．３±０．２°、２０．４±０．２°、 １９．９±０．２°、８．３±０．２°、２０．４±０．２°、 ９．９±０．２°、１９．９±０．２°、８．３±０．２°、２０．４±０．２°、 ９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、 １９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、 ９．９±０．２°、１９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、 ９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、２３．９±０．２°、 １９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、２３．９±０．２°、 ９．９±０．２°、１９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、２３．９±０．２°、 ９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、２３．９±０．２°、１０．６±０．２°、 １９．９±０．２°、８．３±０．２°、２０．４±０．２°、１８．２±０．２°、２３．９±０．２°、１０．６±０．２°、 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.4±0.2°, 18.2±0.2°, 23.9±0.2°, 10.6±0.2°, More preferably, the powder X-ray diffraction pattern of isethionate crystalline Form A comprises diffraction peaks at one or more of the positions where 2θ is 9.9±0.2°, 19.9±0.2°, 8.3±0.2°, 20.5±0.2°, 18.2±0.2°, 23.9±0.2°, and 10.6±0.2°, and preferably at any of 4, 5, or 6 of these positions, for example: ９．９±０．２°、１９．９±０．２°、２０．４±０．２°、１８．２±０．２°、 ９．９±０．２°、８．３±０．２°、２０．５±０．２°、１８．２±０．２°、 ９．９±０．２°、１９．９±０．２°、２０．５±０．２°、１８．２±０．２°、２３．９±０．２°、１０．６±０．２°、 9.9±0.2°, 8.3±0.2°, 20.5±0.2°, 18.2±0.2°, 23.9±0.2°, 10.6±0.2°, More preferably, the powder X-ray diffraction pattern of isethionate salt crystalline form A is substantially as shown in Figure 13; More preferably, isethionate crystalline form A has a DSC pattern as shown in FIG. 14 : Hydrobromide salt crystalline form A, having an X-ray powder diffraction pattern having a diffraction peak at 30.0±0.2° 2θ, or a diffraction peak at 22.3±0.2°, or a diffraction peak at 25.9±0.2°, or a diffraction peak at 29.7±0.2°, or a diffraction peak at 17.0±0.2°, or a diffraction peak at 35.7±0.2°, or a diffraction peak at 33.3±0.2°, or a diffraction peak at 23.4±0. or has a diffraction peak at a position where the angle is 28.6±0.2°, or has a diffraction peak at a position where the angle is 28.8±0.2°, or has a diffraction peak at a position where the angle is 18.1±0.2°, or has a diffraction peak at a position where the angle is 26.6±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 of them, Preferably, the powder X-ray diffraction pattern of the hydrobromide salt crystalline form A comprises at least one or more diffraction peaks at 30.0±0.2°, 22.3±0.2°, and 25.9±0.2° 2θ, preferably two of these, more preferably three of these, and optionally further comprises at least one peak at 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, and 28.8±0.2° 2θ, preferably two, three, four, or five of these, for example ３０．０±０．２°、２２．３±０．２°、 ３０．０±０．２°、２５．９±０．２°、 ２２．３±０．２°、２５．９±０．２°、 ３０．０±０．２°、２２．３±０．２°、２５．９±０．２°、 ３０．０±０．２°、２５．９±０．２°、２９．７±０．２°、 ２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、 ３０．０±０．２°、２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、 ３０．０±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、 ２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、 ３０．０±０．２°、２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、 ３０．０±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、 ２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、 ３０．０±０．２°、２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、 ３０．０±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、 ２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、 ３０．０±０．２°、２２．３±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、 ３０．０±０．２°、２５．９±０．２°、２９．７±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、２８．６±０．２°、 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, More preferably, the powder X-ray diffraction pattern of the hydrobromide salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 30.0±0.2°, 22.3±0.2°, 25.9±0.2°, 29.7±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, and preferably at any of 4, 5, 6, 8, or 10 of these positions, for example: ３０．０±０．２°、２２．３±０．２°、１７．０±０．２°、３５．７±０．２°、 ３０．０±０．２°、２５．９±０．２°、１７．０±０．２°、３５．７±０．２°、 ３０．０±０．２°、２２．３±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、 ３０．０±０．２°、２５．９±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、 ３０．０±０．２°、２２．３±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、２８．６±０．２°、２８．８±０．２°、 ３０．０±０．２°、２５．９±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、２８．６±０．２°、２８．８±０．２°、 ３０．０±０．２°、２２．３±０．２°、１７．０±０．２°、３５．７±０．２°、３３．３±０．２°、２３．４±０．２°、２８．６±０．２°、２８．８±０．２°、１８．１±０．２°、２６．６±０．２°、 30.0±0.2°, 25.9±0.2°, 17.0±0.2°, 35.7±0.2°, 33.3±0.2°, 23.4±0.2°, 28.6±0.2°, 28.8±0.2°, 18.1±0.2°, 26.6±0.2°, More preferably, the acid salt of the compound of formula (I) according to claim 6, characterized in that the powder X-ray diffraction pattern of the hydrobromide salt crystalline form A is substantially as shown in Figure 15.

8. the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Hydrochloride Crystalline Form A and the positions of the corresponding diffraction peaks in FIG. 1 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Hydrochloride Crystalline Form B and the positions of the corresponding diffraction peaks in FIG. 3 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of ethanesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 5 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of ethanesulfonate crystalline form B and the positions of the corresponding diffraction peaks in FIG. 6 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the six highest relative peak intensities in the powder X-ray diffraction pattern of p-toluenesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 7 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the four diffraction peaks with the highest relative peak intensities in the powder X-ray diffraction pattern of methanesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 8 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of Sulfate Crystalline Form A and the positions of the corresponding diffraction peaks in Figure 10 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the powder X-ray diffraction pattern of benzenesulfonate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 12 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the seven highest relative peak intensities in the powder X-ray diffraction pattern of isethionate crystalline form A and the positions of the corresponding diffraction peaks in FIG. 13 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; the 2θ error between the positions of the five diffraction peaks with the highest relative peak intensity in the powder X-ray diffraction pattern of crystalline Form A of the hydrobromide salt and the positions of the corresponding diffraction peaks in Figure 15 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; The acid salt of compound of formula (I) according to claim 7, wherein the 2θ error between the positions of the five diffraction peaks with the highest relative peak intensity in the powder X-ray diffraction pattern of hydrochloride crystalline form C and the corresponding positions of the diffraction peaks in Figure 16 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

9. The acid salt of the compound of formula (I) according to claim 7, characterized in that the crystalline form of the acid salt is a hydrate or anhydrous, and when the crystalline form of the acid salt is a hydrate, the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and further, the water in the hydrate is channel water or crystal water or a combination of both.

10. A process for preparing an acid salt of a compound of formula (I) according to any one of claims 1 to 9, comprising the steps of: 1) Weighing out an appropriate amount of free base and dissolving it in a good solvent; 2) Weighing an appropriate amount of counter ion acid and dissolving it in an organic solvent, the amount of the counter ion acid being preferably 1.0 to 1.5 equivalents; 3) combining the two solutions and stirring to precipitate, or adding an anti-solvent dropwise and then stirring to precipitate; 4) quickly centrifuging or allowing to stand and blow dry to obtain the desired product; where: The good solvent is selected from one or more of acetone, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, and tert-butanol, and is preferably one or more of 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, acetone, and ethyl formate; the organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide, preferably one or more of methanol, ethanol or acetonitrile; the anti-solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate, preferably one or more of water, methyl tert-butyl ether or isopropyl ether; The counter ion acid may be hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, isethionic acid, formic acid, fumanic acid, guar ... acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid or L-malic acid, and preferably methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid or hydrobromic acid, Or, 1) Weighing out an appropriate amount of free base and suspending it in an anti-solvent; 2) Weighing out an appropriate amount of counter ion acid and dissolving it in an organic solvent, the amount of the counter ion acid being preferably 1.0 to 1.5 equivalents; 3) adding the solution to the suspension and stirring for 2 hours; 4) rapidly centrifuging or allowing to stand and blow dry to obtain the salt of the compound of formula (I); where: the anti-solvent is selected from one or more of ethanol, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, dichloromethane, methanol, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol or 3-pentanone, preferably one or more of ethanol, ethyl acetate, isopropanol or isopropyl acetate; the organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide, preferably one or more of methanol, ethanol or acetonitrile; Examples of the counter ion acid include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, and the like.

1. The process according to claim 1, wherein the acid selected from the group consisting of galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid or L-malic acid, and preferably methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid or hydrobromic acid.

11. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt of a compound of formula (I) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable carriers or excipients, Preferably, the weight percentage of the compound of formula (I) is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15 to 40%, even more preferably 20 to 30%, and most preferably 20 to 25%.

12. Use of an acid salt of a compound of formula (I) according to any one of claims 1 to 9 and a pharmaceutical composition according to claim 11 in the manufacture of a medicament for treating angiotensin II-dependent or endothelin-dependent diseases, in particular in the manufacture of a medicament for treating dual-acting angiotensin-dependent and endothelin-dependent diseases. Or use in the manufacture of a medicament for treating pain, sexual dysfunction, hypoxic and ischemic diseases, dementia, neurological diseases, liver diseases, cancer, hypertension, diabetes or kidney diseases, wherein the kidney diseases are selected from diseases or conditions associated with the function of the kidney, glomeruli or mesangial cells of the glomerular system, preferably focal segmental glomerulosclerosis or IgA nephropathy.

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