Acid salt or crystalline form of nitrogen-containing fused ring derivative inhibitor, and its preparation and application

Abstract

The present invention relates to an acid salt or crystalline form of a nitrogen-containing fused ring derivative inhibitor, and its preparation method and application. The salt or crystalline form of the inhibitor of the present invention can be used for the treatment of depression, anxiety, schizophrenia and related diseases such as sex hormone dependence, and has a broad application prospect.

Description

[Technical field]

[0001] The present invention relates to the field of biopharmaceutical technology, in particular to the crystal form and acid salt of an NK3 inhibitor and the preparation method and application thereof. [Background technology]

[0002] Neurokinin (NK) includes substance P (SP), neurokinin A and neurokinin B, and the three corresponding receptors are neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R) and neurokinin 3 receptor (NK3R). All three receptors are G protein-coupled receptors, where NK1R is the most widely distributed and is distributed in the central and peripheral nervous systems, NK2R is mainly distributed in the peripheral nervous system, and NK3R is mainly distributed in the central nervous system. At present, NK receptor inhibitors are widely used in the treatment of diseases such as menopausal hot flashes, depression, and schizophrenia, and it has been proven that NK3R is closely related to symptoms such as hot flashes of menopausal syndrome, and NK3R inhibitors have excellent effects on improving menopausal hot flashes.

[0003] Menopausal hot flashes are a common symptom of menopausal women, including hot flashes and sweating. They are a prominent feature of menopausal syndrome. They are caused by vasomotor dysfunction due to a drop in estrogen levels in the body. When estrogen levels drop, the brain mistakenly believes the body's temperature is too high, so it signals the heart to pump more blood, which causes the sweat glands to release more sweat, along with sweating, palpitations, and dizziness. More than three-quarters of women experience hot flashes during menopause, and 80% of patients experience symptoms that last for more than a year, with some even lasting up to five years after menopause. Currently, the main treatment for menopausal hot flashes is hormone replacement therapy, but this therapy has a high risk of causing diseases such as breast cancer, stroke, coronary heart disease, and dementia. Oral medications such as paroxetine (SSRIs, which treat depression) are the only approved small molecule drugs for treating menopausal hot flashes, and have side effects and are only approved in the United States, so there is a clinical need to develop safer and more effective drugs to treat menopausal syndrome.

[0004] Patent PCT / CN2021 / 109577 discloses a series of NK3R inhibitors, which have excellent effects. In order to meet the needs of clinical development of medicines, the present invention further studies the salt form of the compound of formula I and its crystal form, and the structure of formula (I) is: [ka] As follows. Summary of the Invention

[0005] In order to improve the solubility and solid stability of the product, reduce storage costs, extend the product cycle, and improve the bioavailability of the product, the present invention comprehensively studies the salt forms and crystalline forms of the salts of the above compounds.

[0006] The present invention provides a crystalline form, an acid salt or a crystalline form of a salt thereof, as shown in general formula (I): [ka] Where: R1 is selected from hydrogen, deuterium or halogen, preferably hydrogen, deuterium, fluorine, chlorine or bromine; R3 is hydrogen, deuterium, halogen, C 1-6 Alkyl group, C 1-6 deuterated alkyl group, 3- to 6-membered heterocyclyl group, 1-6 Alkyl group, C 1-6 The deuterated alkyl group and the 3- to 6-membered heterocyclyl group are optionally further substituted with one or more substituents selected from deuterium and halogen, and are preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, azetidinyl, tetrahydropyrrolyl, [ka] and y is 0, 1, 2, 3, 4 or 5.

[0007] In a preferred embodiment of the invention, the specific structure of the compound is [ka] As follows.

[0008] In a further preferred embodiment of the present invention, the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone, an acid salt or a salt thereof is in the form of a crystalline form, and the structure of the compound is [ka] As follows.

[0009] In some embodiments of the present invention, the acid salt of the compound of formula I refers to the salt of the compound of formula I with a pharma- ceutically acceptable acid.In some embodiments of the present invention, it may be an acid addition salt with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like. In some embodiments of the invention, it is selected from the group consisting of benzoic acid, 10-camphorsulfonic acid, chlorotheophylline, 1,2-ethanedisulfonic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, isethionic acid, lactobionic acid, lauryl sulfate, methyl sulfate, naphthoic acid, naphthalenesulfonic acid, stearic acid, oleic acid, pamoic acid, polygalacturonic acid, sulfosalicylic acid, trifluoroacetic acid, 2,2-dichloroacetic acid, acetylglycine, adipic acid, alginic acid, ascorbic acid, 4-acetamidobenzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, camphoric acid, capric acid, caproic acid, caprylic acid, The acid addition salts may be, for example, acid addition salts with carbonic acid, cinnamic acid, cyclohexylsulfamic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glucaric acid, glucoheptonic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, isobutyric acid, lauric acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, orotic acid, palmitic acid, pyroglutamic acid, acetone acid, saccharin, salicylic acid, 4-aminosalicylic acid, sebacic acid, thiocyanic acid, and undecylenic acid.

[0010] Furthermore, in some embodiments of the present invention, the acid salt is selected from a hydrochloride, a methanesulfonate, a nitrate, a sulfate, or a hydrobromide.

[0011] In some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern having a diffraction peak at 9.3±0.2 degrees 2θ, or a diffraction peak at 10.0±0.2 degrees 2θ, or a diffraction peak at 12.0±0.2 degrees 2θ, or a diffraction peak at 12.8±0.2 degrees 2θ, or a diffraction peak at 16.8±0.2 degrees 2θ, or a diffraction peak at 18.6±0.2 degrees 2θ, or a diffraction peak at 19.2±0.2 degrees 2θ. or a diffraction peak at 2θ of 19.8±0.2°, or a diffraction peak at 2θ of 20.2±0.2°, or a diffraction peak at 2θ of 21.8±0.2°, or a diffraction peak at 2θ of 22.5±0.2°, or a diffraction peak at 2θ of 22.8±0.2°, or a diffraction peak at 2θ of 24.2±0.2°, or a diffraction peak at 2θ of 25.4±0.2°, or a diffraction peak at 2θ of 27.5±0.2°, or a diffraction peak at 2θ of 27.8±0.2°, or a diffraction peak at 2θ of 28.9±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein.

[0012] Further, in some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern that contains at least one of the positions 2θ of 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 20.2±0.2°. and preferably includes 2 to 4 of these, more preferably includes 3 to 4, and most preferably includes 4, and optionally may further include one or more diffraction peaks at positions where 2θ is 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, or 22.5±0.2°, and preferably includes 2, 3, 4, or 5 of these, Further, in some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 9.3±0.2°, 10.0±0.2°, 16.8±0.2°, 18.6±0.2°, or 10.0±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, or 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, or 9.3±0.2°, 10.0±0.2°, 18.6±0.2°, 19.8±0.2°, or 10.0±0.2°, 12.0±0.2°, 18.6±0.2°, 19.8±0.2°, or 12.0±0.2°, 12.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 12.8±0.2°, 22.5±0.2°, 18.6±0.2°, 19.8±0.2°, or 9.3±0.2°, 10.0±0.2°, 19.8±0.2°, 20.2±0.2°, or 10.0±0.2°, 12.0±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.0±0.2°, 12.8±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.8±0.2°, 22.5±0.2°, 19.8±0.2°, 20.2±0.2°, or 9.3±0.2°, 10.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 10.0±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, or 9.3±0.2°, 10.0±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 10.0±0.2°, 12.0±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.0±0.2°, 12.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.8±0.2°, 22.5±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 9.3±0.2°, 10.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 10.0±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 12.0±0.2°, 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°, or 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°.

[0013] Furthermore, in some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone optionally has an X-ray powder diffraction pattern further comprising diffraction peaks at one or more positions where 2θ is 15.88±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2°, or 28.9±0.2°, preferably at least any 2 to 4 positions, or 5 to 6 positions, more preferably any 4 or 6 positions, Further, in some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern comprising peaks at at least the following diffraction angles (2θ): 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, or 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2°, or 25.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, or 15.8±0.2°, 24.2±0.2°, 27.5±0.2°, 27.8±0.2°, or 15.8±0.2°, 24.2±0.2°, 27.8±0.2°, 28.9±0.2°, or 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 28.9±0.2°, or 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2° or 28.9±0.2°.

[0014] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone free base comprises peaks at diffraction angles (2θ) that are 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2° and 20.2±0.2°, and the crystalline form is designated as Form A of Formula I compound.

[0015] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone crystalline form further comprises peaks at diffraction angles (2θ) which are 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2° and 28.9±0.2°.

[0016] Further, in some embodiments of the present invention, the crystalline form of the free base of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has characteristic X-ray diffraction peaks, expressed as 2θ angles and d spacings, as shown in Table 1 using Cu-Kα radiation;

[0017] [Table 1]

[0018] Further, in some embodiments of the present invention, the crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern substantially as shown in FIG. 1 and a DSC pattern substantially as shown in FIG. 7.

[0019] In some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern having a diffraction peak at 8.3±0.2 degrees 2θ, or a diffraction peak at 10.1±0.2 degrees 2θ, or a diffraction peak at 15.0±0.2 degrees 2θ, or a diffraction peak at 16.0±0.2 degrees 2θ, or a diffraction peak at 16.5±0.2 degrees 2θ, or a diffraction peak at 17.0±0.2 degrees 2θ. or a diffraction peak at 17.7±0.2° 2θ, or a diffraction peak at 21.5±0.2° 2θ, or a diffraction peak at 22.0±0.2° 2θ, or a diffraction peak at 24.4±0.2° 2θ, or a diffraction peak at 24.7±0.2° 2θ, or a diffraction peak at 27.4±0.2° 2θ, or a diffraction peak at 30.9±0.2° 2θ, or a diffraction peak at 32.2±0.2° 2θ, preferably at any of 2, 4, 6, 8 or 10 positions therein.

[0020] Further, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern of at least 8.3±0.2°, 15.0±0.2°, or 16.5±0.2° 2θ. and preferably includes two of these positions, more preferably includes three of these positions, and optionally further includes one or more of the positions where 2θ is 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 21.5±0.2°, and preferably includes two, three, four, or five of these positions, Further, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 8.3±0.2°, 15.0±0.2°, 10.1±0.2°, 16.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 10.1±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 10.1±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.0±0.2°, 17.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.0±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 17.0±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 21.5±0.2°, or 8.3±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, or 8.3±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 16.5±0.2°, 10.1±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 21.5±0.2°, or 8.3±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 16.5±0.2°, 16.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, or 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2°, or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.7±0.2°, 21.5±0.2°, or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.7±0.2°, or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 21.5±0.2°, or 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2° or 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.7±0.2°, 21.5±0.2°, or 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, 21.5±0.2°.

[0021] Furthermore, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone optionally has an X-ray powder diffraction pattern further including diffraction peaks located at one or more positions where 2θ is 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, or 32.2±0.2°, preferably including at least any 2 to 4 positions, or 5 to 6 positions, more preferably including any 4 or 6 positions, Further, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, or 24.4±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, or 24.4±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, or 24.4±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, or 24.7±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, or 24.7±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, or 25.2±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 27.4±0.2°, 28.5±0.2°, or 24.4±0.2°, 24.7±0.2°, 28.5±0.2°, 30.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, or 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 28.5±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 30.2±0.2°, 32.2±0.2°, or 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 32.2±0.2°.

[0022] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone hydrochloride comprises peaks at diffraction angles (2θ) that are 8.3±0.2°, 10.1±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2° and 21.5±0.2°.

[0023] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone hydrochloride further comprises peaks at diffraction angles (2θ) that are 22.0±0.2°, 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, and 32.2±0.2°.

[0024] Furthermore, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has X-ray characteristic diffraction peaks, expressed as 2θ angles and lattice plane d values, as shown in Table 2 using Cu-Kα radiation;

[0025] [Table 2]

[0026] Further, in some embodiments of the present invention, the crystalline form of the hydrochloride salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

[0027] In some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern having a diffraction peak at 7.1±0.2 degrees 2θ, or a diffraction peak at 10.1±0.2 degrees 2θ, or a diffraction peak at 10.5±0.2 degrees 2θ, or a diffraction peak at 12.0±0.2 degrees 2θ, or a diffraction peak at 13.2±0.2 degrees 2θ, or a diffraction peak at 16.9±0.2 degrees 2θ, or a diffraction peak at 18.7±0.2 degrees 2θ. or a diffraction peak at 2θ of 21.1 ± 0.2 °, or a diffraction peak at 2θ of 16.8 ± 0.2 °, or a diffraction peak at 2θ of 18.6 ± 0.2 °, or a diffraction peak at 2θ of 19.7 ± 0.2 °, or a diffraction peak at 2θ of 21.5 ± 0.2 °, or a diffraction peak at 2θ of 21.7 ± 0.2 °, or a diffraction peak at 2θ of 22.5 ± 0.2 °, or a diffraction peak at 2θ of 23.3 ± 0.2 °, or a diffraction peak at 2θ of 25.5 ± 0.2 °, or a diffraction peak at 2θ of 28.0 ± 0.2 °, preferably at any of 2, 4, 6, 8 or 10 positions included therein.

[0028] Further, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern of at least 7.1±0.2°, 10.1±0.2°, or 10.5±0.2° 2θ. and preferably includes two of them, more preferably includes three of them, and optionally further includes one or more of the diffraction peaks at positions where 2θ is 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, or 21.1±0.2°, preferably includes two, three, four, or five of them; Further, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 13.2±0.2°, or 7.1±0.2°, 10.1±0.2°, 13.2±0.2°, 16.9±0.2°, or 7.1±0.2°, 10.1±0.2°, 16.9±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 16.9±0.2°, or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 13.2±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 13.2±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 16.9±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 16.9±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 16.9±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 16.9±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 16.9±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 16.9±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 16.9±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 16.9±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 18.7±0.2°, 21.1±0.2°, or 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, 21.1±0.2°.

[0029] Further, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone optionally has an X-ray powder diffraction pattern of 16.8±0.2 degrees 2θ, 18.6±0.0 degrees 2θ, or 19.7±0.0 degrees 2θ. and further comprising diffraction peaks located at one or more of the positions at which the azimuth angles are 19.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 28.0±0.2°, and preferably including at least any 2 to 4, or 5 to 6, or 7 to 9, of these positions, and more preferably including any 4, 6, or 8, of these positions, Further, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, or 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, or 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, or 16.8±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, or 16.8±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 21.5±0.2°, 21.7±0.2°, or 16.8±0.2°, 18.6±0.2°, 21.7±0.2°, 22.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.7±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 28.0±0.2°, or 18.6±0.2°, 19.7±0.2°, 21.7±0.2°, 22.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 18.6±0.2°, 19.7±0.2°, 23.3±0.2°, 25.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 25.5±0.2°, 28.0±0.2°, or 19.7±0.2°, 21.5±0.2°, 22.5±0.2°, 23.3±0.2°, or 19.7±0.2°, 21.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 19.7±0.2°, 21.5±0.2°, 25.5±0.2°, 28.0±0.2°, or 21.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.5±0.2°, or 21.5±0.2°, 21.7±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 22.5±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 23.3±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 25.5±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 28.0±0.2°, or 18.6±0.2°, 19.7±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 19.7±0.2°, 21.5±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, or 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.5±0.2°, 28.0±0.2°, or 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 25.5±0.2°, 28.0±0.2°.

[0030] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone methanesulfonate comprises peaks at diffraction angles (2θ) that are 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, 21.1±0.2°, 16.8±0.2° and 18.6±0.2°.

[0031] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone methanesulfonate further comprises peaks at diffraction angles (2θ) that are 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 25.5±0.2°, and 28.0±0.2°.

[0032] Furthermore, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has X-ray characteristic diffraction peaks, expressed as 2θ angles and lattice plane spacing d values, as shown in Table 3 using Cu-Kα radiation;

[0033] [Table 3]

[0034] Furthermore, in some embodiments of the present invention, the crystalline form of the methanesulfonate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

[0035] In some embodiments of the present invention, the crystalline form of the nitrate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern having a diffraction peak at 9.3±0.2 degrees 2θ, or a diffraction peak at 11.9±0.2 degrees 2θ, or a diffraction peak at 12.5±0.2 degrees 2θ, or a diffraction peak at 14.3±0.2 degrees 2θ, or a diffraction peak at 14.6±0.2 degrees 2θ, or a diffraction peak at 16.2±0.2 degrees 2θ. or a diffraction peak at 2θ of 16.7±0.2°, or a diffraction peak at 2θ of 17.9±0.2°, or a diffraction peak at 2θ of 18.7±0.2°, or a diffraction peak at 2θ of 22.9±0.2°, or a diffraction peak at 2θ of 25.1±0.2°, or a diffraction peak at 2θ of 25.9±0.2°, or a diffraction peak at 2θ of 26.6±0.2°, or a diffraction peak at 2θ of 28.2±0.2°, or a diffraction peak at 2θ of 28.6±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein.

[0036] Further, in some embodiments of the present invention, the crystalline form of the nitrate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern of at least 9.3±0.2°, 11.9±0.2°, or 12.5±0.2° 2θ. and preferably includes two of these positions, more preferably includes three of these positions, and optionally further includes one or more of the positions where 2θ is 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, or 17.9±0.2°, and preferably includes two, three, four, or five of these positions, Further, in some embodiments of the present invention, the crystalline form of the nitrate salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern including peaks at at least the following diffraction angles (2θ): 9.3±0.2°, 11.9±0.2°, 14.3±0.2°, 14.6±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.6±0.2°, 16.2±0.2°, or 9.3±0.2°, 11.9±0.2°, 16.2±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.3±0.2°, 16.2±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.3±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.3±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.6±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 14.6±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 16.2±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.2±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.2±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.2±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.7±0.2° or 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 17.9±0.2°, or 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°.

[0037] Furthermore, in some embodiments of the present invention, the crystalline form of the nitrate salt of the compound of formula I (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone optionally has an X-ray powder diffraction pattern further comprising diffraction peaks at one or more positions where 2θ is 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 28.6±0.2°, preferably at least any 2 to 4 positions, or 5 to 7 positions, more preferably any 4 or 6 positions, Further, in some embodiments of the present invention, the crystalline form of the nitrate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, or 18.7±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, or 18.7±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 18.7±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.9±0.2°, 26.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 18.7±0.2°, 22.9±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 26.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 28.2±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 28.6±0.2°, or 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, or 22.9±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 22.9±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 25.1±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, or 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 26.6±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 28.2±0.2°, 28.6±0.2°, or 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.6±0.2°.

[0038] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone free base comprises peaks at diffraction angles (2θ) that are 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2° and 18.7±0.2°.

[0039] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone crystalline form further comprises peaks at diffraction angles (2θ) which are 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2° and 28.6±0.2°.

[0040] Furthermore, in some embodiments of the present invention, the crystalline form of the free base of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has X-ray characteristic diffraction peaks, expressed as 2θ angles and lattice plane d values, as shown in Table 4 using Cu-Kα radiation;

[0041] [Table 4]

[0042] Further, in some embodiments of the present invention, the crystalline form of the nitrate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

[0043] In some embodiments of the present invention, the crystalline form of the sulfate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern having a diffraction peak at 7.1±0.2 degrees 2θ, or a diffraction peak at 13.4±0.2 degrees 2θ, or a diffraction peak at 14.2±0.2 degrees 2θ, or a diffraction peak at 15.5±0.2 degrees 2θ. or a diffraction peak at 2θ=16.3±0.2°, or a diffraction peak at 2θ=17.4±0.2°, or a diffraction peak at 2θ=17.7°, or a diffraction peak at 2θ=18.0±0.2°, or a diffraction peak at 2θ=19.8±0.2°, or a diffraction peak at 2θ=20.1±0.2°, preferably at any of 2, 4, 6, 8 or 10 positions therein.

[0044] Further, in some embodiments of the present invention, the crystalline form of the sulfate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern of at least 7.1±0.2°, 16.3±0.2°, or 18.0±0.2° 2θ. positions, preferably including two of them, more preferably including three of them, and optionally further including one or more of positions where 2θ is 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 17.4±0.2° or 17.7±0.2°, preferably including two, three, four or five of them; Further, in some embodiments of the present invention, the crystalline form of the sulfate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, or 7.1±0.2°, 16.3±0.2°, 15.5±0.2°, 17.4±0.2°, or 7.1±0.2°, 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 17.4±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 17.7±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 17.4±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 17.7±0.2°, or 7.1±0.2°, 16.3±0.2°, 15.5±0.2°, 17.7±0.2°, or 7.1±0.2°, 13.4±0.2°, 14.2±0.2°, 18.0±0.2°, or 7.1±0.2°, 14.2±0.2°, 15.5±0.2°, 18.0±0.2°, or 7.1±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 13.4±0.2°, 15.5±0.2°, 18.0±0.2°, or 7.1±0.2°, 13.4±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 13.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 14.2±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 14.2±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 18.0±0.2°, or 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, 18.0±0.2°, or 16.3±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, 18.0±0.2°, or 16.3±0.2°, 13.4±0.2°, 17.4±0.2°, 18.0±0.2°, or 16.3±0.2°, 13.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 16.3±0.2°, 14.2±0.2°, 17.4±0.2°, 18.0±0.2°, or 16.3±0.2°, 14.2±0.2°, 17.7±0.2°, 18.0±0.2°, or 16.3±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 15.5±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 17.4±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 14.2±0.2°, 15.5±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 15.5±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 16.3±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 17.7±0.2°, 18.0±0.2°, or 7.1±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2°.

[0045] Further, in some embodiments of the present invention, the crystalline form of the sulfate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone optionally has an X-ray powder diffraction pattern of 19.8±0.2 degrees 2θ, 20.1±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, or 22.0±0.2 degrees 2θ. 0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2° or 28.6±0.2°, preferably including at least any 2 to 4 or 5 to 7 of these positions, more preferably including any 4 or 6 of these positions, Further, in some embodiments of the present invention, the crystalline form of the sulfate salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 19.8±0.2°, 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, or 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, or 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, or 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, or 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, or 19.8±0.2°, 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, or 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, or 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, or 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, or 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2°, or 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2°, 28.6±0.2°.

[0046] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone sulfate comprises peaks at diffraction angles (2θ) that are 7.1±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, 18.0±0.2° and 19.8±0.2°.

[0047] Furthermore, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone sulfate further comprises peaks at diffraction angles (2θ) that are 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2°, 28.6±0.2°, and 33.013±0.2°.

[0048] Furthermore, in some embodiments of the present invention, the crystalline form of the sulfate salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has X-ray characteristic diffraction peaks, expressed as 2θ angles and lattice plane d values, as shown in Table 5 using Cu-Kα radiation;

[0049] [Table 5]

[0050] In some embodiments of the present invention, the crystalline form of the sulfate salt of the compound (3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

[0051] In some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern with a diffraction peak at 9.2±0.2 degrees 2θ or a diffraction peak at 12.0±0.0 degrees 2θ. 0.2°、2θ=12.9±0.2°、2θ=14.6±0.2°、2θ=16.8±0.2°、2θ=17.1±0.2°、2θ=18.6±0.2°、2θ=22.7±0.2°。 or a diffraction peak at 2θ=19.5±0.2°, or a diffraction peak at 2θ=19.8±0.2°, or a diffraction peak at 2θ=20.2±0.2°, or a diffraction peak at 2θ=22.5±0.2°, or a diffraction peak at 2θ=25.4±0.2°, or a diffraction peak at 2θ=26.4±0.2°, or a diffraction peak at 2θ=27.5±0.2°, or a diffraction peak at 2θ=27.8±0.2°, or a diffraction peak at 2θ=28.9±0.2°, or a diffraction peak at 2θ=29.3±0.2°, or a diffraction peak at 2θ=32.3±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein.

[0052] In some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has an X-ray powder diffraction pattern having at least one diffraction pattern at 2θ of 9.2±0.2°, 12.0±0.2°, or 12.9±0.2°. and preferably includes two of the positions, more preferably includes three of the positions, and optionally further includes one or more of the positions where 2θ is 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 22.7±0.2°, and preferably includes two, three, four, or five of the positions, Further, in some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 16.8±0.2°, or 9.2±0.2°, 12.0±0.2°, 16.8±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.0±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 16.8±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 17.1±0.2°, 22.7±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, or 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, or 12.0±0.2°, 12.9±0.2°, 17.1±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.9±0.2°, 18.6±0.2°, 22.7±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 22.7±0.2°, or 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 22.7±0.2°, or 12.0±0.2°, 12.9±0.2°, 17.1±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, or 9.2±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.9±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.9±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.9±0.2°, 16.8±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.9±0.2°, 16.8±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.9±0.2°, 17.1±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.0±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 14.6±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.9±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, or 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 12.0±0.2°, 12.9±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 18.6±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 22.7±0.2°, or 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2°.

[0053] Further, in some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone may optionally have a powder X-ray diffraction pattern of 19.5±0.2°, 19.8±0.2° 2θ. , 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2° or 32.3±0.2°, preferably including at least any 2 to 4 or 5 to 7 of these positions, more preferably including any 4 or 6 of these positions, Further, in some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern including peaks at at least the following diffraction angles (2θ): 19.5±0.2°, 19.8±0.2°, 20.2±0.2°, 22.5±0.2°, or 19.8±0.2°, 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, or 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, or 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, or 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, or 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, or 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, or 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, 32.3±0.2°, or 19.5±0.2°, 19.8±0.2°, 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, or 19.8±0.2°, 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, or 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, or 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, or 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, or 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, 32.3±0.2°.

[0054] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone hydrobromide comprises peaks at diffraction angles (2θ) that are 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, 22.7±0.2° and 26.4±0.2°.

[0055] Further, in some embodiments of the present invention, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone hydrobromide comprises peaks at diffraction angles (2θ) that are 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, 32.3±0.2° and 32.589±0.2°.

[0056] Furthermore, in some embodiments of the present invention, the crystalline form of the hydrobromide salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has X-ray characteristic diffraction peaks, expressed as 2θ angles and lattice plane d values, as shown in Table 6 using Cu-Kα radiation;

[0057] [Table 6]

[0058] Further, in some embodiments of the present invention, the crystalline form of the hydrobromide salt of the compound -(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

[0059] As will be appreciated by those of skill in the art, peak positions (2θ) can vary from one XRPD instrument to another, in some cases by as much as 0.2°, and such variations or shifts can be used to describe variability in X-ray diffraction peak positions and intensities with the term "substantially the same." It will also be appreciated by those of skill in the art that factors such as the method of XRPD sample preparation, the XRPD instrument, the crystallinity of the sample, sample volume, and preferred crystal orientation can also cause variations in the relative peak intensities in the XRPD diffractogram of a sample.

[0060] Compared with amorphous substances, the crystalline form obtained by the present invention is more stable chemically and physically, which is advantageous for the manufacture, transportation and storage of pharmaceuticals, and more suitable for the needs of pharmaceutical development.It also has more advantages in the purification, decolorization, filtration and other process operations of pharmaceuticals.Therefore, the crystalline form of the compound of the present invention has great significance for improvement and meets the requirements of clinical development.

[0061] In another aspect of the present invention, there is provided a method for producing the aforementioned crystalline form, said method comprising the steps of: a) weighing out an appropriate amount of compound and dissolving it in an organic solvent to obtain a clear solution; b) stirring, filtering and drying to obtain the desired product; The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, or compositions thereof.

[0062] In another aspect of the present invention, there is provided a method for preparing the aforementioned acid salt or a crystalline form thereof, said method comprising the steps of: a) weighing an appropriate amount of a crystalline form of the free base of the compound and adding it to an organic solvent; b) weighing out an appropriate amount of acid, dissolving it in an organic solvent, stirring and filtering or dissolving and volatilizing to obtain a gel, adding a poor solvent to the gel, stirring and filtering, vacuum drying, and isolating to obtain the target product.

[0063] Where: The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, or a composition thereof, and the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, ethyl ether or compositions thereof; the acid in the acid solution is selected from an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 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-aceto Amidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic 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, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric 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.

[0064] In another aspect of the present invention, there is provided a method for preparing an acid salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone as described above, or a crystalline form thereof, said method comprising the steps of: The method includes the steps of adding the crystalline form A of the free base of the compound (3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone to an organic solvent, adding an acid solution thereto, stirring and filtering or dissolving and evaporating to obtain a gel, adding a poor solvent to the gel, stirring and filtering, vacuum drying, and isolating to obtain the crystalline form of the salt.

[0065] The dissolving refers to a general operation understood by those skilled in the art, which usually involves heating appropriately to dissolve the raw materials or make them into a clear solution, or increasing the amount of solvent to dissolve the raw materials or make them into a clear solution, or the technical solutions may be modified or replaced equivalently, all of which are included in the content of the present invention.

[0066] Further, in some embodiments of the present invention, in the method for producing the present invention, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, or a composition thereof; the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, ethyl ether, or a composition thereof; and the acid solution is selected from a solution of hydrochloric acid in methanol, a solution of methanesulfonic acid in methanol, a solution of nitric acid in methanol, a solution of sulfuric acid in methanol, or a solution of hydrobromic acid in methanol.

[0067] Further, in some embodiments of the present invention, in the process, the organic solvent is selected from tetrahydrofuran or ethyl acetate, the anti-solvent is selected from ethyl acetate, and the acid solution is selected from a solution of hydrochloric acid in methanol, a solution of methanesulfonic acid in methanol, a solution of nitric acid in methanol, a solution of sulfuric acid in methanol, or a solution of hydrobromic acid in methanol.

[0068] Furthermore, in some embodiments of the present invention, the isolated crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone acid salt has an X-ray powder diffraction peak or pattern as described in any one of the above embodiments.

[0069] Further, in some embodiments of the present invention, a substantially pure crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone is obtained by separating in step 3) of the preparation method, and the substantially pure crystalline form refers to a crystalline form having a crystalline form purity of more than 90%.

[0070] Preferably, the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone obtained by separation in step 3) of the preparation process has a purity of more than 95%.

[0071] Most preferably, the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone obtained after separation in step 3) of the preparation process has a purity of more than 98%.

[0072] In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone or an acid salt thereof and a pharma- ceutically acceptable carrier.

[0073] Embodiments according to the present invention include a therapeutically effective amount of the crystalline form, acid salt or crystalline form thereof, said therapeutically effective amount being selected from 0.0001-99%, 0.0001-95%, 0.0001-90%, 0.0001-85%, 0.0001-80%, 0.0001-75%, 0.0001-70%, 0.001-60%, 0.001-55%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10% or 0.01-5%.

[0074] In a further aspect of the present invention, there is provided an application of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone or an acid salt thereof or the pharmaceutical composition in the manufacture of a medicament related to an NK3 inhibitor, preferably in the manufacture of a medicament for treating and / or preventing a psychotic disorder, a cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, an inflammatory disease, vomiting, preeclampsia, an airway-related disease, a reproductive disorder, a sex hormone-dependent disease or a gynecological disease-related disease, more preferably in the manufacture of a medicament for treating and / or preventing a disease related to a menopausal syndrome, the menopausal syndrome including hot flashes, sweating, palpitations, dizziness and obesity symptoms. [Brief description of the drawings]

[0075] [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) free base, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Diagram 2] 1 is a powder X-ray diffraction pattern of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) hydrochloride, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Diagram 3] 1 is a powder X-ray diffraction pattern of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanesulfonate, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Figure 4]1 is a powder X-ray diffraction pattern of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) nitrate, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Diagram 5] 1 is a powder X-ray diffraction pattern of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) sulfate, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Figure 6] 1 is a powder X-ray diffraction pattern of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) hydrobromide, where the X-axis is the diffraction peak angle 2θ (°) and the Y-axis is the peak intensity. [Figure 7] DSC diagram of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) free base, where X is temperature (0° C.) and Y is heat flow (W / G). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] The present invention will now be further described in conjunction with examples, which are not intended to limit the scope of the present invention.

[0077] 1. Preparation of compounds Compound A (R)-(3-(benzo[d]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone [ka]

[0078] Step 1: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine [ka] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one (0.20 g, 0.38 mmol) was dissolved in dichloroethane (1 mL), cooled to 0° C., triethyloxonium tetrafluoroborate (4.5 mL, 4.5 mmol) was added, the reaction was stirred at room temperature for 3 h, water (10 mL) was added, stirred for 30 min, a solid precipitated, filtered, the aqueous phase was extracted with dichloromethane (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.2 g), which was used directly in the next step. MS m / z(ESI):293.2[M+H] + .

[0079] Step 2: Preparation of benzo[d]thiazole-2-formohydrazide [ka] Benzo[d]thiazole-2-carboxylic acid ethyl ester (300 mg, 1.45 mmol) was dissolved in absolute ethanol (10 mL), 85% hydrazine hydrate (102 mg, 1.74 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was filtered and dried to obtain benzo[d]thiazole-2-formohydrazide (270 mg, yield: 96%). MS m / z(ESI):194.2[M+H] + .

[0080] Step 3: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole [ka] (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (200 mg, 0.68 mmol) was dissolved in ethanol (10 mL), benzo[d]thiazole-2-formohydrazide (120 mg, 0.62 mmol) was added, and the reaction was stirred overnight at 80 °C. The reaction solution was spun to dryness, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1 to 1 / 2) to give (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole (100 mg, yield: 38%). MS m / z(ESI):422.2[M+H] + .

[0081] Step 4: Preparation of (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole [ka] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole (100 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the reaction was stirred at room temperature for 1 h, TLC showed complete reaction. Water (10 mL) was added, stirred for 5 min, filtered, and then 3 M sodium hydroxide solution was added to the filtrate until the pH of the aqueous phase was >14. Extraction with dichloromethane (10 mL×3) was performed, and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole (40 mg, yield: 62%). MS m / z(ESI):272.2[M+H] + .

[0082] Step 5: Preparation of (R)-(3-(benzo[d]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone [ka] (R)-2-(8-Methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole (40 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (23 mg, 0.23 mmol) was added followed by 4-fluorobenzoyl chloride (28 mg, 0.18 mmol) and the reaction was stirred at room temperature for 1 h. Water (10 mL) was added and washed, and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain (R)-(3-(benzo[d]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (25 mg, yield: 42%).

[0083] MS m / z(ESI):394.2[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 8.06(d,J=8.1Hz,1H),7.98(d,J=7.9Hz,1H),7.57-7.45(m,4H),7.27-7.16(m,2H),5.78(br s,1H),5.12(d,J=14.6Hz,1H),4.84-4.55(m,1H),4.42-4.35(m,1H),3.60-3.54(m,1H),1.77(d,J=6.9Hz,3H).

[0084] compound 1 (R)-(4-Fluorophenyl-2,3,5,6-d4)(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone [ka] For the preparation of compound 1, see Step 5 of compound A.

[0085] MS m / z(ESI):366.1[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 5.97-5.56(m,1H),5.11-4.79(m,1H),4.73-4.147(m,1H),4.41-4.12(m,1H),3.73-3.37(m,1H),1.90-1.69(m,3H).

[0086] compound 2 (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone [ka]

[0087] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole [ka] Bistriphenylphosphinepalladium dichloride (1.13g, 1.61mmol) was added to 3,5-dichloro-1,2,4-thiadiazole (5g, 32.26mmol) and tributyl(1-ethoxyvinyl)tin (10.48g, 29.03mmol) in anhydrous DMF (20ml), and the reaction solution was heated to 75℃ under nitrogen gas protection for 14 hours. The reaction solution was cooled, quenched with potassium fluoride aqueous solution (50ml), filtered to remove solids, the liquid phase was extracted with ethyl acetate (75ml*2), the organic phase was washed with saturated saline (20ml*6), the organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was separated by column (petroleum ether:ethyl acetate=99:1) to obtain the product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3g, yield: 70%).

[0088] 1H NMR(400MHz,Chloroform-d)δ 5.52(d,J=3.1Hz,1H),4.58(d,J=3.1Hz,1H),4.02(q,J=7.0Hz,2H),1.43(t,J=7.0Hz,3H).

[0089] Step 2: 3-Chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester [ka] A solution of sodium periodate (8.30 g, 38.81 mmol) in water (35 ml) was added to a solution of 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) in dioxane (70 ml), and the reaction mixture was stirred for 2 minutes. Potassium permanganate (460.05 mg, 2.91 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed successively with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 95:5) to obtain the desired product, 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (1 g, yield, 27.03%).

[0090] 1 H NMR(400MHz,Chloroform-d)δ 4.54(q,J=7.1Hz,2H),1.47(t,J=7.2Hz,3H).

[0091] Step 3: 3-Chloro-1,2,4-thiadiazole-5-formohydrazide [ka] Hydrazine hydrate (229 mg, 3.89 mmol, 85% in water) was added to a solution of 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) in ethanol (10 ml), and the reaction was stirred at room temperature for 1 h, then filtered to give the solid product 3-chloro-1,2,4-thiadiazole-5-formohydrazide (440 mg, yield, 95%). MS m / z(ESI):179.0[M+H] + .

[0092] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine [ka] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methyl-piperazin-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL) and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three batches at 10 min intervals at 0° C. The mixture was stirred at 25° C. and reacted for 3 h. The reaction solution was added to a cold aqueous solution of sodium hydroxide solution (2 M, 10 ml), the mixture was separated, the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The desired product (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g) was obtained as a colorless oil. The crude product was used directly in the next step. MS m / z(ESI):293.2[M+H] + .

[0093] Step 5: 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole [ka] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 3-chloro-1,2,4-thiadiazole-5-formohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (10 mL), and the mixture was stirred at 80° C. under nitrogen gas protection for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (eluted with dichloromethane:methanol = 100:0 to 95:5) to obtain the desired product 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole (0.22 g, yield, 23.95%) as a pale yellow solid. MS m / z(ESI):406.8[M+H] + .

[0094] Step 6: 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole [ka]

[0095] 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole (0.22 g, 540.69 μmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25° C. and reacted for 1 hour. The reaction solution was evaporated to dryness under reduced pressure and water (7 ml) was added and the mixture was stirred at room temperature for 10 minutes before filtering to remove solids. The liquid phase was freeze-dried to give the product 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.2 g, yield, 99.77%). MS m / z(ESI):257.0[M+H] + .

[0096] Step 7: 4-Fluoro-2,3,5,6-d4 benzoic acid [ka] Under the protection of nitrogen gas, 10% Pd / C (0.73 g, containing 50% w / w water) was added to a solution of p-fluorobenzoic acid (1.8 g, 12.9 mmol) in isopropanol (50 mL) and deuterated water (100 mL), and the reaction solution was stirred at 100°C for 3 days. The reaction solution was cooled, extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product 4-fluoro-2,3,5,6-d4 benzoic acid (1.5 g, yield: 81%) was obtained. MS m / z(ESI):143.0[MH] -

[0097] Step 8: (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone [ka] 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32 mg, 84 μmol) was added to a solution of 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole trifluoroacetate (20 mg, 56 μmol), 4-fluoro-2,3,5,6-d4 benzoic acid (10 mg, 68 μmol) and N,N-diisopropylethylamine (22 mg, 169 μmol) in N,N-dimethylformamide (1.5 mL), and the reaction was stirred at room temperature for 16 hours. The crude was directly separated by Prep-HPLC to give the product (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone (10 mg, yield: 46%).

[0098] MS m / z(ESI):383.1[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 5.97-5.68(m,1H),4.94-4.81(m,1H),4.74-4.39(m,1H),4.37-4.20(m,1H),3.64-3.46(m,1H),1.76(d,J=6.8Hz,3H).

[0099] compound 3 (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone [ka]

[0100] Synthesis of intermediate 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole: Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole [ka] Bistriphenylphosphinepalladium dichloride (1.13g, 1.61mmol) was added to 3,5-dichloro-1,2,4-thiadiazole (5g, 32.26mmol) and tributyl(1-ethoxyvinyl)tin (10.48g, 29.03mmol) in anhydrous DMF (20ml), and the reaction solution was heated to 75℃ under nitrogen gas protection for 14 hours. The reaction solution was cooled, quenched with potassium fluoride aqueous solution (50ml), filtered to remove solids, the liquid phase was extracted with ethyl acetate (75ml*2), the organic phase was washed with saturated saline (20ml*6), the organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was separated by column (petroleum ether:ethyl acetate=99:1) to obtain the product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3g, yield: 70%).

[0101] 1 H NMR(400MHz,Chloroform-d)δ 5.52(d,J=3.1Hz,1H),4.58(d,J=3.1Hz,1H),4.02(q,J=7.0Hz,2H),1.43(t,J=7.0Hz,3H).

[0102] Step 2: 3-Chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester [ka] A solution of sodium periodate (8.30 g, 38.81 mmol) in water (35 ml) was added to a solution of 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) in dioxane (70 ml), and the reaction mixture was stirred for 2 minutes. Potassium permanganate (460.05 mg, 2.91 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed successively with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 95:5) to obtain the desired product, 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (1 g, yield, 27.03%).

[0103] 1 H NMR(400MHz,Chloroform-d)δ 4.54(q,J=7.1Hz,2H),1.47(t,J=7.2Hz,3H).

[0104] Step 3: 3-Chloro-1,2,4-thiadiazole-5-formohydrazide [ka] Hydrazine hydrate (229 mg, 3.89 mmol, 85% in water) was added to a solution of 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) in ethanol (10 ml), and the reaction was stirred at room temperature for 1 h, then filtered to give the solid product 3-chloro-1,2,4-thiadiazole-5-formohydrazide (440 mg, yield, 95%). MS m / z(ESI):179.0[M+H] + .

[0105] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine [ka] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methyl-piperazin-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL) and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three batches at 10 min intervals at 0° C. The mixture was stirred at 25° C. and reacted for 3 h. The reaction solution was added to a cold aqueous solution of sodium hydroxide solution (2 M, 10 ml), the mixture was separated, the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The desired product (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g) was obtained as a colorless oil. The crude product was used directly in the next step. MS m / z(ESI):293.2[M+H] + .

[0106] Step 5: 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole [ka] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 3-chloro-1,2,4-thiadiazole-5-formohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (10 mL), and the mixture was stirred at 80° C. under nitrogen gas protection and reacted for 14 hr. The reaction solution was concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (eluted with dichloromethane:methanol = 100:0 to 95:5) to obtain the desired product 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole (0.22 g, yield, 23.95%) as a pale yellow solid. MS m / z(ESI):406.8[M+H] + .

[0107] Step 6: 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole [ka] 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole (0.22 g, 540.69 μmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25° C. and reacted for 1 hour. The reaction solution was evaporated to dryness under reduced pressure and water (7 ml) was added and the mixture was stirred at room temperature for 10 minutes before filtering to remove solids. The liquid phase was lyophilized to give the product 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.2 g, yield, 99.77%). MS m / z(ESI):257.0[M+H] + .

[0108] Synthesis of intermediate 3-deutero-4-fluoro-benzoyl chloride: Step 1: Preparation of 3-deutero-4-fluoro-benzoic acid [ka] 3-Bromo-4-fluorobenzoic acid (5 g, 22.83 mmol) was dissolved in deuterated sodium hydroxide solution (30 mL, 2 M in DO) and zinc powder (5.97 g, 91.32 mmol) was added. The mixture was stirred at 25° C. and reacted for 24 hours. The reaction solution was filtered to remove solids, and the aqueous phase was adjusted to pH=1 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 3-deuterated-4-fluoro-benzoic acid (3 g, yield: 93.12%). MS m / z(ESI):139.8[MH] -

[0109] Step 2: Preparation of 3-deutero-4-fluoro-benzoyl chloride [ka] 3-Deuterium-4-fluoro-benzoic acid (200 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (359.77 mg, 2.83 mmol) was added, followed by N,N-dimethylformamide (0.05 mL), and the mixture was stirred at 25° C. and reacted for 2 hours. The reaction solution was concentrated under reduced pressure. The residue 3-deuterium-4-fluoro-benzoyl chloride (0.22 g) was used directly in the next step.

[0110] Synthesis of the target product (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone: [ka] 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.35 g, 0.94 mmol) and triethylamine (286.59 mg, 2.83 mmol) were dissolved in dichloromethane (5 mL) and 3-deuterium-4-fluoro-benzoyl chloride (210.89 mg, 1.32 mmol) was added. The mixture was stirred at 25° C. and reacted for 20 minutes. The reaction was quenched by adding saturated saline (5 mL) to the reaction solution, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography to obtain the product (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone (66 mg, 172.03 μmol, yield: 18.22%) as a white solid.

[0111] MS m / z(ESI):379.8[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 7.58-7.40(m,2H),7.22-7.10(m,1H),5.99-5.61(m,1H),5.01-4.80(m,1H), 4.80-4.43(m,1H),4.38-4.16(m,1H),3.68-3.45(m,1H),1.88-1.68(m,3H).

[0112] compound 4 (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-chlorophenyl-3-d)methanone [ka]

[0113] Step 1: Preparation of 3-deutero-4-chloro-benzoic acid [ka] 3-Bromo-4-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in 2M NaOD / DO (15 mL) solution, and zinc powder (5.55 g, 84.94 mmol) was added. The mixture was stirred at 25° C. and reacted for 96 hours. The reaction solution was filtered to remove solids, and the aqueous phase was adjusted to pH=1 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography to obtain the product 3-deuterium-4-chloro-benzoic acid (1.3 g, yield: 38.85%). MS m / z(ESI):156.0[MH] -

[0114] Step 2: Preparation of 3-deutero-4-chloro-benzoyl chloride [ka]

[0115] 3-Deuterium-4-chloro-benzoic acid (0.1 g, 634.63 μmol) was dissolved in DCM (5 mL), oxalyl chloride (161.10 mg, 1.27 mmol) was added, followed by DMF (0.05 mL), and the mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated under reduced pressure. The residue 3-deuterium-4-chloro-benzoyl chloride (110 mg) was obtained and used directly in the next step.

[0116] Step 3: For the preparation of compound 4, see compound 3. MS m / z(ESI):395.9[M+H] + . 1H NMR(400MHz,Chloroform-d)δ 7.51-7.44(m,1H),7.44-7.36(m,2H),6.12-5.57(m,1H),4.99-4.79(m,1H),4 .78-4.35(m,1H),4.35-4.15(m,1H),3.67-3.42(m,1H),1.76(d,J=6.9Hz,3H).

[0117] Example 5 (R)-(3-(3-fluoro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone [ka] For the preparation of compound 5, see compound 3. MS m / z(ESI):364.1[M+H] + .

[0118] compound 6 (R)-(3-(3-(3,3-difluoroazetidin-1-yl)-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone [ka]

[0119] Step 1: (R)-3-(3,3-difluoroazetidin-1-yl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole [ka] (R)-3-chloro-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole (75 mg, 184.33 μmol), 3,3-difluoroazetidine hydrochloride (238.77 mg, 1.84 mmol), N,N-diisopropylethylamine (476.46 mg, 3.69 mmol, 642.12 μL) were dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (180.17 mg, 552.98 μmol) was added. The mixture was reacted at 110° C. for 1 hour using a microwave. The reaction solution was concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (dichloromethane:methanol = 20:1) to obtain the target product (R)-3-(3,3-difluoroazetidin-1-yl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole (60 mg, 129.45 μmol, yield: 70.23%). MS m / z(ESI):464.2[M+H] + .

[0120] In the next step, reference was made to compound A to obtain (R)-(3-(3-(3,3-difluoroazetidin-1-yl)-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone. [ka] MS m / z(ESI):437.1[M+H] + . 1H NMR(400MHz,Chloroform-d)δ 7.55-7.41(m,2H),7.23-7.11(m,1H),5.97-5.51(m,1H),4.90-4.76(m,1H),4 .71-4.44(m,5H),4.35-4.12(m,1H),3.62-3.38(m,1H),1.75(d,J=6.9Hz,3H).

[0121] compound 7 (R)-(3-(3-(3-fluoroazetidin-1-yl)-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone [ka]

[0122] For the preparation of compound 7, see compound 6. MS m / z(ESI):419.1[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 7.58-7.39(m,2H),7.23-7.12(m,1H),5.92-5.62(m,1H),5.58 -5.33(m,1H),4.90-4.76(m,1H),4.72-4.03(m,6H),3.63-3.40(m,1H),1.75(d,J=6.9Hz,3H).

[0123] compound 9 (R)-(3-(3-(azetidin-1-yl)-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone [ka] For the preparation of compound 8, see compound 6.

[0124] MS m / z(ESI):401.1[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ 7.55-7.40(m,2H),7.23-7.12(m,1H),5.85-5.62(m,1H),4.91-4.78(m,1H),4.75-4.52(m,1H),4 .35-4.12(m,4H),3.74-3.59(m,1H),3.59-3.43(m,1H),2.54-2.38(m,2H),1.75(d,J=6.9Hz,3H).

[0125] Biological Test Evaluation The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0126] Test Example 1: Measurement of the effect of the compound of the present invention on calcium ion flux in cells stably expressing NK3 receptor Experimental Objective: The objective of this experiment is to measure the inhibitory effect of compounds on the NK3 receptor.

[0127] Experimental equipment: 384-well test plate (Corning; 3712), Pipette (Axygen), FLIPR (Molecular Devices).

[0128] Experimental Reagents: DMEM (Invitrogen; 11965), Fetal bovine serum (Biowest; S1810-500), Dialyzed serum (S-FBS-AU-065; Serana), Penicillin and streptomycin (Biowest; L0022-100), Hygromycin B (CABIOCHEM, 400052), Matrigel (BD; 354230), DMSO (Sigma; D2650), HBSS (Invitrogen; 14065), HEPES (Invitrogen; 15630080), Probenecid (Sigma; P8761), BSA (renview; FA016), Trypsin (HDB;0458).

[0129] Testing Method: 1. Preparation of buffer: 1 x HBSS, 20 mM HEPES, 2.5 mM probenecid (probenecid is 400 mM stock in 1 M NaOH), 0.1% BSA. On the day of the experiment, probenecid and BSA are freshly added. Experimental buffers include dye buffer and compound dilution buffer, etc.

[0130] 2. After digesting the cells with trypsin, 1 × 10 4 The cells were seeded into a 384-well test plate at a density of 10 cells / well and incubated for 16 to 24 hours (at least overnight).

[0131] 3. The culture medium was discarded, 20 μL of dye was added, and the cells were incubated at 37°C in the dark for 60 minutes, after which the calcium signal was read.

[0132] 4. Prepare antagonists before the experiment, add 5μL / well of 5x concentration of antagonist compound to 384-well test plate, incubate 15min at room temperature protected from light, transfer test plate to FLIPR, add 5μL / well of 6x concentration of agonist compound, read values ​​using FLIPR, save data, total assay volume is 30μL, including 20μL / well of dye buffer, 5μL / well of 5x concentration of experimental compound, and 5μL / well of 6x concentration of agonist compound.

[0133] How to process experimental data: Calcium signal values ​​were read by FLIPR, and the calculated output at each sampling time point during the experiment was the ratio of the 340 / 510 nm and 380 / 510 nm wavelength signals, with the maximum minus the minimum calculated from the ratio signal curve. Percent inhibition and the IC of compounds were calculated by fitting the 10-point concentration data to a parametric nonlinear equation using GraphPad prism. 50 values ​​were calculated.

[0134] Test Results: [Table 7]

[0135] Test conclusion: As can be seen from the data in the table, the compounds of formula I of the present invention exhibited good inhibitory activity in functional calcium flux experiments in cells stably expressing NK3.

[0136] Test Example 2: Measurement of the effect of the compounds of the present invention on calcium ion flux in cells stably expressing NK1 / NK2 receptors Experimental Objective: The objective of this experiment is to measure the inhibitory effect of compounds on the NK1 / NK2 receptors.

[0137] Experimental equipment: 384-well test plate (Corning; 3712), Pipette (Axygen), FLIPR (Molecular Devices).

[0138] Experimental Reagents: DMEM (Invitrogen; 11965), Fetal bovine serum (Biowest; S1810-500), Dialyzed serum (S-FBS-AU-065; Serana), Penicillin and streptomycin (Biowest; L0022-100), Hygromycin B (CABIOCHEM, 400052), Matrigel (BD; 354230), DMSO (Sigma; D2650), HBSS (Invitrogen; 14065), HEPES (Invitrogen; 15630080), Probenecid (Sigma; P8761), BSA (renview; FA016), Trypsin (HDB;0458).

[0139] Testing Method: 1. Preparation of buffer: 1xHBSS, 20mM HEPES, 2.5mM probenecid (probenecid is 400mM stock in 1M NaOH), 0.1% BSA. On the day of the experiment, probenecid and BSA were added freshly. Experimental buffers include dye buffer and compound dilution buffer.

[0140] 2. After digesting the cells with trypsin, 1 × 10 4 The cells were seeded into a 384-well test plate at a density of 10 cells / well and incubated for 16 to 24 hours (at least overnight).

[0141] 3. The culture medium was discarded, and 20 μL of dye was added. The cells were incubated at 37°C in the dark for 60 minutes, and calcium signals were read.

[0142] 4. Antagonists were prepared before the experiment. Antagonist pattern: 5 μL / well of 5x concentration of antagonist compound was added to 384-well-test plate and incubated at room temperature, protected from light, for 15 min. Test plate was transferred to FLIPR and 5 μL / well of 6x concentration of agonist compound was added. FLIPR was used to read and store data. Total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of 5x concentration of test compound, and 5 μL / well of 6x concentration of agonist compound.

[0143] How to process experimental data: Calcium signal values ​​were read by FLIPR. The calculated output at each sampling time point during the experiment was the ratio of 340 / 510 nm and 380 / 510 nm wavelength signals. A maximum minus minimum calculation was obtained from the ratio signal curve. Percent inhibition and ten-point concentration data were fitted to a parametric nonlinear logistic equation to calculate compound IC values ​​using GraphPad prism. 50 values ​​were calculated.

[0144] Test Results: The compounds of the present invention have the following effects on calcium ion flux in cells stably expressing NK1 / NK2 receptors: NK1R IC 50 (nM) value and NK2R IC 50 All (nM) values ​​were shown to be >10,000.

[0145] Test conclusion: The compounds of the present invention showed good selectivity in functional calcium flux assays in cells stably expressing NK3 and NK1 / NK2 cell receptors.

[0146] Test Example 3: Measurement of the effect of the compounds of the present invention on IP1 in cells stably expressing HEK293-NK3 1. Purpose of the experiment: The purpose of this example is to measure the antagonistic effect of compounds on HEK293-NK3 cell activity.

[0147] 2. Laboratory equipment and reagents: 2.1 Laboratory equipment and consumables: 384-well cell plate (Corning:3824), 384-well Echo Compound Plate (Labcyte: LP-0200), Bravo Tip (Agilent:10734-202), Plate reader EnVision Multilabel Reader (PE:2104-0010), Pipetting workstation Bravo (Agilent) and ECHO 550 (LABCYTE), Liquid pipette (Multidrop Combi).

[0148] 2.2 Experimental Reagents: DMEM, high glucose (Gibco:12100), Fetal bovine serum (Biosera:FB-1058 / 500), P / S(Biosera:XC-A4122), 5X Matrigel (Corning:354230), IP-ONE-Gq Kit (Cisbio:62IPAPEJ), Agonist Senktide (MCE:HY-P0187), Positive control compound Talnetant (MCE: HY-14552), Complete medium: DMEM + 10% FBS + 1X P / S, 1X Matrigel: Dilute 5X Matrigel in DMEM, Cell line: HDB HEK293-NK3, ​​Huiyuan Biotechnology (Shanghai) Co., Ltd.

[0149] 3. Experimental Method: 1. Coat a 150 mm culture dish with 1× Matrigel and incubate at room temperature for 10 minutes.

[0150] 2. Culture the HEK293-NK3 cell line in complete medium and seeded onto coated culture dishes at 37°C, 5% CO2 until it reached 70%-90% confluence.

[0151] 3. Preparation of positive control compounds and test compounds: 1) Using the Bravo instrument, dilute the compound concentration to 11 percent on a 384-well Echo compound plate (LABCYTE: LP-0200); 2) Then, using the instrument ECHO, 10 nL of compound (compound stock concentration, for example, highest concentration percent 10 mM) was transferred from each well to a 384-well-cell plate (Corning:3824) and waited at room temperature.

[0152] 4. The cells were digested and resuspended in 1X Stimulation Buffer (IP-ONE-Gq Kit), seeded into 384-well cell culture plates (previously containing the test compound) at 5,000 cells / well / 5μL using a Multidrop Combi, centrifuged at 300 rpm at room temperature for 60 seconds, and then incubated at 37℃, 5% CO2 for 15 minutes.

[0153] 5. Remove the cell culture plate from the CO2 incubator and incubate with 5 μL of 2X EC 80( (final concentration: 3 nM) was added, the mixture was centrifuged at room temperature at 300 rpm for 60 seconds, and then cultured at 37°C in 5% CO2 for 2 hours.

[0154] 6. Remove the cell culture plate from the CO2 incubator, add 5 μL of IP1 d2 reagent using the Multidrop Combi, add 5 μL of IP1 Tb Cryptate Antibody reagent, centrifuge at 300 rpm for 60 seconds at room temperature, and then leave at room temperature for 1 hour.

[0155] 7. The labels were read using an EnVision Multilabel Reader and the data was collected.

[0156] How to process experimental data: The ratio of the fluorescent signal values ​​was read and collected using an EnVision Multilabel Reader, and the data on the percentage of antagonism was calculated based on the readings of the low control (DMSO control) and high control (positive compound) experimental groups.

number

[0157] 4. Experimental Results: [Table 8]

[0158] 5. Test conclusion: As can be seen from the data in the table, the compounds of the present invention showed good antagonistic activity in the experiment of functional IP1 stably expressing NK3 cells.

[0159] Test Example 4: Pharmacokinetics measurement in SD rats 1. Research purpose: SD rats were used as test animals, and the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma and brain tissue) when orally administered at a dose of 5 mg / kg was examined.

[0160] 2. Experimental plan: 2.1 Experimental Chemicals: Compounds of the present invention examples are self-prepared.

[0161] 2.2 Experimental animals: [Table 9]

[0162] 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.

[0163] 2.4 Administration: SD rats, 21 per group, male, were administered po after overnight fasting, with a dose of 5 mg / kg and a dosing volume of 10 mL / kg.

[0164] 2.5 Sampling: Before and after administration, at 0, 0.5, 1, 2, 4, 8, and 24 hours, the rats were sacrificed with CO2, and 8 mL of blood was collected from the heart, placed in an EDTA-K2 test tube, and centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma and store at -80°C. Whole brain tissue was removed, weighed, placed in a 2 mL centrifuge tube, and stored at -80°C.

[0165] 2.6 Sample Processing: 1) 160 μL of acetonitrile was added to 40 μL of plasma sample to cause precipitation, and after mixing, the sample was centrifuged at 3500 × g for 5 to 20 minutes.

[0166] 2) 30 μL of plasma and brain homogenate samples were precipitated by adding 90 μL of acetonitrile containing an internal standard (100 ng / mL), mixed, and then centrifuged at 13,000 rpm for 8 minutes.

[0167] 3) Take 70μL of the treated supernatant solution, add 70μL of water, vortex and mix for 10 minutes, then take 20μL and perform LC / MS / MS to analyze the concentration of the test compound, the LC / MS / MS analysis instrument was AB Sciex API 4000 Qtrap.

[0168] 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: Liquid A is 0.1% formic acid aqueous solution, and Liquid B is acetonitrile ·Flow rate: 0.4mL / min The elution time was 0 to 4.0 minutes, and the eluent was as follows:

[0169] [Table 10]

[0170] 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 3 below:

[0171] [Table 11] NA: Not detected.

[0172] 4. Test conclusion: As can be seen from the results of the pharmacokinetic experiments in rats in the table, the compounds of the examples of the present invention exhibit good metabolic properties, and the exposure AUC and maximum blood concentration C max Both were good.

[0173] Test Example 5: Effect of the compound of the present invention on luteinizing hormone (LH) content in plasma of bilaterally ovariectomized (OVX) rats 1. Purpose of the experiment: The purpose of this example is to determine the effect of compounds on luteinizing hormone (LH) in bilaterally ovariectomized (OVX) rat plasma.

[0174] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: Balance (PR2202ZH / E, OHAUS), Centrifuge (5424R, Eppendorf), Microplate reader (BioTek Synergy H1), Plate washer (Thermo Scientific), Pipettes (Eppendorf & Rainin), Pure water equipment (Thermo Scientific),

[0175] 2.2 Experimental Reagents: CMCNa (30036365, Sinopharm Reagent), Tween 80 (30189828, Sinopharm Reagent), The Rat LH ELISA Kit (S-type) was purchased from Shibayagi, Japan, with the catalog number AKRLH-010S, and contains Assay buffer C, Sample dilution buffer G, Washing buffer, biotinylated anti-LHα antibody, HRP-conjugated streptavidin, and the color developer Chromogen (TMB).

[0176] 2.3 Experimental animals: Bilaterally ovariectomized SD rats, 10 weeks old, female, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The animals were kept in an SPF grade animal room with 5 SD rats per cage. The cages, bedding, food and water were sterilized at high temperature before use, and all animals had free access to food and water.

[0177] 3. Experimental Method: Group-dosing: 10-week-old female SD rats were used in the experiment 3 weeks after bilateral ovariectomy. Before the experiment, the SD rats were fasted overnight, and before administration, the SD rats were randomly grouped into groups of 3. Each administration group was orally administered with a different test compound, with a dose of 30 mg / kg and an administration volume of 10 mL / kg.

[0178] Sample collection: 0.2-0.3 mL of whole blood was collected from each group of SD rats before and after administration at 0, 0.5, 1, 2, 4, and 8 hours, placed in EDTA-K2 test tubes, homogenized by shaking up and down, centrifuged at 4℃, 5000 rpm for 5 min, and the plasma was separated and stored in an ultra-low temperature refrigerator (-80±10℃).

[0179] Sample detection: All reagents, samples and ELISA plate were moved to room temperature of 20-25℃, equilibrated for at least 30min, dissolved, vortexed, centrifuged and waited. Standard curve was made with Assay buffer C in the following order of concentrations: 10, 5, 2.5, 1.25, 0.625, 0.313, 0. Sample was diluted 2-fold with Sample dilution buffer G and left at room temperature for 10min. Next, the sample from the previous step was diluted 2.5-fold with Assay buffer C, left at room temperature and waited. 1x Washing buffer was added to the 96-well plate, and the plate was washed with 300μL / well, and repeated 4 times. According to the set standard curve wells and sample wells, 50μL of the corresponding standard and sample were added to each well, mixed evenly, the plate was sealed and incubated at 20-25℃ for 2h. 50μL of 1x biotinylated anti-LHα antibody was added to each well, mixed evenly, the plate was sealed, and incubated at 20-25℃ for 1h. 1x Washing buffer was added, the plate was washed with 300μL / well, and this was repeated 4 times. 50μL of the prepared 1x HRP-conjugated streptavidin was added to each well, mixed evenly, the plate was sealed, and incubated at 20-25℃ for 0.5h. 1x Washing buffer was added, the plate was washed with 300μL / well, and this was repeated 4 times. 50μL of chromogen (TMB) was added per well, mixed evenly, and incubated at 20-25℃ for 20min. 50μL of stop solution (1M H2SO4) was added per well, and mixed evenly. The OD value of each well was read by a microplate reader at a wavelength of 450nm.

[0180] 4. How to process the experimental data: Graphpad was used to generate standard curves and calculate sample concentrations. If dilutions were performed for sample detection, the final calculation required multiplying by the corresponding dilution factor to obtain the actual concentration of the sample.

[0181] 5. Experimental Results: [Table 12]

[0182] 6. Experimental conclusion: As can be seen from the data in the table, the compounds of the examples of the present invention can significantly reduce the LH content in the plasma of ovariectomized rats (OVX).

[0183] Test Example 6: Pharmacodynamic study of test compounds in Senktide-induced bilateral ovariectomized rat tail temperature model 1. Purpose of the experiment: The effect of test compounds on tail temperature in senktide-induced bilateral ovariectomized rats is evaluated.

[0184] 2. Laboratory equipment and reagents: 2.1 Equipment: Balance (BSA2202s-CW, Sartorius), Thermometer (BAT-10, Physitemp), Probe (SST-1, Physitemp), 2.2 Reagents Senktide (106128-89-6, MCE), NaCl (10019318, Sinopharm Reagent), DMSO (D2650-100ML, Sigma), CMCNa (30036365, Sinopharm Reagent), Tween 80 (30189828, Sinopharm Reagent).

[0185] 2.3 Experimental animals Bilaterally ovariectomized SD rats, 10 weeks old, female, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The animals were kept in an SPF grade animal room with 5 SD rats per cage. The cages, bedding, food and water were sterilized at high temperature before use, and all animals had free access to food and water.

[0186] 2.4 Test Compounds: Compounds of the present invention examples are self-prepared.

[0187] 3 Experimental Procedure: Ten-week-old female SD rats were allowed to recover for two weeks after bilateral ovariectomy, and then randomly divided into groups of eight animals each into a negative control group, a model group, and an administration group according to their body weight. The probe was fixed with medical tape to the dorsal side of the rat's tail, 1 to 2 cm away from the base of the tail.

[0188] The negative control group and the model group were orally administered with the solvent, and each administration group was orally administered with a different test compound, the dosage was 30 mg / Kg, and the administration volume was 10 mL / kg.

[0189] Thirty minutes after oral administration of the solvent or test compound, the negative control group was subcutaneously injected with physiological saline (injection volume 5 mL / kg), and the model group and each treatment group were subcutaneously injected with Senktide (injection volume 5 mL / kg) at a concentration of 0.2 mg / mL to induce symptoms such as hot flashes. Tail skin temperature (TST) was measured and recorded 0 minutes before injection, and was measured every 5 minutes after injection for a total of 75 minutes.

[0190] 4. Data processing: The tail temperature change value (ΔTST) at each time point relative to the zero point was calculated, and a ΔTST-time curve of the tail temperature change was created, and the area under the curve (AUC ΔTST ) was calculated.

number

number

[0191] 5. Experimental Results: [Table 13]

[0192] 6. Test conclusion: As can be seen from the data in the table, the compounds of the examples of the present invention can effectively suppress the hot flash symptoms induced by Senktide in ovariectomized rats.

[0193] II. Research into compound salts and their crystal forms 1. Terminology As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and dosage forms which, within the scope of sound medical judgment, are suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem complications, and are commensurate with a reasonable risk / benefit ratio.

[0194] The term "substantially pure" as used herein refers to, in some preferred embodiments of the invention, the crystalline structure of the compound of Formula I being in substantially pure form, having an HPLC purity or crystalline purity of substantially 90% or more, inclusive, preferably 95% or more, more preferably 98% or more, and most preferably 99.5% or more.

[0195] As used herein, "crystal form" or "crystal morph" refers to a crystal form that has the same chemical composition but different spatial arrangement of the molecules, atoms and / or ions that make up the crystal. Crystal forms, crystalline forms, have the same chemical composition but different packing and geometric arrangements, and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate and similar properties. Based on their temperature-stability relationship, two polymorphs may be monotropic or tautomeric. In a monotropic system, the relative stability between the two solid phases remains unchanged when the temperature is changed. Conversely, in a tautomeric system, there is a transition temperature at which the stability of the two phases switches ((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN:)-8247-0237).

[0196] The crystalline sample of the present invention may be provided in substantially pure phase homogeneity, meaning that there is a majority of a single crystalline structure and optionally a minor amount of one or more other crystalline structures. The presence of more than one crystalline structure of the present invention in a sample can be determined by techniques such as powder X-ray diffraction (XRPD) or solid-state nuclear magnetic resonance (SSNMR). For example, in a comparison of an experimentally measured XRPD pattern (observed) and a simulated XRPD pattern (calculated), the presence of additional peaks can indicate more than one crystalline structure in the sample. The simulated XRPD can be calculated from single crystal X-ray data (see Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196, April 1963; see also Yin. S., Scaringe, RP, DiMarco, J., Galella, M and Gougoutas, JZ, American Pharmaceutical Review. 2003.6.2.80). Preferably, the crystalline structure has a substantially pure phase homogeneity in which less than 10%, preferably less than 5%, and more preferably less than 2% of the total peak area in the experimentally measured XRPD pattern is produced by additional peaks not present in the simulated XRPD pattern. Most preferred are crystalline forms of the present invention having substantially pure phase homogeneity, with less than 1% of the total peak area in the experimentally measured XRPD pattern being produced by additional peaks not present in the simulated XRPD pattern.

[0197] The various crystalline structures of the present invention described herein can be distinguished from one another using various analytical techniques known to those skilled in the art, including, but not limited to, solid state nuclear magnetic resonance (SSNMR) spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA).

[0198] The crystalline structures of the present invention can be produced in a variety of ways, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state transformation from another phase, crystallization from supercritical fluids, and jet spray. Techniques for crystallization or recrystallization of the crystalline structures from solvent mixtures include, for example, solvent evaporation, lowering the temperature of the solvent mixture, seeding a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (stripping solvent) to the solvent mixture. Crystalline structures, including polymorphs, can be produced using high-throughput crystallization techniques.

[0199] Drug crystals, including polymorphs, and methods for the preparation and characterization of drug crystals are disclosed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd ed., SSCI, West Lafayette, Indiana, 1999.

[0200] Seed crystals may be added to any crystal form mixture to promote crystallization. As will be appreciated by those skilled in the art, seed crystals are used as a means to control the growth of a particular crystal form structure or to control the particle size distribution of the crystal form product. In contrast, as described in "Programmed cooling of batch crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377, the calculation of the amount of seed crystals required depends on the size of the available seed crystals and the required size of the average product particle. In general, small size varieties are required to effectively control the growth of crystals in the patch. Small size seed crystals can be generated by sieving, grinding or pulverizing larger crystals or by microcrystallization of the solution, and it should be noted that grinding or pulverizing crystals cannot cause any change in the crystallinity of the desired crystal structure (i.e., becoming amorphous or another polymorph).

[0201] Crystal structures equivalent to those disclosed or claimed in the present invention may exhibit similar, but not entirely identical, analytical properties within reasonable error ranges depending on testing conditions, purity, equipment, and other common variables known to those skilled in the art. However, as will be apparent to those skilled in the art, various modifications and variations can be made to the present invention without departing from the scope and spirit of the invention. Other embodiments of the present invention will be apparent to those skilled in the art upon consideration of the specification and practice of the invention disclosed herein. Applicants intend the specification and embodiments to be considered illustrative, rather than limiting in scope.

[0202] As used herein, the term "room temperature" or "RT" refers to a temperature between 20 and 25 0 C(68~77 0 F) refers to the ambient temperature.

[0203] 2. Experimental materials The reagents used in the examples of the present invention are commercially available industrial or analytical reagents, and the methods for synthesizing the compounds are prepared according to the methods in the following examples.

[0204] 3. Analysis method 3.1 X-ray powder diffraction Those skilled in the art will recognize that powder X-ray diffraction patterns may be obtained with measurement errors that depend on the measurement conditions used. In particular, it is generally known that the intensities in X-ray powder diffraction patterns may vary depending on the material conditions used. It should be further understood that the relative intensities may also vary depending on the experimental conditions, and accordingly, the exact intensities should not be taken into consideration. In addition, the measurement error of conventional powder X-ray powder diffraction angles is generally about 5% or less, and it should be understood that such measurement error degree belongs to the above diffraction angles. Therefore, it should be understood that the crystal structure of the present invention is not limited to a crystal structure that provides an X-ray powder diffraction pattern that is completely the same as the X-ray powder diffraction pattern shown in the drawings disclosed herein. Any crystal structure that provides a powder X-ray diffraction pattern that is substantially the same as that disclosed in the drawings is within the scope of the present invention. The ability to determine that the X-ray powder diffraction patterns are substantially the same is within the ability of a person skilled in the art. Calibrate with other appropriate standards known to those skilled in the art. However, the relative intensities may vary depending on the size and shape of the crystals.

[0205] The crystalline polymorphs of the compound of formula I are characterized by their X-ray powder diffraction patterns. Therefore, the X-ray powder diffraction patterns of the salts were collected on a Bruker D8 Advance X-ray powder diffractometer with a GADDS (general area diffraction detector system) CS working in reflection mode using Cu Kα radiation (1.54 Å). The tube voltage and current were set to collect and scan at 40 kV and 25 mA, respectively. The samples were scanned for 180 seconds in the 2θ range of 4.0° to 40°. The diffractometer was calibrated with a corundum standard for peak positions expressed in 2θ. All analyses were performed at room temperature, typically 20°C to 30°C. The data were collected and analyzed using DIFFRAC.COMMANDER. The diffractograms were analyzed with jade6 software. The preparation of XRPD samples was performed by placing the samples on a single crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure that the surface of the sample was flat and had an appropriate height. The sample holder was then placed in a Bruker XRPD instrument, and powder X-ray diffraction patterns were collected with the instrument parameters described above. Measurement differences associated with the results of such X-ray powder diffraction analyses were caused by a variety of factors, including (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (those errors that occur during the measurement of peak positions), and (e) material properties (e.g., preferably orientation errors). Calibration errors and sample height errors usually caused all peaks to shift in the same direction. In general, this calibration factor can make the measured peak positions match the expected peak positions and fall within the expected 2θ values ​​of ±0.2°.

[0206] The 2θ (°) values ​​and intensity values ​​(% of the maximum peak value) of each of the crystal polymorphs obtained in the examples of the present invention are shown in Tables 1 to 6.

[0207] 3.2. Differential scanning calorimetry Differential scanning calorimetry (DSC) experiments were performed on a NETZSCH DSC 214 polymer instrument. Samples (approximately 1-6 milligrams) were weighed onto aluminum disks, recorded to the nearest milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 40 milliliters per minute. o 10 in C o Data was collected at a heating rate of 1000 C / min. Endothermic peaks were plotted as they trended downwards. However, those skilled in the art will recognize that in DSC measurements, there is some variability in the onset and maximum temperatures measured, depending on the heating rate, crystal shape and purity, and other measurement parameters.

[0208] The specific examples and preparation examples provided below illustrate, by way of example, certain aspects of embodiments of the present invention, and the scope of the following examples is not intended to limit the scope of the present invention in any way.

[0209] Example 1 40 mg of the free base of compound 3 was weighed, added with 10 mL of methanol, and heated to 60° C. to dissolve, resulting in a substantially clear solution, filtered, stirred at room temperature overnight, filtered, and the solid was dried under vacuum at 50° C. for 24 h to obtain crystalline form A of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone free base.

[0210] The obtained crystalline form A of the free base of Compound 3 was analyzed by X-ray powder diffractometer (XRPD) and differential scanning calorimetry (DSC), respectively. The model number of the XRPD instrument used was BRUKER D8 ADVANCE, and the model number of the DSC instrument used was NETZSCH DSC 214 polymer. The parameters of the XRPD analysis method were as follows: Cu K-ray (40 kV, 25 mA), the scanning step size was 0.02° / S (2θ value), the scanning rate was 12° / min (2θ value), and the scanning range was 4°-40° (2θ value). The parameters of the DSC analysis method were as follows: the temperature range was 25°-300°, the scanning rate was 10° per minute, and the protective gas was nitrogen gas (flow rate 40 ml / min). The XRPD analysis diagram was as shown in FIG. 1, and the DSC analysis diagram was as shown in FIG. 7.

[0211] Example 2 100 mg of the crystalline form A of the free base of compound 3 was weighed, 2 mL of ethyl acetate was added thereto, and 1 mol / L of hydrochloric acid in methanol was added thereto in a molar ratio of 1:1.2 to make it cloudy, and the mixture was stirred at room temperature for 24 hours, and then filtered. The solid was vacuum dried overnight at 50° C. to obtain a hydrochloride solid of the compound, which has the XRPD diagram shown in FIG. 2.

[0212] Example 3 Weigh out 50mg of crystalline form A of compound 3 free base, add 400μL of tetrahydrofuran, add 1mol / L methanesulfonic acid methanol solution thereto with a molar ratio of 1:1.2, open the resulting clear liquid at room temperature to evaporate the solvent to obtain a gel, add 400μL of ethyl acetate thereto, stir at room temperature for 8 hours, and then filter. The resulting solid is vacuum dried at 50℃ for 24h to obtain compound methanesulfonic acid salt solid, which has the XRPD diagram shown in Figure 3 below.

[0213] Example 4 Weigh out 50mg of crystalline form A of compound 3 free base, add 400μL of tetrahydrofuran, add 1mol / L nitric acid in methanol at 1:1.2 molar ratio, open the resulting clear liquid at room temperature to evaporate the solvent and obtain a gel, add 400μL of ethyl acetate thereto, stir at room temperature for 8 hours, and then filter. The resulting solid is vacuum dried at 50℃ for 24h to obtain a nitrate solid of compound 3, which has the XRPD diagram shown in Figure 4 below.

[0214] Example 5 100 mg of the crystalline form A of the free base of compound 3 was weighed, 2 mL of ethyl acetate was added thereto, and 1 mol / L sulfuric acid in methanol was added thereto at a molar ratio of 1:1.2 to make it turbid, and the mixture was stirred at room temperature for 24 hours, and then filtered. The solid was vacuum dried overnight at 50° C. to obtain a sulfate solid of compound I, which has the XRPD diagram shown in FIG. 5.

[0215] Example 6 100 mg of the crystalline form A of the free base of compound 3 was weighed, 2 mL of ethyl acetate was added thereto, and 1 mol / L of hydrobromic acid in methanol was added thereto in a molar ratio of 1:1.2 to make it cloudy, and the mixture was stirred at room temperature for 24 hours, and then filtered. The solid was vacuum dried overnight at 50° C. to obtain a hydrobromide salt solid of the compound, which has the XRPD diagram shown in FIG. 6.

[0216] Example 7: Sample stability testing study of crystalline form A

[0217] The crystal form A of the free base of compound 3 of the present invention was used to prepare a sample, and the stability was examined for 5 days and 10 days under the conditions of 5000lx light irradiation, high temperature 60℃, high humidity 92.5%RH, and high temperature and humidity 50℃ 75%RH. The content was measured by HPLC external standard method, and the change of related substances was calculated by chromatographic peak area normalization method. The experimental results are shown in Table 7.

[0218] [Table 14]

[0219] Conclusion: After being left under light, high temperature and / or high humidity conditions for 10 days, the total amount of impurities and the amount of single impurities did not increase significantly, showing good stability.

[0220] Example 8: Experimental study of sample hygroscopicity of crystalline form A

[0221] The crystalline form A of the free base of Compound 3 was placed in saturated water vapor with different relative humidities to dynamically equilibrate the compound with the water vapor, and the weight increase rate of the compound due to moisture absorption after equilibration was calculated.

[0222] Conclusion: Form A of the free base absorbed moisture under RH 80% and its weight increased by about 0.2720%, showing slight hygroscopicity. The XRPD pattern of Form A of the free base did not change after two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, i.e., the crystal form was unchanged.

[0223] Finally, it should be explained that the above examples are merely used to explain the technical solution of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the best embodiment, those skilled in the art will understand that modifications or equivalent replacements may be made to the technical solution of the invention without departing from the spirit and scope of the technical solution of the present invention, and all of them are within the scope of the claims of the present invention.

Claims

1. A crystalline form or an acid salt of a compound represented by general formula (I), 【Chemistry 1】 Where: R １ is selected from hydrogen, deuterium or a halogen, preferably hydrogen, deuterium, fluorine, chlorine or bromine; R ２ is hydrogen, deuterium, halogen, C １－６ Alkyl group, C １－６ deuterated alkyl group, 3- to 6-membered heterocyclyl group, １－６ Alkyl group, C １－６ The deuterated alkyl and 3- to 6-membered heterocyclyl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen, preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, azetidinyl, tetrahydropyrrolyl, 【Chemistry 2】 and y is 0, 1, 2, 3, 4 or 5;

2. The specific structure of the compound is 【Chemistry 3】 2. The crystalline form or acid salt of claim 1, wherein

3. It is a crystalline form of the free base of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone, The powder X-ray diffraction pattern has a diffraction peak at 2θ of 9.3±0.2°, or a diffraction peak at 2θ of 10.0±0.2°, or a diffraction peak at 2θ of 12.0±0.2°, or a diffraction peak at 2θ of 12.8±0.2°, or a diffraction peak at 2θ of 16.8±0.2°, or a diffraction peak at 2θ of 18.6±0.2°, or a diffraction peak at 2θ of 19.2±0.2°, or a diffraction peak at 2θ of 19.8±0.2°, or a diffraction peak at 2θ of 20.2±0.2°, or a diffraction peak at 2θ of or a diffraction peak at 2θ of 21.8±0.2°, or a diffraction peak at 2θ of 22.5±0.2°, or a diffraction peak at 2θ of 22.8±0.2°, or a diffraction peak at 2θ of 24.2±0.2°, or a diffraction peak at 2θ of 25.4±0.2°, or a diffraction peak at 2θ of 27.5±0.2°, or a diffraction peak at 2θ of 27.8±0.2°, or a diffraction peak at 2θ of 28.9±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least diffraction peaks located at one or more of the positions where 2θ is 16.8±0.2°, 18.6±0.2°, 19.9±0.2° or 20.2±0.2°, preferably 2 to 4 of these positions, more preferably 3 to 4 positions, most preferably 4 positions, and optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2° or 22.5±0.2°, preferably 2, 3, 4 or 5 of these positions, for example ９．３±０．２°、１０．０±０．２°、１６．８±０．２°、１８．６±０．２°、 １０．０±０．２°、１２．０±０．２°、１６．８±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．８±０．２°、１６．８±０．２°、１８．６±０．２°、 １２．８±０．２°、２２．５±０．２°、１６．８±０．２°、１８．６±０．２°、 ９．３±０．２°、１０．０±０．２°、１８．６±０．２°、１９．８±０．２°、 １０．０±０．２°、１２．０±０．２°、１８．６±０．２°、１９．８±０．２°、 １２．０±０．２°、１２．８±０．２°、１８．６±０．２°、１９．８±０．２°、 １２．８±０．２°、２２．５±０．２°、１８．６±０．２°、１９．８±０．２°、 ９．３±０．２°、１０．０±０．２°、１９．８±０．２°、２０．２±０．２°、 １０．０±０．２°、１２．０±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．０±０．２°、１２．８±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．８１２．８±０．２°、２２．５±０．２°、１９．８±０．２°、２０．２±０．２°、 ９．３４±０．２°、１０．０±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、 １０．０±０．２°、１２．０±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、 １２．０±０．２°、１２．８±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、 １２．８±０．２°、２２．５±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、 ９．３４±０．２°、１０．０±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １０．０±０．２°、１２．０±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．０±０．２°、１２．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．８±０．２°、２２．５±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 ９．３±０．２°、１０．０±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １０．０±０．２°、１２．０±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．０±０．２°、１２．８±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．８±０．２°、２２．５±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 ９．３±０．２°、１０．０±０．２°、１２．０±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １０．０±０．２°、１２．０±０．２°、１２．８±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １２．０±０．２°、１２．８±０．２°、２２．５±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 ９．３±０．２°、１０．０±０．２°、１２．０±０．２°、１２．８±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 １０．０±０．２°、１２．０±０．２°、１２．８±０．２°、２２．５±０．２°、１６．８±０．２°、１８．６±０．２°、１９．８±０．２°、２０．２±０．２°、 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°, and 20.2±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2° or 28.9±0.2°, preferably at least any 2 to 4 or 5 to 6 of these positions, more preferably any 4 or 6 of these positions, for example １５．８±０．２°、２４．２±０．２°、２５．４±０．２°、２７．５±０．２°、 ２４．２±０．２°、２５．４±０．２°、２７．５±０．２°、２７．８±０．２°、 ２５．４±０．２°、２７．５±０．２°、２７．８±０．２°、２８．９±０．２°、 １５．８±０．２°、２４．２±０．２°、２７．５±０．２°、２７．８±０．２°、 １５．８±０．２°、２４．２±０．２°、２７．８±０．２°、２８．９±０．２°、 １５．８±０．２°、２４．２±０．２°、２５．４±０．２°、２８．９±０．２°、 15.8±0.2°, 24.2±0.2°, 25.4±0.2°, 27.5±0.2°, 27.8±0.2° or 28.9±0.2°; More preferably, the crystalline form according to claim 1 or 2, characterized in that its powder X-ray diffraction pattern is substantially as shown in Figure 1 and its DSC pattern is substantially as shown in Figure 7.

4. The acid in the acid salt is selected from inorganic acids or organic acids, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from 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, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl selected from sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric 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; 3. The acid salt according to claim 1 or 2, characterized in that it is preferably hydrochloric acid, methanesulfonic acid, nitric acid, sulfuric acid or hydrobromic acid.

5. The acid salt according to claim 4, characterized in that it is an acid salt of (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone, preferably in the crystalline form of the acid salt.

6. It is a crystalline form of the hydrochloride salt, the powder X-ray diffraction pattern of which has a diffraction peak at 8.3±0.2° 2θ, or a diffraction peak at 10.1±0.2° 2θ, or a diffraction peak at 15.0±0.2° 2θ, or a diffraction peak at 16.5±0.2° 2θ, or a diffraction peak at 16.0±0.2° 2θ, or a diffraction peak at 17.0±0.2° 2θ, or a diffraction peak at 17.7±0.2° 2θ, or a diffraction peak at 21.5±0.2° 2θ, or a diffraction peak at 22.0±0.2° 2θ, or a diffraction peak at 24.4±0.2° 2θ, or a diffraction peak at 24.7±0.2° 2θ, or a diffraction peak at 27.4±0.2° 2θ. or a diffraction peak at 2θ of 30.9±0.2°, or a diffraction peak at 2θ of 32.2±0.2°, preferably optionally at 2, 4, 6, 8 or 10 positions therein, preferably the powder X-ray diffraction pattern includes at least a diffraction peak located at one or more positions among positions where 2θ is 8.3±0.2°, 15.0±0.2°, or 16.5±0.2°, preferably including two of these, more preferably including three of these, and optionally further including a diffraction peak located at one or more positions among positions where 2θ is 10.11±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°, or 21.5±0.2°, preferably including two, three, four or five of these, for example ８．３±０．２°、１５．０±０．２°、１０．１±０．２°、１６．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１０．１±０．２°、１７．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１０．１±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１０．１±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．０±０．２°、１７．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．０±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１７．０±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１７．０±０．２°、２１．５±０．２°、 ８．３±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．０±０．２°、 ８．３±０．２°、１６．５±０．２°、１０．１±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１６．５±０．２°、１０．１±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、２１．５±０．２°、 ８．３±０．２°、１６．５±０．２°、１６．０±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１６．５±０．２°、１６．０±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１６．５±０．２°、１７．０±０．２°、１７．７±０．２°、２１．５±０．２°、 １５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．０±０．２°、 １５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．０±０．２°、１７．７±０．２°、 １５．０±０．２°、１６．５±０．２°、１７．０±０．２°、１７．７±０．２°、２１．５±０．２°、 １５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．０±０．２°、１７．７±０．２°、 １５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．７±０．２°、２１．５±０．２°、 １５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．７±０．２°、 １５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、２１．５±０．２°、 １５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．０±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１７．０±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．７±０．２°、２１．５±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．０±０．２°、１７．７±０．２°、 ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１６．０±０．２°、１７．０±０．２°、１７．７±０．２°、２１．５±０．２°、 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2° or 21.5±0.2°, ８．３±０．２°、１５．０±０．２°、１６．５±０．２°、１０．１±０．２°、１６．０±０．２°、１７．７±０．２°、２１．５±０．２°、 8.3±0.2°, 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°, and 21.5±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, 30.2±0.2° or 32.2±0.2°, preferably at least any 2 to 4 or 5 to 6 of these positions, more preferably any 4 or 6 of these positions, for example ２４．４±０．２°、２４．７±０．２°、２５．２±０．２°、２７．４±０．２°、 ２４．４±０．２°、２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、 ２４．４±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、 ２４．４±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．７±０．２°、２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、 ２４．７±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、 ２４．７±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、 ２５．２±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、２７．４±０．２°、２８．５±０．２°、 ２４．４±０．２°、２４．７±０．２°、２８．５±０．２°、３０．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、 ２４．７±０．２°、２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２５．２±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、２７．４±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、２５．２±０．２°、２８．５±０．２°、３０．２±０．２°、３２．２±０．２°、 ２４．４±０．２°、２４．７±０．２°、２５．２±０．２°、２７．４±０．２°、３０．２±０．２°、３２．２±０．２°、 24.4±0.2°, 24.7±0.2°, 25.2±0.2°, 27.4±0.2°, 28.5±0.2°, and 32.2±0.2°, More preferably, the crystalline form of the acid salt according to claim 5 has an X-ray powder diffraction pattern substantially as shown in FIG.

7. It is a crystalline form of the methanesulfonate salt, and its powder X-ray diffraction pattern has a diffraction peak at 7.1±0.2° 2θ, or a diffraction peak at 10.1±0.2° 2θ, or a diffraction peak at 10.5±0.2° 2θ, or a diffraction peak at 12.0±0.2° 2θ, or a diffraction peak at 13.2±0.2° 2θ, or a diffraction peak at 16.9±0.2° 2θ, or a diffraction peak at 18.7±0.2° 2θ, or a diffraction peak at 21.1±0.2° 2θ, or a diffraction peak at 16.8±0.2° 2θ. or a diffraction peak at 2θ of 18.6±0.2°, or a diffraction peak at 2θ of 19.7±0.2°, or a diffraction peak at 2θ of 21.5±0.2°, or a diffraction peak at 2θ of 21.7±0.2°, or a diffraction peak at 2θ of 22.5±0.2°, or a diffraction peak at 2θ of 23.3±0.2°, or a diffraction peak at 2θ of 25.5±0.2°, or a diffraction peak at 2θ of 28.0±0.2°, preferably at any of 2, 4, 6, 8 or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least one or more of the diffraction peaks at 2θ of 7.1±0.2°, 10.1±0.2° or 10.5±0.2°, preferably two of these, more preferably three of these, and optionally further comprises one or more of the diffraction peaks at 2θ of 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2° or 21.1±0.2°, preferably two, three, four or five of these, e.g. ７．１±０．２°、１０．１±０．２°、１２．０±０．２°、１３．２±０．２°、 ７．１±０．２°、１０．１±０．２°、１３．２±０．２°、１６．９±０．２°、 ７．１±０．２°、１０．１±０．２°、１６．９±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１２．０±０．２°、１６．９±０．２°、 ７．１±０．２°、１０．１±０．２°、１２．０±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１２．０±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１３．２±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１３．２±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１６．９±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１３．２±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、１６．９±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１６．９±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１６．９±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１６．９±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１３．２±０．２°、１６．９±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、１６．９±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１６．９±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１６．９±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１３．２±０．２°、１６．９±０．２°、１８．７±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１３．２±０．２°、１６．９±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１６．９±０．２°、１８．７±０．２°、２１．１±０．２°、 ７．１±０．２°、１０．１±０．２°、１０．５±０．２°、１２．０±０．２°、１３．２±０．２°、１８．７±０．２°、２１．１±０．２°、 7.1±0.2°, 10.1±0.2°, 10.5±0.2°, 12.0±0.2°, 13.2±0.2°, 16.9±0.2°, 18.7±0.2°, and 21.1±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 23.3±0.2°, 25.5±0.2° or 28.0±0.2°, preferably comprising at least any 2 to 4, or 5 to 6, or 7 to 9, of these positions, more preferably any 4, 6, or 8, of these positions, for example １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、 １９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、 ２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 ２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 ２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、 １６．８±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、 １６．８±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、２１．５±０．２°、２１．７±０．２°、 １６．８±０．２°、１８．６±０．２°、２１．７±０．２°、２２．５±０．２°、 １６．８±０．２°、１８．６±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．７±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２２．５±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２８．０±０．２°、 １８．６±０．２°、１９．７±０．２°、２１．７±０．２°、２２．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １８．６±０．２°、１９．７±０．２°、２３．３±０．２°、２５．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２５．５±０．２°、２８．０±０．２°、 １９．７±０．２°、２１．５±０．２°、２２．５±０．２°、２３．３±０．２°、 １９．７±０．２°、２１．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １９．７±０．２°、２１．５±０．２°、２５．５±０．２°、２８．０±０．２°、 ２１．５±０．２°、２１．７±０．２°、２３．３±０．２°、２５．５±０．２°、 ２１．５±０．２°、２１．７±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 ２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２２．５±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２３．３±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２５．５±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２８．０±０．２°、 １８．６±０．２°、１９．７±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １９．７±０．２°、２１．５±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、 １８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、２１．５±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．７±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２２．５±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 １６．８±０．２°、１８．６±０．２°、１９．７±０．２°、２１．５±０．２°、２１．７±０．２°、２３．３±０．２°、２５．５±０．２°、２８．０±０．２°、 16.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 21.7±0.2°, 22.5±0.2°, 25.5±0.2°, 28.0±0.2°, More preferably, the crystalline form of the acid salt according to claim 5 has an X-ray powder diffraction pattern substantially as shown in FIG.

8. It is a crystalline form of the nitrate salt, the powder X-ray diffraction pattern of which has a diffraction peak at 9.3±0.2° 2θ, or a diffraction peak at 11.9±0.2° 2θ, or a diffraction peak at 12.5±0.2° 2θ, or a diffraction peak at 14.3±0.2° 2θ, or a diffraction peak at 14.6±0.2° 2θ, or a diffraction peak at 16.2±0.2° 2θ, or a diffraction peak at 16.7±0.2° 2θ, or a diffraction peak at 17.9±0.2° 2θ. or a diffraction peak at 2θ of 18.7±0.2°, or a diffraction peak at 2θ of 22.9±0.2°, or a diffraction peak at 2θ of 25.1±0.2°, or a diffraction peak at 2θ of 25.9±0.2°, or a diffraction peak at 2θ of 26.6±0.2°, or a diffraction peak at 2θ of 28.2±0.2°, or a diffraction peak at 2θ of 28.6±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least one or more of the diffraction peaks at 2θ of 9.3±0.2°, 11.9±0.2° or 12.5±0.2°, preferably two of these, more preferably three of these, and optionally further comprises one or more of the diffraction peaks at 2θ of 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2° or 17.9±0.2°, preferably two, three, four or five of these, e.g. ９．３±０．２°、１１．９±０．２°、１４．３±０．２°、１４．６±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．６±０．２°、１６．２±０．２°、 ９．３±０．２°、１１．９±０．２°、１６．２±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．３±０．２°、１６．２±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．３±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．３±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．６±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１４．６±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１６．２±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１６．２±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１６．２±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１６．２±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１６．２±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、１６．２±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１６．２±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１６．２±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１６．２±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、１６．２±０．２°、１６．７±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．６±０．２°、１６．２±０．２°、１６．７±０．２°、１７．９±０．２°、 ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１６．２±０．２°、１６．７±０．２°、１７．９±０．２°、 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.7±0.2° or 17.9±0.2°, ９．３±０．２°、１１．９±０．２°、１２．５±０．２°、１４．３±０．２°、１４．６±０．２°、１６．２±０．２°、１７．９±０．２°、 9.3±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 14.6±0.2°, 16.2±0.2°, 16.7±0.2°, and 17.9±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.2±0.2° or 28.6±0.2°, preferably comprising at least any 2 to 4 or 5 to 7 of these positions, more preferably any 4 or 6 of these positions, for example １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２５．９±０．２°、 １８．７±０．２°、２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、 １８．７±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、 １８．７±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．９±０．２°、２６．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２６．６±０．２°、２８．２±０．２°、 １８．７±０．２°、２２．９±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２６．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２８．２±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２８．６±０．２°、 ２２．９±０．２°、２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、 ２２．９±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、 ２２．９±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 ２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、 ２５．１±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 ２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、 ２２．９±０．２°、２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２５．１±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．９±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２６．６±０．２°、２８．２±０．２°、２８．６±０．２°、 １８．７±０．２°、２２．９±０．２°、２５．１±０．２°、２５．９±０．２°、２８．２±０．２°、２８．６±０．２°、 18.7±0.2°, 22.9±0.2°, 25.1±0.2°, 25.9±0.2°, 26.6±0.2°, 28.6±0.2°, More preferably, the crystalline form of the acid salt according to claim 5, characterized in that its powder X-ray diffraction pattern is substantially as shown in Figure 4.

9. It is a crystalline form of the Sulfate Salt, the powder X-ray diffraction pattern of which has a diffraction peak at 7.1±0.2° 2θ, or a diffraction peak at 13.4±0.2° 2θ, or a diffraction peak at 14.2±0.2° 2θ, or a diffraction peak at 15.5±0.2° 2θ, or a diffraction peak at 16.3±0.2° 2θ, or a diffraction peak at 17.4±0.2° 2θ, or a diffraction peak at 17.7° 2θ, or a diffraction peak at 18.0±0.2° 2θ, or a diffraction peak at 19.8±0.2° 2θ, or a diffraction peak at 20.1±0.2° 2θ, preferably at any of 2, 4, 6, 8 or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least one or more of the diffraction peaks at 2θ of 7.1±0.2°, 16.3±0.2° or 18.0±0.2°, preferably two of these, more preferably three of these, and optionally further comprises one or more of the diffraction peaks at 2θ of 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 17.4±0.2° or 17.7±0.2°, preferably two, three, four or five of these, e.g. ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１５．５±０．２°、 ７．１±０．２°、１６．３±０．２°、１５．５±０．２°、１７．４±０．２°、 ７．１±０．２°、１６．３±０．２°、１７．４±０．２°、１７．７±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１５．５±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１７．４±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１７．７±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１７．４±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１７．７±０．２°、 ７．１±０．２°、１６．３±０．２°、１５．５±０．２°、１７．７±０．２°、 ７．１±０．２°、１３．４±０．２°、１４．２±０．２°、１８．０±０．２°、 ７．１±０．２°、１４．２±０．２°、１５．５±０．２°、１８．０±０．２°、 ７．１±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１３．４±０．２°、１５．５±０．２°、１８．０±０．２°、 ７．１±０．２°、１３．４±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１３．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１４．２±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１４．２±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 １６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１８．０±０．２°、 １６．３±０．２°、１４．２±０．２°、１５．５±０．２°、１８．０±０．２°、 １６．３±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 １６．３±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 １６．３±０．２°、１３．４±０．２°、１５．５±０．２°、１８．０±０．２°、 １６．３±０．２°、１３．４±０．２°、１７．４±０．２°、１８．０±０．２°、 １６．３±０．２°、１３．４±０．２°、１７．７±０．２°、１８．０±０．２°、 １６．３±０．２°、１４．２±０．２°、１７．４±０．２°、１８．０±０．２°、 １６．３±０．２°、１４．２±０．２°、１７．７±０．２°、１８．０±０．２°、 １６．３±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１５．５±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１５．５±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１５．５±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１５．５±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１５．５±０．２°、１７．４±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１４．２±０．２°、１５．５±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１５．５±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１７．４±０．２°、１７．７±０．２°、１８．０±０．２°、 ７．１±０．２°、１６．３±０．２°、１３．４±０．２°、１４．２±０．２°、１５．５±０．２°、１７．７±０．２°、１８．０±０．２°、 7.1±0.2°, 13.4±0.2°, 14.2±0.2°, 15.5±0.2°, 16.3±0.2°, 17.4±0.2°, 17.7±0.2°, and 18.0±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 19.8±0.2°, 20.1±0.2°, 21.0±0.2°, 21.2±0.2°, 22.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2° or 28.6±0.2°, preferably comprising at least any 2 to 4 or 5 to 7 of these positions, more preferably any 4 or 6 of these positions, for example １９．８±０．２°、２０．１±０．２°、２１．０±０．２°、２１．２±０．２°、 ２０．１±０．２°、２１．０±０．２°、２１．２±０．２°、２２．６±０．２°、 ２１．０±０．２°、２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、 ２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、 ２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、２５．４±０．２°、 １９．８±０．２°、２０．１±０．２°、２１．０±０．２°、２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、 ２０．１±０．２°、２１．０±０．２°、２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、 ２１．０±０．２°、２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、２５．４±０．２°、 ２１．２±０．２°、２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、２５．４±０．２°、２６．１±０．２°、 ２２．６±０．２°、２４．０±０．２°、２４．８±０．２°、２５．４±０．２°、２６．１±０．２°、２７．９±０．２°、 24.0±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.9±0.2°, and 28.6±0.2°, More preferably, the crystalline form of the acid salt according to claim 5, characterized in that its powder X-ray diffraction pattern is substantially as shown in Figure 5.

10. It is a crystalline form of the hydrobromide salt, the powder X-ray diffraction pattern of which has a diffraction peak at 9.2±0.2 degrees 2θ, or a diffraction peak at 12.0±0.2 degrees 2θ, or a diffraction peak at 12.9±0.2 degrees 2θ, or a diffraction peak at 14.6±0.2 degrees 2θ, or a diffraction peak at 16.8±0.2 degrees 2θ, or a diffraction peak at 17.1±0.2 degrees 2θ, or a diffraction peak at 18.6±0.2 degrees 2θ, or a diffraction peak at 22.7±0.2 degrees 2θ, or a diffraction peak at 19.5±0.2 degrees 2θ, or a diffraction peak at 19.8±0.2 degrees 2θ. or a diffraction peak at 2θ of 20.2±0.2°, or a diffraction peak at 2θ of 22.5±0.2°, or a diffraction peak at 2θ of 25.4±0.2°, or a diffraction peak at 2θ of 26.4±0.2°, or a diffraction peak at 2θ of 27.5±0.2°, or a diffraction peak at 2θ of 27.8±0.2°, or a diffraction peak at 2θ of 28.9±0.2°, or a diffraction peak at 2θ of 29.3±0.2°, or a diffraction peak at 2θ of 32.3±0.2°, preferably at any of 2, 4, 6, 8, or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least one or more of the positions where 2θ is 9.2±0.2°, 12.0±0.2° or 12.9±0.2°, preferably two of these, more preferably three of these, and optionally further comprises one or more of the positions where 2θ is 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2° or 22.7±0.2°, preferably two, three, four or five of these, e.g. ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、１６．８±０．２°、 ９．２±０．２°、１２．０±０．２°、１６．８±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．０±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１６．８±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１６．８±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１７．１±０．２°、２２．７±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、 １２．０±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、 １２．０±０．２°、１２．９±０．２°、１７．１±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．９±０．２°、１８．６±０．２°、２２．７±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、２２．７±０．２°、 １２．０±０．２°、１２．９±０．２°、１６．８±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．９±０．２°、１６．８±０．２°、２２．７±０．２°、 １２．０±０．２°、１２．９±０．２°、１７．１±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、 ９．２±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．９±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．９±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．９±０．２°、１６．８±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．９±０．２°、１６．８±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．９±０．２°、１７．１±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．０±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１４．６±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．９±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、 １２．０±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、 １２．０±０．２°、１２．９±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 １２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１６．８±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１７．１±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１８．６±０．２°、２２．７±０．２°、 ９．２±０．２°、１２．０±０．２°、１２．９±０．２°、１４．６±０．２°、１６．８±０．２°、１７．１±０．２°、２２．７±０．２°、 9.2±0.2°, 12.0±0.2°, 12.9±0.2°, 14.6±0.2°, 16.8±0.2°, 17.1±0.2°, 18.6±0.2°, and 22.7±0.2°, More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more of the positions where 2θ is 19.5±0.2°, 19.8±0.2°, 20.2±0.2°, 22.5±0.2°, 25.4±0.2°, 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2° or 32.3±0.2°, preferably comprising at least any 2 to 4 or 5 to 7 of these positions, more preferably any 4 or 6 of these positions, for example １９．５±０．２°、１９．８±０．２°、２０．２±０．２°、２２．５±０．２°、 １９．８±０．２°、２０．２±０．２°、２２．５±０．２°、２５．４±０．２°、 ２０．２±０．２°、２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、 ２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、 ２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、２７．８±０．２°、 ２６．４±０．２°、２７．５±０．２°、２７．８±０．２°、２８．９±０．２°、 ２７．５±０．２°、２７．８±０．２°、２８．９±０．２°、２９．３±０．２°、 ２７．８±０．２°、２８．９±０．２°、２９．３±０．２°、３２．３±０．２°、 １９．５±０．２°、１９．８±０．２°、２０．２±０．２°、２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、 １９．８±０．２°、２０．２±０．２°、２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、 ２０．２±０．２°、２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、２７．８±０．２°、 ２２．５±０．２°、２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、２７．８±０．２°、２８．９±０．２°、 ２５．４±０．２°、２６．４±０．２°、２７．５±０．２°、２７．８±０．２°、２８．９±０．２°、２９．３±０．２°、 26.4±0.2°, 27.5±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, and 32.3±0.2°, More preferably, the crystalline form of the hydrobromide salt of the compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone has a powder X-ray diffraction pattern substantially as shown in FIG.

6. The crystalline form of an acid salt according to claim 5.

11. The acid salt or its crystal form according to any one of claims 4 to 10, wherein 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.

12. 12. The acid salt or a crystalline form thereof according to any one of claims 4 to 11, characterized in that the salt is a hydrate or anhydrous, and when the 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, and more preferably 0.5, 1, 2 or 3.

13. A method for producing the crystalline form according to any one of claims 1 to 3, comprising the steps of: a) Weigh out an appropriate amount of compound and dissolve it in an organic solvent to obtain a clear solution; b) Stirring, filtering and drying to obtain the desired product; wherein the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, or compositions thereof.

14. A method for producing the acid salt or a crystalline form thereof according to any one of claims 4 to 12, comprising the steps of: a) weighing an appropriate amount of a crystalline form of the free base of a compound and adding it to an organic solvent; b) weighing out an appropriate amount of acid, dissolving it in an organic solvent, stirring and filtering or dissolving and evaporating it to obtain a gel, adding a poor solvent to the gel, stirring and filtering, vacuum drying, and isolating to obtain the target product; Where: the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, or compositions thereof; the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, ethyl ether, or compositions thereof; The acid is selected from inorganic acids or organic acids, where the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from 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, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanoic ... 2-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric 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, preferably the acid is selected from hydrochloric acid, methanesulfonic acid, nitric acid, sulfuric acid or hydrobromic acid.

15. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form, acid salt or crystalline form thereof according to any one of claims 1 to 12, and a pharma- ceutically acceptable carrier.

16. 16. The crystalline form, acid salt or crystalline form thereof according to any one of claims 1 to 12, comprising a therapeutically effective amount of the crystalline form, acid salt or crystalline form thereof, said therapeutically effective amount comprising 0.0001-99%, 0.0001-95%, 0.0001-90%, 0.0001-85%, 0.0001-80%, 0.0001-75%, 0.0001-70%, 0.001-60%, 0.001-55%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10% or 0.01-5%.

17. 16. The use of the crystalline form, acid salt or crystalline form thereof according to any one of claims 1 to 12, and the pharmaceutical composition according to claim 15 in the manufacture of a medicament related to an NK3 inhibitor, preferably in the manufacture of a medicament for treating and / or preventing a psychotic disorder, a cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, an inflammatory disease, vomiting, pre-eclampsia, a respiratory tract-related disease, a reproductive disorder, a sex hormone-dependent disease or a gynecological disease-related disease, more preferably in the manufacture of a medicament for treating and / or preventing a disease related to menopausal syndrome, said menopausal syndrome including hot flashes, sweating, palpitations, dizziness and obesity symptoms.

Images