Acid salt or crystal form of pyridine derivative inhibitor and preparation method and application thereof

Abstract

The present application relates to a kind of acid salt or crystal form of nitrogen-containing and cyclic derivative inhibitor, and its preparation method and application.The salt of the inhibitor of the present application or its crystal form can be used as the treatment of depression, anxiety, schizophrenia and sex hormone-dependent diseases, and has wide application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to a crystal form of an NK3 inhibitor, an acid salt and a preparation method and application thereof. BACKGROUND

[0002] Neurokinin (NK) includes substance P (SP), neurokinin A and neurokinin B, and the corresponding three types of receptors are neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R) and neurokinin 3 receptor (NK3R). The three types of receptors are all G protein-coupled receptors, wherein 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 have been applied to the treatment of menopausal hot flashes, depression, schizophrenia and the like, and in particular, NK3R is closely related to menopausal hot flashes and the like symptoms of menopausal syndrome, and NK3R inhibitors have been proved to have a good effect on improving menopausal hot flashes.

[0003] Menopausal hot flashes refer to the symptoms of menopausal hot flashes and sweating that occur frequently in menopausal people, and are the prominent performance characteristics of menopausal syndrome. Menopausal hot flashes are caused by vasomotor dysfunction due to the decrease of estrogen level in the body. When the estrogen in the body decreases, the brain will mistakenly think that the body temperature is too high, so the brain will send a signal to the heart to pump more blood, and the sweat glands will release more sweat, accompanied by sweating, palpitations, dizziness and the like. More than three out of four women have menopausal hot flashes, and 80% of patients have this symptom for more than 1 year, and some can last for about 5 years after menopause. At present, the treatment for menopausal hot flashes mainly is hormone replacement therapy, but this therapy is easy to cause breast cancer, stroke, coronary heart disease, dementia and the like, and has a relatively large risk coefficient. Oral drugs, such as paroxetine (belonging to the SSRIs class of drugs, used for treating depression), are the only small-molecule drugs approved for the treatment of menopausal hot flashes, and also have the problem of side effects, and are only approved in the United States, so there is a need to develop safer and more effective menopausal syndrome treatment drugs in the clinic.

[0004] A series of NK3R inhibitors are disclosed in patent PCT / CN2021 / 109577, and the compounds have a good effect. The present application further studies the salt form and crystal form of the compound of formula I to meet the needs of clinical development of drugs, and the structure of formula (I) is as follows:

[0005] SUMMARY

[0006] 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, this invention has conducted a comprehensive study on the salt form and crystal form of the above-mentioned compounds.

[0007] This invention provides a crystal form of general formula (I), an acid salt thereof, or a salt thereof:

[0008]

[0009] in:

[0010] R1 is selected from hydrogen, deuterium, or halogen; preferably hydrogen, deuterium, fluorine, chlorine, or bromine;

[0011] R3 is selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl groups, 3-6 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 The deuterated alkyl group and 3-6-membered heterocyclic group are optionally further substituted with one or more substituents of deuterium and halogen; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, azacyclobutyl, tetrahydropyrrolyl.

[0012] y can be 0, 1, 2, 3, 4 or 5.

[0013] In a preferred embodiment of the present invention, the specific structure of the compound is as follows:

[0014]

[0015]

[0016] In a further preferred embodiment of the present invention, the crystal form, acid salt, or crystal form 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) ketone is described below:

[0017]

[0018] In certain embodiments of the present application, the acid salt of the compound of Formula I refers to a salt of the compound of Formula I with a pharmaceutically acceptable acid. In certain embodiments of the present application, it can be an acid addition salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like inorganic acids, and formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like organic acids. In certain embodiments of the present application, it can be an acid addition salt with benzoic acid, 10-camphorsulfonic acid, chlorochine, 1,2-ethanedisulfonic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, isethionic acid, lactobionic acid, lauryl sulfuric acid, methylsulfuric acid, 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, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, di(tert-butyl) naphthalene disulfonic 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, pyruvic acid, phthalamidic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, thiocyanic acid, undecylenic acid.

[0019] Further, in certain embodiments of the present application, the acid salt is selected from hydrochloride, methanesulfonate, nitrate, sulfate or hydrobromide.

[0020] In some embodiments of the present application, 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, free base form, has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 9.3 ± 0.2°, or 10.0 ± 0.2°, or 12.0 ± 0.2°, or 12.8 ± 0.2°, or 16.8 ± 0.2°, or 18.6 ± 0.2°, or 19.2 ± 0.2°, or 19.8 ± 0.2°, or 20.2 ± 0.2°, or 21.8 ± 0.2°, or 22.5 ± 0.2°, or 22.8 ± 0.2°, or 24.2 ± 0.2°, or 25.4 ± 0.2°, or 27.5 ± 0.2°, or 27.8 ± 0.2°, or 28.9 ± 0.2°; preferably, 2-4 peaks, more preferably, 3-4 peaks, most preferably, 4 peaks; optionally, further comprising one or more peaks at 2-theta = 9.3 ± 0.2°, or 10.0 ± 0.2°, or 12.0 ± 0.2°, or 12.8 ± 0.2°, or 16.8 ± 0.2°, or 18.6 ± 0.2°, or 19.2 ± 0.2°, or 19.8 ± 0.2°, or 20.2 ± 0.2°, or 21.8 ± 0.2°, or 22.5 ± 0.2°, or 22.8 ± 0.2°, or 24.2 ± 0.2°, or 25.4 ± 0.2°, or 27.5 ± 0.2°, or 27.8 ± 0.2°, or 28.9 ± 0.2°.

[0021] Further, in some embodiments of the present application, 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, free base form, has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 16.8 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2°, or 20.2 ± 0.2°; preferably, 2-4 peaks, more preferably, 3-4 peaks, most preferably, 4 peaks; optionally, further comprising one or more peaks at 2-theta = 9.3 ± 0.2°, or 10.0 ± 0.2°, or 12.0 ± 0.2°, or 12.8 ± 0.2°, or 22.5 ± 0.2°; preferably, 2, 3, 4, or 5 peaks.

[0022] Further, in certain embodiments of the present application, the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, free base form, has a powder X-ray diffraction pattern comprising at least the following peaks, in terms of diffraction angles (2Θ):

[0023] 9.3 ± 0.2°, 10.0 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0024] or 10.0 ± 0.2°, 12.0 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0025] or 12.0 ± 0.2°, 12.8 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0026] or 12.8 ± 0.2°, 22.5 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0027] or 9.3 ± 0.2°, 10.0 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2°;

[0028] or 10.0 ± 0.2°, 12.0 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2°;

[0029] or 12.0 ± 0.2°, 12.8 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2°;

[0030] or 12.8 ± 0.2°, 22.5 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2°;

[0031] or 9.3 ± 0.2°, 10.0 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°;

[0032] or 10.0 ± 0.2°, 12.0 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°;

[0033] or 12.0 ± 0.2°, 12.8 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°;

[0034] or 12.8 ± 0.2°, 22.5 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°;

[0035] or 9.3 ±0.2°, 10.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°;

[0036] or 10.0±0.2°, 12.0±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°;

[0037] or 12.0±0.2°, 12.8±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°;

[0038] or 12.8±0.2°, 22.5±0.2°, 16.8±0.2°, 18.6±0.2°, 19.8±0.2°;

[0039] or 9.3 ±0.2°, 10.0±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°;

[0040] or 10.0±0.2°, 12.0±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°;

[0041] or 12.0±0.2°, 12.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°;

[0042] or 12.8±0.2°, 22.5±0.2°, 18.6±0.2°, 19.8±0.2°, 20.2±0.2°;

[0043] 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°;

[0044] 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°;

[0045] 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°;

[0046] 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°;

[0047] 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°;

[0048] 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°;

[0049] 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°;

[0050] 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°;

[0051] 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°;

[0052] 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°.

[0053] Further, in certain embodiments of the application, the free base crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern optionally further comprising one or more of diffraction peaks at 2-theta = 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 2-4 thereof, or 5-6 thereof, further preferably, any 4 or 6 thereof;

[0054] Further, in certain embodiments of the application, the free base crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ) of:

[0055] 15.8 ± 0.2°, 24.2 ± 0.2°, 25.4 ± 0.2°, 27.5 ± 0.2°;

[0056] or 24.2 ± 0.2°, 25.4 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°;

[0057] or 25.4 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°, 28.9 ± 0.2°;

[0058] or 15.8 ± 0.2°, 24.2 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°;

[0059] or 15.8 ± 0.2°, 24.2 ± 0.2°, 27.8 ± 0.2°, 28.9 ± 0.2°;

[0060] or 15.8 ± 0.2°, 24.2 ± 0.2°, 25.4 ± 0.2°, 28.9 ± 0.2°;

[0061] 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°.

[0062] Further, in certain embodiments of the application, the free base crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ) of:

[0063] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone further comprises peaks at diffraction angles (2 theta) of 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°.

[0064] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone further comprises peaks at diffraction angles (2 theta) of 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°.

[0065] Table 1

[0066]

[0067]

[0068] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone further comprises peaks at diffraction angles (2 theta) of 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°. Figure 1 Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone further comprises peaks at diffraction angles (2 theta) of 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°. Figure 7

[0069] ​In some embodiments of the present application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 8.3 ± 0.2°, 10.1 ± 0.2°, 15.0 ± 0.2°, 16.0 ± 0.2°, 16.5 ± 0.2°, 17.0 ± 0.2°, 17.7 ± 0.2°, 21.5 ± 0.2°, 22.0 ± 0.2°, 24.4 ± 0.2°, 24.7 ± 0.2°, 27.4 ± 0.2°, 30.9 ± 0.2°, or 32.2 ± 0.2°; preferably, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks are included.

[0070] Further, in some embodiments of the present application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 8.3 ± 0.2°, 15.0 ± 0.2°, or 16.5 ± 0.2°; preferably, 2 peaks are included, more preferably, 3 peaks are included; optionally, further, one or more peaks at 2-theta = 10.1 ± 0.2°, 16.0 ± 0.2°, 17.0 ± 0.2°, 17.7 ± 0.2°, or 21.5 ± 0.2°; preferably, 2, 3, 4, or 5 peaks are included;

[0071] Further, in some embodiments of the present application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 8.3 ± 0.2°, 15.0 ± 0.2°, 10.1 ± 0.2°, 16.0 ± 0.2°;

[0072] 8.3 ± 0.2°, 15.0 ± 0.2°, 10.1 ± 0.2°, 16.0 ± 0.2°;

[0073] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0074] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0075] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0076] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0077] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0078] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0079] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0080] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0081] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0082] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0083] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0084] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0085] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0086] or 8.3 ±0.2°, 15.0±0.2°, 10.1±0.2°, 17.0±0.2°;

[0087] or 8.3 ±0.2°, 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 21.5±0.2°;

[0088] or 8.3 ±0.2°, 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°;

[0089] or 8.3 ±0.2°, 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 21.5±0.2°;

[0090] or 8.3 ±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°,

[0091] or 8.3 ±0.2°, 16.5±0.2°, 10.1±0.2°, 17.0±0.2°, 17.7±0.2°;

[0092] or 8.3 ±0.2°, 16.5±0.2°, 10.1±0.2°, 17.7±0.2°, 21.5±0.2°;

[0093] or 8.3 ±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 21.5±0.2°;

[0094] or 8.3 ±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°;

[0095] or 8.3 ±0.2°, 16.5±0.2°, 16.0±0.2°, 17.7±0.2°, 21.5±0.2°;

[0096] or 8.3 ±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°;

[0097] or 15.0±0.2°, 16.5±0.2°, 10.1±0.2°, 16.0±0.2°, 17.0±0.2°;

[0098] or 15.0±0.2°, 16.5±0.2°, 16.0±0.2°, 17.0±0.2°, 17.7±0.2°;

[0099] or 15.0±0.2°, 16.5±0.2°, 17.0±0.2°, 17.7±0.2°, 21.5±0.2°;

[0100] 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°;

[0101] 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°;

[0102] 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°;

[0103] 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°;

[0104] 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°;

[0105] 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°;

[0106] 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°;

[0107] 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°;

[0108] 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°;

[0109] 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°;

[0110] 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°;

[0111] 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°;

[0112] 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°, 21.5 ± 0.2°.

[0113] 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°, 21.5 ± 0.2°.

[0114] 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°, 21.5 ± 0.2°.

[0115] 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°, 21.5 ± 0.2°.

[0116] Further, in certain embodiments of the application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks: at 2-theta = 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 2-4, or 5-6, of any of these peaks, and further preferably, 4 or 6 of any of these peaks;

[0117] Further, in certain embodiments of the application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks: at 2-theta = 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 2-4, or 5-6, of any of these peaks, and further preferably, 4 or 6 of any of these peaks;

[0118] 24.4 ± 0.2°, 24.7 ± 0.2°, 25.2 ± 0.2°, 27.4 ± 0.2°;

[0119] or 24.4 ± 0.2°, 25.2 ± 0.2°, 27.4 ± 0.2°, 28.5 ± 0.2°;

[0120] or 24.4 ± 0.2°, 27.4 ± 0.2°, 28.5 ± 0.2°, 30.2 ± 0.2°.

[0121] or 24.4+0.2°, 28.5+0.2°, 30.2+0.2°, 32.2+0.2°;

[0122] or 24.7+0.2°, 25.2+0.2°, 27.4+0.2°, 28.5+0.2°;

[0123] or 24.7+0.2°, 27.4+0.2°, 28.5+0.2°, 30.2+0.2°;

[0124] or 24.7+0.2°, 28.5+0.2°, 30.2+0.2°, 32.2+0.2°;

[0125] or 25.2+0.2°, 27.4+0.2°, 28.5+0.2°, 30.2+0.2°;

[0126] or 25.2+0.2°, 28.5+0.2°, 30.2+0.2°, 32.2+0.2°;

[0127] or 27.4+0.2°, 28.5+0.2°, 30.2+0.2°, 32.2+0.2°;

[0128] or 24.4+0.2°, 24.7+0.2°, 27.4+0.2°, 28.5+0.2°;

[0129] or 24.4+0.2°, 24.7+0.2°, 28.5+0.2°, 30.2+0.2°;

[0130] or 24.4+0.2°, 24.7+0.2°, 30.2+0.2°, 32.2+0.2°;

[0131] 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°;

[0132] 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°;

[0133] 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°;

[0134] 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°;

[0135] 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°;

[0136] 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°;

[0137] 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°.

[0138] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone hydrochloride salt crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) of 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°.

[0139] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone hydrochloride salt crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) of 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°.

[0140] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone hydrochloride salt crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) of 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°.

[0141] Table 2

[0142]

[0143]

[0144] Further, in certain embodiments of the present application, the hydrochloride salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,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 Figure 2

[0145] In certain embodiments of the present application, the mesylate salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,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 2Θ of 7.1 ± 0.2°, or a diffraction peak at 2Θ of 10.1 ± 0.2°, or a diffraction peak at 2Θ of 10.5 ± 0.2°, or a diffraction peak at 2Θ of 12.0 ± 0.2°, or a diffraction peak at 2Θ of 13.2 ± 0.2°, or a diffraction peak at 2Θ of 16.9 ± 0.2°, or a diffraction peak at 2Θ of 18.7 ± 0.2°, 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, comprising any optional 2, 4, 6, 8 or 10 of the diffraction peaks.

[0146] ​Furthermore, in certain embodiments of the present invention, the methanesulfonate crystal form 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) methyl ketone has a powder X-ray diffraction pattern containing at least one or more diffraction peaks located at 2θ of 7.1±0.2°, 10.1±0.2°, or 10.5±0.2°; preferably containing two, more preferably three; optionally, further, it may also contain one or more 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 containing two, three, four, or five.

[0147] Furthermore, in certain embodiments of the present invention, the methanesulfonate crystal form of 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) ketone has a powder X-ray diffraction pattern containing at least the peaks located at the following diffraction angles (2θ):

[0148] 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 13.2±0.2°;

[0149] Or 7.1±0.2°, 10.1±0.2°, 13.2±0.2°, 16.9±0.2°;

[0150] Or 7.1±0.2°, 10.1±0.2°, 16.9±0.2°, 18.7±0.2°;

[0151] Or 7.1±0.2°, 10.1±0.2°, 18.7±0.2°, 21.1±0.2°;

[0152] Or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 16.9±0.2°;

[0153] Or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 18.7±0.2°;

[0154] Or 7.1±0.2°, 10.1±0.2°, 12.0±0.2°, 21.1±0.2°;

[0155] Or 7.1±0.2°, 10.1±0.2°, 13.2±0.2°, 18.7±0.2°;

[0156] or 7.1 +0.2°, 10.1 +0.2°, 13.2 +0.2°, 21.1 +0.2°;

[0157] or 7.1 +0.2°, 10.1 +0.2°, 16.9 +0.2°, 21.1 +0.2°;

[0158] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 12.0 +0.2°, 13.2 +0.2°;

[0159] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 13.2 +0.2°, 16.9 +0.2°;

[0160] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 16.9 +0.2°, 18.7 +0.2°;

[0161] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 18.7 +0.2°, 21.1 +0.2°;

[0162] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 12.0 +0.2°, 16.9 +0.2°;

[0163] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 12.0 +0.2°, 18.7 +0.2°;

[0164] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 12.0 +0.2°, 21.1 +0.2°;

[0165] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 13.2 +0.2°, 18.7 +0.2°;

[0166] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 13.2 +0.2°, 21.1 +0.2°;

[0167] or 7.1 +0.2°, 10.1 +0.2°, 10.5 +0.2°, 16.9 +0.2°, 21.1 +0.2°;

[0168] 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°;

[0169] 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°;

[0170] 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°;

[0171] 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°;

[0172] 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°;

[0173] 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°;

[0174] 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°;

[0175] 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°;

[0176] 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°;

[0177] 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°;

[0178] 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°.

[0179] Further, in certain embodiments of the application, the mesylate salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following diffraction peaks at 2-theta = 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 at least 2-4, or 5-6, or 7-9 of these peaks, and further preferably, 4, 6, or 8 of these peaks;

[0180] Further, in certain embodiments of the application, the mesylate salt crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following diffraction peaks at 2-theta = 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 at least 2-4, or 5-6, or 7-9 of these peaks, and further preferably, 4, 6, or 8 of these peaks;

[0181] 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 21.5 ± 0.2°;

[0182] or 18.6 ± 0.2°, 19.7 ± 0.2°, 21.5 ± 0.2°, 21.7 ± 0.2°;

[0183] or 19.7 ± 0.2°, 21.5 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°;

[0184] or 21.5 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°;

[0185] or 21.7 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0186] or 22.5 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0187] or 16.8 ± 0.2°, 19.7 ± 0.2°, 21.5 ± 0.2°, 21.7 ± 0.2°;

[0188] or 16.8 ± 0.2°, 21.5 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°;

[0189] or 16.8 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°;

[0190] or 16.8 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0191] or 16.8 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0192] or 16.8 ± 0.2°, 18.6 ± 0.2°, 21.5 ± 0.2°, 21.7 ± 0.2°;

[0193] or 16.8 ± 0.2°, 18.6 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°;

[0194] or 16.8 ± 0.2°, 18.6 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°;

[0195] or 16.8 ± 0.2°, 18.6 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0196] or 16.8 ± 0.2°, 18.6 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0197] or 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 21.7 ± 0.2°;

[0198] or 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 22.5 ± 0.2°;

[0199] or 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 23.3 ± 0.2°;

[0200] or 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 25.5 ± 0.2°;

[0201] or 16.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 28.0 ± 0.2°;

[0202] or 18.6 ± 0.2°, 19.7 ± 0.2°, 21.7 ± 0.2°, 22.5 ± 0.2°;

[0203] or 18.6 ± 0.2°, 19.7 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°;

[0204] or 18.6 ± 0.2°, 19.7 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0205] or 18.6 ± 0.2°, 19.7 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0206] or 19.7 ± 0.2°, 21.5 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°;

[0207] or 19.7 ± 0.2°, 21.5 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0208] or 19.7 ± 0.2°, 21.5 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0209] or 21.5 ± 0.2°, 21.7 ± 0.2°, 23.3 ± 0.2°, 25.5 ± 0.2°;

[0210] or 21.5 ± 0.2°, 21.7 ± 0.2°, 25.5 ± 0.2°, 28.0 ± 0.2°;

[0211] 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°;

[0212] 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°;

[0213] 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°;

[0214] 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°;

[0215] 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°;

[0216] 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°;

[0217] 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°;

[0218] 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°;

[0219] 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°;

[0220] 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°;

[0221] 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°;

[0222] 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°;

[0223] 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°;

[0224] 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°;

[0225] 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°;

[0226] 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°;

[0227] 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°;

[0228] 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°;

[0229] 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°;

[0230] 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°;

[0231] 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°;

[0232] 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°;

[0233] 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°;

[0234] 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°;

[0235] 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°;

[0236] 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°;

[0237] 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°;

[0238] 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°;

[0239] 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°.

[0240] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone methanesulfonic acid salt crystalline Form powder X-ray diffraction pattern includes peaks at diffraction angles (2 theta) of 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°.

[0241] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone methanesulfonic acid salt crystalline Form powder X-ray diffraction pattern includes peaks at diffraction angles (2 theta) of 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°.

[0242] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone methanesulfonic acid salt crystalline Form powder X-ray diffraction pattern includes peaks at diffraction angles (2 theta) of 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°.

[0243] Table 3

[0244]

[0245] Further, in some embodiments of the present application, the compound is a mesylate salt crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern substantially as shown in Figure 3

[0246] In some embodiments of the present application, the compound is a nitrate salt crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern having a diffraction peak at 2-theta = 9.3 ± 0.2°, or a diffraction peak at 2-theta = 11.9 ± 0.2°, or a diffraction peak at 2-theta = 12.5 ± 0.2°, or a diffraction peak at 2-theta = 14.3 ± 0.2°, or a diffraction peak at 2-theta = 14.6 ± 0.2°, or a diffraction peak at 2-theta = 16.2 ± 0.2°, or a diffraction peak at 2-theta = 16.7 ± 0.2°, or a diffraction peak at 2-theta = 17.9 ± 0.2°, or a diffraction peak at 2-theta = 18.7 ± 0.2°, or a diffraction peak at 2-theta = 22.9 ± 0.2°, or a diffraction peak at 2-theta = 25.1 ± 0.2°, or a diffraction peak at 2-theta = 25.9 ± 0.2°, or a diffraction peak at 2-theta = 26.6 ± 0.2°, or a diffraction peak at 2-theta = 28.2 ± 0.2°, or a diffraction peak at 2-theta = 28.6 ± 0.2°; preferably, comprising 2, 4, 6, 8 or 10 optional diffraction peaks thereof.

[0247] Further, in some embodiments of the present application, the compound is a nitrate salt crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern comprising at least one or more of the diffraction peaks at 2-theta = 9.3 ± 0.2°, 11.9 ± 0.2° or 12.5 ± 0.2°; preferably, 2 thereof, more preferably, 3 thereof; optionally, further comprising one or more of the diffraction peaks at 2-theta = 14.3 ± 0.2°, 14.6 ± 0.2°, 16.2 ± 0.2°, 16.7 ± 0.2° or 17.9 ± 0.2°; preferably, 2, 3, 4 or 5 thereof;

[0248] ​Further, in certain embodiments of the application, a crystalline form of the nitrate salt of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least the following peaks at the following diffraction angles (2Θ):

[0249] 9.3 ± 0.2°, 11.9 ± 0.2°, 14.3 ± 0.2°, 14.6 ± 0.2°;

[0250] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.6 ± 0.2°, 16.2 ± 0.2°;

[0251] or 9.3 ± 0.2°, 11.9 ± 0.2°, 16.2 ± 0.2°, 16.7 ± 0.2°;

[0252] or 9.3 ± 0.2°, 11.9 ± 0.2°, 16.7 ± 0.2°, 17.9 ± 0.2°;

[0253] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.3 ± 0.2°, 16.2 ± 0.2°;

[0254] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.3 ± 0.2°, 16.7 ± 0.2°;

[0255] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.3 ± 0.2°, 17.9 ± 0.2°;

[0256] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.6 ± 0.2°, 16.7 ± 0.2°;

[0257] or 9.3 ± 0.2°, 11.9 ± 0.2°, 14.6 ± 0.2°, 17.9 ± 0.2°;

[0258] or 9.3 ± 0.2°, 11.9 ± 0.2°, 16.2 ± 0.2°, 17.9 ± 0.2°;

[0259] or 9.3 ± 0.2°, 11.9 ± 0.2°, 12.5 ± 0.2°, 14.3 ± 0.2°, 14.6 ± 0.2°;

[0260] or 9.3 ± 0.2°, 11.9 ± 0.2°, 12.5 ± 0.2°, 14.6 ± 0.2°, 16.2 ± 0.2°;

[0261] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 16.7±0.2°;

[0262] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 16.7±0.2°;

[0263] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.2±0.2°;

[0264] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 16.7±0.2°;

[0265] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 14.3±0.2°, 17.9±0.2°;

[0266] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 16.7±0.2°;

[0267] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 14.6±0.2°, 17.9±0.2°;

[0268] or 9.3 ±0.2°, 11.9±0.2°, 12.5±0.2°, 16.2±0.2°, 17.9±0.2°;

[0269] 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°;

[0270] 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°;

[0271] 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°;

[0272] 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°;

[0273] 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°;

[0274] 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°;

[0275] 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°;

[0276] 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°;

[0277] 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°;

[0278] 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°;

[0279] 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°;

[0280] 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°;

[0281] 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°;

[0282] 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°.

[0283] Further, in certain embodiments of the application, the crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone nitrate salt has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks at 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° in terms of diffraction angles (2Θ); preferably at least 2-4, or 5-7, or further preferably, 4 or 6 of these peaks;

[0284] Further, in certain embodiments of the application, the crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone nitrate salt has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks at 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° in terms of diffraction angles (2Θ); preferably at least 2-4, or 5-7, or further preferably, 4 or 6 of these peaks;

[0285] 18.7 ± 0.2°, 22.9 ± 0.2°, 25.1 ± 0.2°, 25.9 ± 0.2°;

[0286] or 18.7 ± 0.2°, 25.1 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°;

[0287] or 18.7 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°;

[0288] or 18.7 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°;

[0289] or 18.7 ± 0.2°, 22.9 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°;

[0290] or 18.7 ± 0.2°, 22.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°;

[0291] or 18.7 ± 0.2°, 22.9 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°;

[0292] or 18.7 ± 0.2°, 22.9 ± 0.2°, 25.1 ± 0.2°, 26.6 ± 0.2°;

[0293] or 18.7 ± 0.2°, 22.9 ± 0.2°, 25.1 ± 0.2°, 28.2 ± 0.2°;

[0294] or 18.7 ± 0.2°, 22.9 ± 0.2°, 25.1 ± 0.2°, 28.6 ± 0.2°;

[0295] or 22.9 ± 0.2°, 25.1 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°;

[0296] or 22.9 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°;

[0297] or 22.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°;

[0298] or 25.1 ± 0.2°, 25.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°;

[0299] or 25.1 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°;

[0300] or 25.9 ± 0.2°, 26.6 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°;

[0301] 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°;

[0302] 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°;

[0303] 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°;

[0304] 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°;

[0305] 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°;

[0306] 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°;

[0307] 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°.

[0308] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone free base crystalline form includes peaks at diffraction angles (2 theta) of 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°.

[0309] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone free base crystalline form includes peaks at diffraction angles (2 theta) of 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°.

[0310] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4- thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl-3-d) methanone free base crystalline form has X-ray characteristic diffraction peaks, expressed in terms of 2 theta angles and interplanar spacing d values, using Cu-Ka radiation, as shown in Table 4:

[0311] Table 4

[0312]

[0313] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4- thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl-3-d) methanone free base crystalline form has X-ray characteristic diffraction peaks, expressed in terms of 2 theta angles and interplanar spacing d values, using Cu-Ka radiation, as shown in Table 4:Figure 4 as shown.

[0314] In some embodiments of the present application, the sulfate salt crystalline form of the compound (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 7.1 ± 0.2°, or at 2-theta = 13.4 ± 0.2°, or at 2-theta = 14.2 ± 0.2°, or at 2-theta = 15.5 ± 0.2°, or at 2-theta = 16.3 ± 0.2°, or at 2-theta = 17.4 ± 0.2°, or at 2-theta = 17.7 ± 0.2°, or at 2-theta = 18.0 ± 0.2°, or at 2-theta = 19.8 ± 0.2°, or at 2-theta = 20.1 ± 0.2°; preferably, comprising 2, 4, 6, 8 or 10 peaks at any of the above angles.

[0315] Further, in some embodiments of the present application, the sulfate salt crystalline form of the compound (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 7.1 ± 0.2°, or at 2-theta = 16.3 ± 0.2°, or at 2-theta = 18.0 ± 0.2°; more preferably, comprising 2 peaks; optionally, further comprising one or more peaks at 2-theta = 13.4 ± 0.2°, 14.2 ± 0.2°, 15.5 ± 0.2°, 17.4 ± 0.2°, or 17.7 ± 0.2°; preferably, comprising 2, 3, 4 or 5 peaks at any of the above angles.

[0316] Further, in some embodiments of the present application, the sulfate salt crystalline form of the compound (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 7.1 ± 0.2°, or at 2-theta = 16.3 ± 0.2°, or at 2-theta = 18.0 ± 0.2°; more preferably, comprising 2 peaks; optionally, further comprising one or more peaks at 2-theta = 13.4 ± 0.2°, 14.2 ± 0.2°, 15.5 ± 0.2°, 17.4 ± 0.2°, or 17.7 ± 0.2°; preferably, comprising 2, 3, 4 or 5 peaks at any of the above angles.

[0317] 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 14.2 ± 0.2°;

[0318] or 7.1 ± 0.2°, 16.3 ± 0.2°, 14.2 ± 0.2°, 15.5 ± 0.2°;

[0319] or 7.1 + 0.2°, 16.3 + 0.2°, 15.5 + 0.2°, 17.4 + 0.2°;

[0320] or 7.1 + 0.2°, 16.3 + 0.2°, 17.4 + 0.2°, 17.7 + 0.2°;

[0321] or 7.1 + 0.2°, 16.3 + 0.2°, 13.4 + 0.2°, 15.5 + 0.2°;

[0322] or 7.1 + 0.2°, 16.3 + 0.2°, 13.4 + 0.2°, 17.4 + 0.2°;

[0323] or 7.1 + 0.2°, 16.3 + 0.2°, 13.4 + 0.2°, 17.7 + 0.2°;

[0324] or 7.1 + 0.2°, 16.3 + 0.2°, 14.2 + 0.2°, 17.4 + 0.2°;

[0325] or 7.1 + 0.2°, 16.3 + 0.2°, 14.2 + 0.2°, 17.7 + 0.2°;

[0326] or 7.1 + 0.2°, 16.3 + 0.2°, 15.5 + 0.2°, 17.7 + 0.2°;

[0327] or 7.1 + 0.2°, 13.4 + 0.2°, 14.2 + 0.2°, 18.0 + 0.2°;

[0328] or 7.1 + 0.2°, 14.2 + 0.2°, 15.5 + 0.2°, 18.0 + 0.2°;

[0329] or 7.1 + 0.2°, 15.5 + 0.2°, 17.4 + 0.2°, 18.0 + 0.2°;

[0330] or 7.1 + 0.2°, 17.4 + 0.2°, 17.7 + 0.2°, 18.0 + 0.2°;

[0331] or 7.1 + 0.2°, 13.4 + 0.2°, 15.5 + 0.2°, 18.0 + 0.2°;

[0332] or 7.1 + 0.2°, 13.4 + 0.2°, 17.4 + 0.2°, 18.0 + 0.2°;

[0333] or 7.1 + 0.2°, 13.4 + 0.2°, 17.7 + 0.2°, 18.0 + 0.2°;

[0334] or 7.1 ± 0.2°, 14.2 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0335] or 7.1 ± 0.2°, 14.2 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0336] or 7.1 ± 0.2°, 15.5 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0337] or 16.3 ± 0.2°, 13.4 ± 0.2°, 14.2 ± 0.2°, 18.0 ± 0.2°;

[0338] or 16.3 ± 0.2°, 14.2 ± 0.2°, 15.5 ± 0.2°, 18.0 ± 0.2°;

[0339] or 16.3 ± 0.2°, 15.5 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0340] or 16.3 ± 0.2°, 17.4 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0341] or 16.3 ± 0.2°, 13.4 ± 0.2°, 15.5 ± 0.2°, 18.0 ± 0.2°;

[0342] or 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0343] or 16.3 ± 0.2°, 13.4 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0344] or 16.3 ± 0.2°, 14.2 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0345] or 16.3 ± 0.2°, 14.2 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0346] or 16.3 ± 0.2°, 15.5 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°;

[0347] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 14.2 ± 0.2°, 18.0 ± 0.2°;

[0348] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0349] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0350] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0351] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0352] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0353] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0354] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0355] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0356] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0357] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0358] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0359] or 7.1 ± 0.2°, 16.3 ± 0.2°, 13.4 ± 0.2°, 17.4 ± 0.2°, 18.0 ± 0.2°;

[0360] 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°;

[0361] 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°;

[0362] 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°;

[0363] 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°;

[0364] 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°;

[0365] 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°;

[0366] 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°;

[0367] 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°;

[0368] 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°;

[0369] 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°;

[0370] 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°.

[0371] Further, in certain embodiments of the application, the crystalline form of the sulfate salt of the compound (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks at 2-theta = 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 at least 2-4, or 5-7, of these peaks, and further preferably, 4 or 6 of these peaks;

[0372] Further, in certain embodiments of the application, the crystalline form of the sulfate salt of the compound (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has a powder X-ray diffraction pattern that optionally further comprises one or more of the following peaks at 2-theta = 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 at least 2-4, or 5-7, of these peaks, and further preferably, 4 or 6 of these peaks;

[0373] 19.8 ± 0.2°, 20.1 ± 0.2°, 21.0 ± 0.2°, 21.2 ± 0.2°;

[0374] or 20.1 ± 0.2°, 21.0 ± 0.2°, 21.2 ± 0.2°, 22.6 ± 0.2°;

[0375] or 21.0 ± 0.2°, 21.2 ± 0.2°, 22.6 ± 0.2°, 24.0 ± 0.2°;

[0376] or 21.2 ± 0.2°, 22.6 ± 0.2°, 24.0 ± 0.2°, 24.8 ± 0.2°;

[0377] or 22.6 ± 0.2°, 24.0 ± 0.2°, 24.8 ± 0.2°, 25.4 ± 0.2°;

[0378] 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°;

[0379] 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°;

[0380] 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°;

[0381] 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°;

[0382] 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°;

[0383] 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°.

[0384] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone sulfate salt Form 2 includes peaks at diffraction angles (2 theta) of 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°.

[0385] Further, in certain embodiments of the application, the powder X-ray diffraction pattern of the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone sulfate salt Form 2 includes peaks at diffraction angles (2 theta) of 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°.

[0386] Further, in certain embodiments of the application, the crystalline form of the sulfate salt of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value using Cu-Ka radiation as shown in Table 5:

[0387] Table 5

[0388]

[0389]

[0390] In certain embodiments of the application, the crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone sulfate salt is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5

[0391] ​In some embodiments of the present application, the compound is a crystalline form of the hydrobromide salt of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 9.2 ± 0.2°, 12.0 ± 0.2°, or 12.9 ± 0.2°; preferably 2 peaks, more preferably 3 peaks; optionally, further comprising one or more peaks at 2-theta = 14.6 ± 0.2°, 16.8 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°, or 22.7 ± 0.2°; preferably 2, 3, 4, or 5 peaks; and most preferably 3 peaks.

[0392] In some embodiments of the present application, the compound is a crystalline form of the hydrobromide salt of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern comprising at least one peak at 2-theta = 9.2 ± 0.2°, 12.0 ± 0.2°, or 12.9 ± 0.2°; preferably 2 peaks, more preferably 3 peaks; optionally, further comprising one or more peaks at 2-theta = 14.6 ± 0.2°, 16.8 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°, or 22.7 ± 0.2°; preferably 2, 3, 4, or 5 peaks; and most preferably 3 peaks.

[0393] Further, in certain embodiments of the application, the compound is a crystalline form of the hydrobromide salt of 3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d)methanone having a powder X-ray diffraction pattern comprising at least the following peaks, in terms of diffraction angles (2Θ):

[0394] 9.2 ± 0.2°, 12.0 ± 0.2°, 14.6 ± 0.2°, 16.8 ± 0.2°;

[0395] or 9.2 ± 0.2°, 12.0 ± 0.2°, 16.8 ± 0.2°, 17.1 ± 0.2°;

[0396] or 9.2 ± 0.2°, 12.0 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°;

[0397] or 9.2 ± 0.2°, 12.0 ± 0.2°, 18.6 ± 0.2°, 22.7 ± 0.2°;

[0398] or 9.2 ± 0.2°, 12.0 ± 0.2°, 14.6 ± 0.2°, 17.1 ± 0.2°;

[0399] or 9.2 ± 0.2°, 12.0 ± 0.2°, 14.6 ± 0.2°, 18.6 ± 0.2°;

[0400] or 9.2 ± 0.2°, 12.0 ± 0.2°, 14.6 ± 0.2°, 22.7 ± 0.2°;

[0401] or 9.2 ± 0.2°, 12.0 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0402] or 9.2 ± 0.2°, 12.0 ± 0.2°, 16.8 ± 0.2°, 22.7 ± 0.2°;

[0403] or 9.2 ± 0.2°, 12.0 ± 0.2°, 17.1 ± 0.2°, 22.7 ± 0.2°;

[0404] or 12.0 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 16.8 ± 0.2°;

[0405] or 12.0 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 17.1 ± 0.2°;

[0406] or 12.0 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°;

[0407] or 12.0 ± 0.2°, 12.9 ± 0.2°, 18.6 ± 0.2°, 22.7 ± 0.2°;

[0408] or 12.0 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 17.1 ± 0.2°;

[0409] or 12.0 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 18.6 ± 0.2°;

[0410] or 12.0 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 22.7 ± 0.2°;

[0411] or 12.0 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0412] or 12.0 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 22.7 ± 0.2°;

[0413] or 12.0 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 22.7 ± 0.2°;

[0414] or 9.2 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 16.8 ± 0.2°;

[0415] or 9.2 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 17.1 ± 0.2°;

[0416] or 9.2 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°;

[0417] or 9.2 ± 0.2°, 12.9 ± 0.2°, 18.6 ± 0.2°, 22.7 ± 0.2°;

[0418] or 9.2 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 17.1 ± 0.2°;

[0419] or 9.2 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 18.6 ± 0.2°;

[0420] or 9.2 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 22.7 ± 0.2°;

[0421] or 9.2 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 18.6 ± 0.2°;

[0422] or 9.2 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 22.7 ± 0.2°;

[0423] or 9.2 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 22.7 ± 0.2°;

[0424] 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°;

[0425] or 12.0 ± 0.2°, 12.9 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°, 22.7 ± 0.2°;

[0426] or 12.0 ± 0.2°, 12.9 ± 0.2°, 14.6 ± 0.2°, 17.1 ± 0.2°, 18.6 ± 0.2°;

[0427] 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°;

[0428] 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°;

[0429] 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°;

[0430] 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°;

[0431] 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°;

[0432] 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°;

[0433] 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°;

[0434] 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°;

[0435] 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°;

[0436] 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°.

[0437] Further, in certain embodiments of the application, the compound is a crystalline form of the hydrobromide salt of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern comprising one or more peaks at 2-theta = 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 at least 2-4, or 5-7, of these peaks, and further preferably, 4 or 6 of these peaks.

[0438] Further, in certain embodiments of the application, the compound is a crystalline form of the hydrobromide salt of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, which has a powder X-ray diffraction pattern comprising one or more peaks at 2-theta = 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 at least 2-4, or 5-7, of these peaks, and further preferably, 4 or 6 of these peaks.

[0439] 19.5 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 22.5 ± 0.2°;

[0440] or 19.8 ± 0.2°, 20.2 ± 0.2°, 22.5 ± 0.2°, 25.4 ± 0.2°;

[0441] or 20.2 ± 0.2°, 22.5 ± 0.2°, 25.4 ± 0.2°, 26.4 ± 0.2°;

[0442] or 22.5 ± 0.2°, 25.4 ± 0.2°, 26.4 ± 0.2°, 27.5 ± 0.2°;

[0443] or 25.4 ± 0.2°, 26.4 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°;

[0444] or 26.4 ± 0.2°, 27.5 ± 0.2°, 27.8 ± 0.2°, 28.9 ± 0.2°;

[0445] or 27.5 ± 0.2°, 27.8 ± 0.2°, 28.9 ± 0.2°, 29.3 ± 0.2°;

[0446] or 27.8 ± 0.2°, 28.9 ± 0.2°, 29.3 ± 0.2°, 32.3 ± 0.2°;

[0447] 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°;

[0448] 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°;

[0449] 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°;

[0450] 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°;

[0451] 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°;

[0452] 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°.

[0453] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone hydrobromide crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) of 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°.

[0454] Further, in certain embodiments of the application, the (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone hydrobromide crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) of 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°.

[0455] Further, in certain embodiments of the present application, the crystalline form of the hydrobromide salt of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value using Cu-Ka radiation as shown in Table 6:

[0456] Table 6

[0457]

[0458]

[0459] Further, in certain embodiments of the present application, the crystalline form of the hydrobromide salt of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,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 Figure 6 .

[0460] As those skilled in the art will appreciate, the peak positions (2 theta) will vary somewhat from XRPD instrument to XRPD instrument, and sometimes this variation can be as much as 0.2° 2 theta. Thus, this variation or shift can also be expressed using the term "substantially the same" in reference to the variability of X-ray diffraction peak positions and intensities. In addition, those skilled in the art will also appreciate that variations in the relative intensities of the peaks in the XRPD diffraction pattern of a sample will also result from factors such as sample preparation method, XRPD instrument, sample crystallinity, sample amount, and crystal preferred orientation.

[0461] Compared to amorphous form, the crystalline form of the present application is more stable in both chemical and physical properties, and is more suitable for drug production, transportation and storage, and is more suitable for drug development needs. It is also more advantageous for drug purification, decolorization, filtration and other process operations. Therefore, the crystalline form of the compound of the present application has great improvement significance and meets the requirements of clinical development.

[0462] Another aspect of the present application provides a method for preparing the aforementioned crystalline form, comprising the following steps:

[0463] a) weigh an appropriate amount of the compound, dissolve it with an organic solvent, and dissolve the solution,

[0464] b) stir, filter, and dry to obtain the target product;

[0465] 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 combination thereof.

[0466] Another aspect of the present application provides a method for preparing the acid salt or the crystal form thereof as described above, comprising the following steps:

[0467] a) weighing an appropriate amount of the free base crystal form of the compound into an organic solvent;

[0468] b) weighing an appropriate amount of acid, dissolving with an organic solvent, stirring and then filtering or dissolving and then evaporating to obtain a gel, adding an anti-solvent to the gel and stirring and filtering, vacuum drying, and separating to obtain the target product.

[0469] wherein:

[0470] 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 combination thereof; the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether or a combination thereof; the acid in the acid solution is selected from inorganic acid or 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, acetoxyhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic 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-naphthalene disulfonic 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, pantothenic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluenesulfonic acid or L-malic acid.

[0471] In another aspect, the present application provides a method for preparing the 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 or a crystalline form thereof, comprising the steps of:

[0472] The crystalline form A of the free base of 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 is added into an organic solvent, an acid solution is added thereto, and after stirring, a gel is obtained by filtration or dissolution and evaporation. The gel is stirred after adding an anti-solvent thereto, filtered, and dried under vacuum to obtain a crystalline form of the salt.

[0473] The dissolution refers to the general operation of those skilled in the art, and generally, the raw material can be dissolved or dissolved clean by appropriate heating, or the raw material can be dissolved or dissolved clean by increasing the amount of solvent, or the technical solution is modified or replaced equivalently, which should be covered in the content of the present application.

[0474] Further, in some embodiments of the present application, the organic solvent in the preparation method 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 combination thereof; the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether or a combination thereof; and the acid solution is selected from methanolic hydrochloric acid solution, methanolic methanesulfonic acid solution, methanolic nitric acid solution, methanolic sulfuric acid solution or methanolic hydrobromic acid solution.

[0475] Further, in some embodiments of the present application, the organic solvent in the preparation method is selected from tetrahydrofuran or ethyl acetate; the anti-solvent is selected from ethyl acetate; and the acid solution is selected from methanolic hydrochloric acid solution, methanolic methanesulfonic acid solution, methanolic nitric acid solution, methanolic sulfuric acid solution or methanolic hydrobromic acid solution.

[0476] Further, in some embodiments of the present application, the crystalline form of the 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 obtained by the separation has a powder X-ray diffraction peak or pattern as described in any one of the preceding embodiments.

[0477] Further, in some embodiments of the present application, the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone obtained in step 3) of the preparation method is substantially pure; the substantially pure crystalline form refers to a crystalline form having a purity greater than 90%.

[0478] Preferably, the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone obtained in step 3) of the preparation method has a purity greater than 95%.

[0479] Most preferably, the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone obtained in step 3) of the preparation method has a purity greater than 98%.

[0480] In another aspect of the present application, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of the crystalline form of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone or an acid salt thereof and a pharmaceutically acceptable carrier.

[0481] In the embodiments of the present application, a therapeutically effective amount of the crystalline form, the acid salt or the crystalline form thereof is 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%.

[0482] In another aspect, the present invention provides the use of the aforementioned (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) methyl ketone or its acid salts, or the aforementioned pharmaceutical compositions, in the preparation of NK3 inhibitor-related medicaments, preferably in the preparation of medicaments for the treatment and / or prevention of psychotic disorders, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, sex hormone-dependent diseases, or gynecological diseases; more preferably, in the preparation of medicaments for the treatment and / or prevention of menopausal syndrome-related diseases, wherein the menopausal syndrome includes hot flashes, sweating, palpitations, dizziness, and obesity symptoms. Attached Figure Description

[0483] Figure 1 Powder X-ray diffraction pattern of the free base crystal 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); X-axis is the diffraction peak angle 2θ (°), and Y-axis is the peak intensity.

[0484] Figure 2 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; X-axis is the diffraction peak angle 2θ (°), and Y-axis is the peak intensity.

[0485] Figure 3 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; X-axis is the diffraction peak angle 2θ (°), and Y-axis is the peak intensity.

[0486] Figure 4 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; X-axis is the diffraction peak angle 2θ (°), and Y-axis is the peak intensity.

[0487] Figure 5Powder X-ray diffraction pattern of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8- methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) sulfate; X-axis is the diffraction peak angle 2 theta (°), Y-axis is the intensity of the peak.

[0488] Figure 6 Powder X-ray diffraction pattern of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8- methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) sulfate; X-axis is the diffraction peak angle 2 theta (°), Y-axis is the intensity of the peak.

[0489] Figure 7 DSC pattern of (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) free base; X-axis is temperature (°C), Y-axis is heat flow (W / G). DETAILED DESCRIPTION

[0490] The application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0491] I. Preparation of the compound

[0492] Compound A

[0493] (R)-(3-(B enzo[d]thiazol-2-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-fluorophenyl)methanone

[0494]

[0495] First step: Preparation of (R)-l-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl- 1,2,3,6-tetrahydropyrazine

[0496]

[0497] (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, and triethyl oxonium tetrafluoroborate (4.5 mL, 4.5 mmol) was added. The reaction was stirred at room temperature for 3 h, water (10 mL) was added, and stirred for half an hour. A solid was precipitated, which was filtered. The aqueous phase was extracted with dichloromethane (20 mL x 2), and the combined organic phase was 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.

[0498] MS m / z (ESI): 293.2 [M+H] + .

[0499] Second Step: Preparation of benz[d]thiazole-2-carbohydrazide

[0500]

[0501] Benz[d]thiazole-2-carboxylic acid ethyl ester (300 mg, 1.45 mmol) was dissolved in anhydrous ethanol (10 mL), and 85% hydrazine hydrate (102 mg, 1.74 mmol) was added. The reaction was stirred at room temperature for 4 h. Filtration and drying gave benz[d]thiazole-2-carbohydrazide (270 mg, yield: 96%).

[0502] MS m / z (ESI): 194.2 [M+H] + .

[0503] Third Step: 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)benz[d]thiazole

[0504]

[0505] (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), and benz[d]thiazole-2-carbohydrazide (120 mg, 0.62 mmol) was added. The reaction was stirred at 80 °C overnight. The reaction was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1 ~ 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)benz[d]thiazole (100 mg, yield: 38%).

[0506] MS m / z (ESI): 422.2 [M+H] + .

[0507] Fourth Step: Preparation of (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)benzo[d]thiazole

[0508]

[0509] (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 hour, TLC showed that the reaction was complete. Water (10 mL) was added and stirred for 5 minutes, after filtration, 3M sodium hydroxide solution was added to the filtrate until the pH of the aqueous phase was >14. Extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, 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%).

[0510] MS m / z (ESI): 272.2 [M+H] + .

[0511] Fifth Step: 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

[0512]

[0513] (R)-2-(8-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole (40 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), triethylamine (23 mg, 0.23 mmol) was added, then 4-fluorobenzoyl chloride (28 mg, 0.18 mmol) was added, the reaction was stirred at room temperature for 1 hour. Water (10 mL) was added and washed with dichloromethane (10 mL x 2), the organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, 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-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (25 mg, yield: 42%).

[0514] MS m / z (ESI): 394.2 [M+H] + .

[0515] 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.27 - 7.16 (m, 2H), 5.78 (br s, 1H), 5.12 (d, J = 14.6 Hz, 1H), 4.84 - 4.55 (m, 1H), 4.42 - 4.35 (m, 1H), 3.60 - 3.54 (m, 1H), 1.77 (d, J = 6.9 Hz, 3H).

[0516] Compound 1

[0517] (R)-(4-Fluorophenyl-2,3,5,6-d4)(8-methyl-3-(3-(methyl-d3)-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone

[0518]

[0519] Compound 1 was prepared according to the fifth step of Reference Compound A.

[0520] MS m / z (ESI): 366.1 [M+H] + .

[0521] 1H NMR (400 MHz, 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).

[0522] Compound 2

[0523] (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

[0524]

[0525] First Step: 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0526]

[0527] Bis(triphenylphosphine)palladium dichloride (1.13 g, 1.61 mmol) was added to 3,5-dichloro-1,2,4-thiadiazole (5 g, 32.26 mmol) and tributyl(1-ethoxyvinyl)tin (10.48 g, 29.03 mmol) in anhydrous DMF (20 ml), the reaction was heated to 75 °C under nitrogen protection for 14 hours. The reaction was cooled, quenched with aqueous potassium fluoride solution (50 ml), the solid was removed by filtration, the liquid phase was extracted with ethyl acetate (75 ml*2), the organic phase was washed with saturated brine (20 ml*6), the organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was column separated (petroleum ether: ethyl acetate = 99:1) to obtain 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3 g, yield: 70%).

[0528] 1 H NMR (400 MHz, Chloroform-d) δ 5.52 (d, J = 3.1 Hz, 1H), 4.58 (d, J = 3.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

[0529] Second Step: 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester

[0530]

[0531] A solution of sodium periodate (8.30 g, 38.81 mmol) in water (35 ml) was added to a solution of 3-chloro-5-(l-ethoxyvinyl)-l,2,4-thiadiazole (3.7 g, 19.41 mmol) in dioxane (70 ml) and the reaction stirred for 2 minutes. Potassium permanganate (460.05 mg, 2.91 mmol) was then added to the reaction and the reaction stirred at room temperature overnight. The reaction was extracted with ethyl acetate (100 mL x 3) and the organic phase was combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with petroleum ether: ethyl acetate = 100:0 to 95:5) to give the target product 3-chloro-l,2,4-thiadiazole-5-carboxylic acid ethyl ester (1 g, yield, 27.03%).

[0532] 1 H NMR (400 MHz, Chloroform-d) δ 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0533] Third Step: 3-Chloro-l,2,4-thiadiazole-5-carboxylic acid hydrazide

[0534]

[0535] Hydrazine hydrate (229 mg, 3.89 mmol, 85% aqueous solution) was added to a solution of 3-chloro-l,2,4-thiadiazole-5-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) in ethanol (10 ml) and the reaction stirred at room temperature for 1 hour. The solid product 3-chloro-l,2,4-thiadiazole-5-carboxylic acid hydrazide (440 mg, yield, 95%) was then obtained by filtration.

[0536] MS m / z (ESI): 179.0 [M+H] + .

[0537] Fourth Step: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0538]

[0539] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methyl-piperazin-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL), at 0 °C, triethyl oxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three portions with 10 min interval. The mixture was stirred at 25 °C for 3 h. The reaction was added to cold aqueous sodium hydroxide solution (2 M, 10 ml), the mixture was partitioned, the aqueous phase was extracted with dichloromethane (10 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target 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.

[0540] MS m / z (ESI): 293.2 [M+H] + .

[0541] 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

[0542]

[0543] (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-carbohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (10 mL), the mixture was stirred at 80 °C for 14 h under nitrogen protection. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (dichloromethane:methanol = 100:0 to 95:5 elution) to obtain the target 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 light yellow solid.

[0544] MS m / z (ESI): 406.8 [M+H] + .

[0545] 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

[0546]

[0547] Dissolve 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 umol) in dichloromethane (1.5 mL), add trifluoroacetic acid (3 mL). The mixture was stirred at 25 °C for 1 hour. The reaction solution was evaporated under reduced pressure, then water (7 ml) was added, the mixture was stirred at room temperature for 10 minutes, and then the solid was removed by filtration. The liquid was freeze-dried to obtain 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 salt (0.2 g, yield, 99.77%)

[0548] MS m / z (ESI): 257.0 [M+H] + .

[0549] Step 7: 4-fluoro-2,3,5,6-d4 benzoic acid

[0550]

[0551] Under nitrogen protection, 10% Pd / C (0.73 g, 50% w / w water content) was added to a solution of p-fluorobenzoic acid (1.8 g, 12.9 mmol) in isopropanol (50 mL) and deuterium water (100 mL), and the reaction was stirred at 100 °C for 3 days. The reaction 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 target product 4-fluoro-2,3,5,6-d4 benzoic acid (1.5 g, yield: 81%) was obtained.

[0552] MS m / z (ESI): 143.0 [M-H] -

[0553] 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

[0554]

[0555] 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 umol), 4-fluoro-2,3,5,6- d4benzoic acid (10 mg, 68 umol) and N,N-diisopropylethylamine (22 mg, 169 umol) in N,N- dimethylformamide (1.5 ml) was added 2-(7-oxidation benzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32 mg, 84 umol) and the reaction stirred at room temperature for 16 hours. The crude product 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%).

[0556] MS m / z (ESI): 383.1 [M+H] + .

[0557] 1 H NMR (400 MHz, 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=6.8 Hz, 3H).

[0558] Compound 3

[0559] (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

[0560] (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

[0561]

[0562] 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:

[0563] First step: 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0564]

[0565] Add dichlorobis(triphenylphosphine) palladium (1.13 g, 1.61 mmol) to 3,5-dichloro-1,2,4-thiadiazole (5 g, 32.26 mmol) and tributyl(1-ethoxyvinyl)tin (10.48 g, 29.03 mmol) in anhydrous DMF (20 ml), and heat the reaction mixture to 75 °C under nitrogen for 14 h. Cool the reaction mixture, quench with aqueous potassium fluoride (50 ml), filter off the solids, and extract the liquid phase with ethyl acetate (75 ml x 2). Wash the organic phase with saturated brine (20 ml x 6), dry, and evaporate the organic phase to dryness to give the crude product. Column chromatography of the crude product (petroleum ether: ethyl acetate = 99:1) gives 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3 g, yield: 70%).

[0566] 1 H NMR (400 MHz, Chloroform-d) δ 5.52 (d, J = 3.1 Hz, 1H), 4.58 (d, J = 3.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

[0567] Second step: 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester

[0568]

[0569] Add a solution of sodium periodate (8.30 g, 38.81 mmol) in water (35 ml) to a solution of 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) in dioxane (70 ml), stir the reaction mixture for 2 min, then add potassium permanganate (460.05 mg, 2.91 mmol) to the reaction mixture, and stir the reaction mixture at room temperature overnight. Extract the reaction mixture with ethyl acetate (100 ml x 3), combine the organic phases, wash successively with saturated brine (50 ml x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by flash chromatography on silica gel (elution with petroleum ether: ethyl acetate = 100:0 to 95:5) to give the target product 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (1 g, yield, 27.03%).

[0570] 1 H NMR (400 MHz, Chloroform-d) δ 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0571] Third step: 3-chloro-1,2,4-thiadiazole-5-carboxylic acid hydrazide

[0572]

[0573] Hydrazine hydrate (229 mg, 3.89 mmol, 85% aqueous solution) was added to a solution of 3-chloro-l,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 hour. The solid product 3-chloro-l,2,4-thiadiazole-5-carboxyhydrazide (440 mg, yield, 95%) was obtained after filtration.

[0574] MS m / z (ESI): 179.0 [M+H] + .

[0575] Fourth step: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro- 2H-pyrazine

[0576]

[0577] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methyl-piperazin-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL) and triethyl oxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added at 0 °C in three portions with 10 minutes interval. The mixture was stirred at 25 °C for 3 hours. The reaction was added to cold aqueous sodium hydroxide solution (2 M, 10 ml) and the mixture was partitioned. The aqueous phase was extracted with dichloromethane (10 mL x 2) and the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target 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.

[0578] MS m / z (ESI): 293.2 [M+H] + .

[0579] Fifth step: 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H- [l,2,4]triazolo[4,3-a]pyrazin-3-yl]-l,2,4-thiadiazole

[0580]

[0581] (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-carbohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (10 mL), the mixture was stirred at 80 °C for 14 h under nitrogen protection. The reaction solution was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (dichloromethane:methanol = 100:0 to 95:5 elution) to give the target 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 light yellow solid.

[0582] MS m / z (ESI): 406.8 [M+H] + .

[0583] 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

[0584]

[0585] 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 umol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25 °C for 1 h. The reaction solution was evaporated to dryness under reduced pressure, then water (7 ml) was added, the mixture was stirred at room temperature for 10 min, and then the solid was removed by filtration. The liquid was freeze-dried to give the trifluoroacetate salt of 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 (0.2 g, yield, 99.77%).

[0586] MS m / z (ESI): 257.0 [M+H] + .

[0587] Synthesis of intermediate 3-deuterium-4-fluoro-benzoyl chloride:

[0588] Step 1: Preparation of 3-deuterium-4-fluoro-benzoic acid

[0589]

[0590] Dissolve 3-bromo-4-fluorobenzoic acid (5 g, 22.83 mmol) in sodium deuterium oxide (30 mL, 2M in D2O), add zinc powder (5.97 g, 91.32 mmol). The mixture was stirred at 25 °C for 24 hours. The reaction solution was filtered to remove the solid, the aqueous phase was adjusted to pH = 1 with 1N HC1, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 3-deuterium-4-fluoro-benzoic acid (3 g, yield: 93.12%).

[0591] MS m / z (ESI): 139.8 [M-H] -

[0592] Second step: preparation of 3-deuterium-4-fluoro-benzoyl chloride

[0593]

[0594] Dissolve 3-deuterium-4-fluoro-benzoic acid (200 mg, 1.42 mmol) in dichloromethane (5 mL), add oxalyl chloride (359.77 mg, 2.83 mmol), then add N,N-dimethylformamide (0.05 mL), and stir the mixture at 25 °C for 2 hours. Concentrate the reaction solution under reduced pressure. The residue 3-deuterium-4-fluoro-benzoyl chloride (0.22 g) is used directly in the next step.

[0595] 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:

[0596]

[0597] 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 (0.35 g, 0.94 mmol) and triethylamine (286.59 mg, 2.83 mmol) in dichloromethane (5 mL) was added 3-deuterium-4-fluoro- benzoyl chloride (210.89 mg, 1.32 mmol). The mixture was stirred at 25 °C for 20 min. The reaction was quenched by adding saturated brine (5 mL), and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was separated by preparative high performance liquid chromatography to give (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 umol, yield: 18.22%) as a white solid.

[0598] MS m / z (ESI): 379.8 [M+H] + .

[0599] 1 H NMR (400 MHz, 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).

[0600] Compound 4

[0601] (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

[0602]

[0603] First Step: Preparation of 3-deuterium-4-chloro-benzoic acid

[0604]

[0605] Dissolve 3-bromo-4-chlorobenzoic acid (5 g, 21.23 mmol) in 2M NaOD / D2O (15 mL) solution, add zinc powder (5.55 g, 84.94 mmol). The mixture was stirred at 25 °C for 96 hours. The reaction solution was filtered to remove the solid, the aqueous phase was adjusted to pH = 1 with 1N HC1, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the organic phase was 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%).

[0606] MS m / z (ESI): 156.0 [M-H] -

[0607] Second step: preparation of 3-deuterium-4-chloro-benzoyl chloride

[0608]

[0609] Dissolve 3-deuterium-4-chloro-benzoic acid (0.1 g, 634.63 umol) in DCM (5 mL), add oxalyl chloride (161.10 mg, 1.27 mmol), then add DMF (0.05 mL), and stir the mixture at 25 °C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the residue 3-deuterium-4-chloro-benzoyl chloride (110 mg), which is directly used in the next step.

[0610] Third step: preparation of compound 4 Reference compound 3.

[0611] MS m / z (ESI): 395.9 [M+H] + .

[0612] 1 H NMR (400 MHz, 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 = 6.9 Hz, 3H).

[0613] Example 5

[0614] (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

[0615]

[0616] Reference compound 3 was prepared.

[0617] MS m / z (ESI): 364.1 [M+H] + .

[0618] Compound 6

[0619] (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

[0620]

[0621] First step: (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

[0622]

[0623] (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 subjected to microwave reaction at 110 °C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by flash 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%).

[0624] MS m / z (ESI): 464.2 [M+H] + .

[0625] Subsequent step to compound A gave (R)-(3-(3-(3,3-difluoroazetidin-l-yl)-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone

[0626]

[0627] MS m / z (ESI): 437.1 [M+H] + .

[0628] 1 H NMR (400 MHz, 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=6.9 Hz, 3H).

[0629] Compound 7

[0630] (R)-(3-(3-(3-fluoroazetidin-l-yl)-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone

[0631]

[0632] Compound 7 was prepared according to the procedure described for compound 6.

[0633] MS m / z (ESI): 419.1 [M+H] + .

[0634] 1 H NMR (400 MHz, 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=6.9 Hz, 3H).

[0635] Compound 9

[0636] (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

[0637]

[0638] Reference compound 6 was prepared according to the procedure described in Example 1.

[0639] MS m / z (ESI): 401.1 [M+H] + .

[0640] 1 H NMR (400 MHz, 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=6.9 Hz, 3H).

[0641] Biological test evaluation

[0642] The application will be further described in the following test examples, but these examples are not meant to limit the scope of the application.

[0643] Test Example 1: Determination of the effect of the compounds of the application on the calcium ion flow in cells stably expressing the NK3 receptor

[0644] Purpose of the experiment: the purpose of this test example is to measure the inhibitory effect of the compounds on the NK3 receptor.

[0645] Experimental equipment:

[0646] 384-well assay plates (Corning; 3712);

[0647] Pipettes (Axygen);

[0648] FLIPR (Molecular Devices).

[0649] Experimental reagents:

[0650] DMEM (Invitrogen; 11965);

[0651] Fetal bovine serum (Biowest; S1810-500);

[0652] Dialysis serum (S-FBS-AU-065; Serana);

[0653] Penicillin and streptomycin (Biowest; L0022-100);

[0654] Hygromycin B (CABIOCHEM, 400052);

[0655] Matrigel (BD; 354230);

[0656] DMSO (Sigma; D2650);

[0657] HBSS (Invitrogen; 14065);

[0658] HEPES (Invitrogen; 15630080);

[0659] Probenecid (Sigma; P8761);

[0660] BSA (renview; FA016);

[0661] Trypsin (HDB; 0458).

[0662] Experimental methods:

[0663] 1. Buffer preparation: 1x HBSS, 20mM HEPES, 2.5mM probenecid (probenecid is 400mM stock in 1M NaOH), 0.1% BSA; probenecid and BSA are freshly added on the day of experiment; experimental buffers include dye buffer and compound dilution buffer, etc.

[0664] 2. Cells are seeded at a density of 1x10 4 cells / well after trypsinization into 384-well assay plates and incubated for 16-24 hours (at least overnight).

[0665] 3. Discard culture medium and add 20μL dye; incubate at 37°C for 60min in the dark, and read the calcium signal.

[0666] 4. Prepare antagonist before experiment; add 5uL / well of 5x antagonist compound into 384-well assay plate, incubate at room temperature for 15 min in dark; transfer the assay plate to FLIPR, add 5uL / well of 6x agonist compound; read the data by FLIPR and save the data; the total assay volume is 30uL, including 20uL / well of dye buffer, 5uL / well of 5x experimental compound and 5uL / well of 6x agonist compound.

[0667] Experimental data processing method:

[0668] Read the calcium signal value by FLIPR, the calculated output result of each sampling time point in the experiment is the ratio of 340 / 510nm and 380 / 510nm wavelength signal, and the maximum value minus the minimum value is calculated from the ratio signal curve; use GraphPad prism to fit the percentage inhibition rate and ten-point concentration data to the parameter nonlinear logistic formula to calculate the IC 50 value of the compound.

[0669] Experimental results:

[0670] Table 7: IC 50 value of compound in stable NK3 receptor cell function calcium ion flow ability experiment

[0671]

[0672]

[0673] Experimental conclusion:

[0674] From the data in the table, it can be seen that the compound of formula I of the present application shows good inhibitory activity in the stable NK3 cell function calcium flow experiment.

[0675] Test example 2, determination of the effect of the compound of the present application on the calcium ion flow ability in stable NK1 / NK2 receptor cells Experimental purpose: The purpose of this test example is to measure the inhibitory effect of the compound on NK1 / NK2 receptor.

[0676] Experimental instrument:

[0677] 384-well assay plate (Corning; 3712);

[0678] Pipette (Axygen);

[0679] FLIPR (Molecular Devices).

[0680] Experimental reagent:

[0681] DMEM (Invitrogen; 11965);

[0682] Fetal bovine serum (Biowest; S1810-500);

[0683] Dialyzed serum (S-FBS-AU-065; Serana);

[0684] Penicillin and streptomycin (Biowest; L0022-100);

[0685] Hygromycin B (CABIOCHEM, 400052);

[0686] Matrigel (BD; 354230);

[0687] DMSO (Sigma; D2650);

[0688] HBSS (Invitrogen; 14065);

[0689] HEPES (Invitrogen; 15630080);

[0690] Probenecid (Sigma; P8761);

[0691] BSA (renview; FA016);

[0692] Trypsin (HDB; 0458).

[0693] Experimental methods:

[0694] 1. Buffer preparation: 1x HBSS, 20mM HEPES, 2.5mM probenecid (probenecid is 400mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA are added fresh on the day of the experiment. Experimental buffers include dye buffer and compound dilution buffer, etc.

[0695] 2. Cells are seeded at a density of 1x10 4 cells / well after trypsinization into 384-well assay plates and incubated for 16-24 hours (at least overnight).

[0696] 3. Culture medium is discarded and 20μL of dye is added. Incubate at 37°C for 60min in the dark and read the calcium signal.

[0697] 4. Prepare antagonists prior to experiment. Antagonist mode: Add 5 uL / well of 5x antagonist compound to 384-well assay plates and incubate at room temperature for 15 min in the dark. Transfer the assay plates to the FLIPR and add 5 uL / well of 6x agonist compound. Read values using the FLIPR and save data. Total assay volume is 30 uL, including 20 uL / well dye buffer, 5 uL / well of 5x test compound, and 5 uL / well of 6x agonist compound.

[0698] Experimental data processing method:

[0699] Read calcium signal values by FLIPR. The calculated output at each sampling time point in the experiment is the ratio of 340 / 510 nm and 380 / 510 nm wavelength signals. The calculation of the maximum minus the minimum comes from the ratio signal curve. Use GraphPad Prism to fit the percent inhibition and ten-point concentration data to the parametric nonlinear logistic formula to calculate the IC 50 values of the compounds.

[0700] Experimental results:

[0701] The compounds of the present application exhibit NK1R IC 50 (nM) values and NK2R IC 50 (nM) values of >10,000 in calcium flux assays in cells stably expressing NK1 / NK2 receptors.

[0702] Experimental conclusions:

[0703] The compounds of the present application show good selectivity in calcium flux assays in cells stably expressing NK3 and NK1 / NK2 receptors.

[0704] Test Example 3, Determination of the effect of the compounds of the present application on IP1 in cells stably expressing HEK293-NK3 cells

[0705] 1. Purpose of the experiment:

[0706] The purpose of this test example is to measure the antagonistic effect of the compounds on the activity of HEK293-NK3 cells.

[0707] 2. Experimental instruments and reagents:

[0708] 2.1 Experimental instruments and consumables:

[0709] 384-well cell plates (Corning: 3824);

[0710] 384-well Echo compound plates (Labcyte: LP-0200);

[0711] Bravo Tip (Agilent: 10734-202);

[0712] Plate reader EnVision Multilabel Reader (PE: 2104-0010);

[0713] Pipetting workstations Bravo (Agilent) and ECHO 550 (LABCYTE);

[0714] Liquid dispenser (Multidrop Combi).

[0715] 2.2 Experimental reagents:

[0716] DMEM, high glucose (Gibco: 12100);

[0717] Fetal bovine serum (Biosera: FB-1058 / 500);

[0718] P / S (Biosera: XC-A4122);

[0719] 5X Matrigel (Corning: 354230);

[0720] IP-ONE-Gq Kit (Cisbio: 62IPAPEJ);

[0721] Agonist Senktide (MCE: HY-P0187);

[0722] Positive control compound Talnetant (MCE: HY-14552);

[0723] Complete medium: DMEM + 10% FBS + 1X P / S; 1X Matrigel: dilute 5X Matrigel with DMEM;

[0724] Cell strain: HDB HEK293-NK3, Shanghai Genomics Co., Ltd.

[0725] 3. Experimental method:

[0726] 1. Coat a 150mm culture dish with 1X Matrigel, 10 minutes at room temperature.

[0727] 2. Culture the HEK293-NK3 cell strain with complete medium, seed in the coated culture dish, 37°C, 5% CO2 to 70%~90% confluence.

[0728] 3. Prepare positive control compound and test compound:

[0729] 1) Dilute the compound 11 concentration points on 384-well-Echo compound plate (LABCYTE: LP-0200) with instrument Bravo;

[0730] 2) Then transfer 10 nL compound (compound storage concentration, for example 10 mM for the highest concentration point) per well to 384-well-cell plate (Corning: 3824) with instrument ECHO; keep at room temperature for use.

[0731] 4. Digest the cells and resuspend in IX Stimulation Buffer (IP-ONE-Gq Kit), seed 5,000 cells / well / 5 μL to 384-well-cell culture plate (the plate has been added with test compound) with Multidrop Combi, centrifuge at 300 rpm for 60 seconds at room temperature, then incubate at 37°C, 5% CO2for 15 minutes.

[0732] 5. Take the cell culture plate out of the CO2incubator, add 5 μL 2X EC 80 (final concentration 3 nM) with Multidrop Combi, centrifuge at 300 rpm for 60 seconds at room temperature, then incubate at 37°C, 5% CO2for 2 hours.

[0733] 6. Take the cell culture plate out of the CO2incubator, add 5 μL IP1 d2 reagent, add 5 μL IP1 Tb Cryptate Antibody reagent with Multidrop Combi, centrifuge at 300 rpm for 60 seconds at room temperature, then keep at room temperature for 1 hour.

[0734] 7. Read the plate with EnVision Multilabel Reader, collect the data at the same time.

[0735] Method of data processing:

[0736] EnVision Multilabel Reader collects the ratio of fluorescence signal value, according to the reading value of Low control (DMSO control) and High control (positive compound) experimental groups, calculates the data of percentage antagonism {% antagonism = (Ratio sample - Ratio low control) / (Ratio high control - Ratio low control) x 100}, the concentration of test compound after 3-fold dilution of the reaction system is 10 uM to 0.17 nM, using XLFit to fit the percentage antagonism and 11-point concentration data to the parameter nonlinear logistic formula to calculate the IC50 Values.

[0737] 4. Experimental results:

[0738] Table 8 IC50 values of compounds in IP1 antagonism in stable NK3 receptor expressing cells 50 Values

[0739]

[0740] 5. Experimental conclusions:

[0741] From the data in the table, it can be seen that the compound of the present application shows good antagonistic activity in the IP1 experiment of stable NK3 cell function.

[0742] Test Example 4: Pharmacokinetic determination in SD rats

[0743] 1. Purpose of the study:

[0744] The pharmacokinetic behavior of the compound of the present application in rats (plasma and brain tissue) was studied in SD rats as test animals, at a dose of 5 mg / kg administered orally.

[0745] 2. Experimental protocol:

[0746] 2.1 Experimental drugs:

[0747] The compound of the present application was self-made.

[0748] 2.2 Experimental animals:

[0749] SD Rat, 21 per group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0750] 2.3 Formulation prescription:

[0751] 0.5% CMC-Na (1% Tween 80), ultrasonic dissolution, prepared into a clear solution or uniform suspension.

[0752] 2.4 Administration:

[0753] SD rats, 21 per group, male; after fasting overnight, p.o. at a dose of 5 mg / kg, with a drug volume of 10 mL / kg.

[0754] 2.5 Sample collection:

[0755] Rats were sacrificed by CO2 at 0, 0.5, 1, 2, 4, 8 and 24 hours before and after administration, 8 mL of blood was collected from the heart and placed in EDTA-K2 test tubes, and the plasma was separated by centrifugation at 6000 rpm for 6 min at 4°C and stored at -80°C; the whole brain tissue was weighed and placed in a 2 mL centrifuge tube and stored at -80°C.

[0756] 2.6 Sample processing:

[0757] 1) 40 uL of the plasma sample was added with 160 uL of acetonitrile for precipitation, and then centrifuged at 3500 x g for 5-20 min.

[0758] 2) 30 uL of the plasma and brain homogenate sample was added with 90 uL of acetonitrile containing an internal standard (100 ng / mL) for precipitation, and then centrifuged at 13000 rpm for 8 min.

[0759] 3) 70 uL of the supernatant after treatment was added with 70 uL of water, vortexed for 10 min, and then 20 uL was taken for LC / MS / MS analysis of the concentration of the test compound. The LC / MS / MS analyzer was AB Sciex API 4000 Qtrap.

[0760] 2.7 Liquid phase analysis:

[0761] • Liquid phase condition: Shimadzu LC-20AD pump

[0762] • Chromatographic column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm) Mobile phase: A liquid was 0.1% formic acid aqueous solution, and B liquid was acetonitrile

[0763] • Flow rate: 0.4 mL / min

[0764] • Elution time: 0-4.0 min, and the eluent was as follows:

[0765]

[0766] 3. Test results and analysis

[0767] The main pharmacokinetic parameters were calculated by WinNonlin 6.1, and the results of the rat pharmacokinetic experiment are shown in Table 9 below:

[0768] Table 9: Results of rat pharmacokinetic experiment

[0769]

[0770] NA: not detected.

[0771] 4. Experimental conclusion:

[0772] From the rat pharmacokinetic experiment results in the table, it can be seen that the compound of the embodiment of the application shows good metabolic properties, and the exposure amount AUC and the maximum blood drug concentration C max All show good.

[0773] Test Example 5, Effect of the Compound of the Invention on the Content of Luteinizing Hormone (LH) in the Plasma of Bilateral Ovariectomized (OVX) Rats

[0774] 1. Experimental purpose:

[0775] The purpose of this test example is to measure the effect of the compound on the content of luteinizing hormone (LH) in the plasma of bilateral ovariectomized (OVX) rats.

[0776] 2. Experimental instruments and reagents:

[0777] 2.1 Experimental instruments:

[0778] Balance (PR2202ZH / E, OHAUS);

[0779] Centrifuge (5424R, Eppendorf);

[0780] Microplate Reader (BioTek Synergy H1);

[0781] Plate washer (Thermo Scientific);

[0782] Pipette (Eppendorf & Rainin);

[0783] Pure water instrument (Thermo Scientific);

[0784] 2.2 Experimental reagents:

[0785] CMC Na (30036365, National Pharmaceutical Reagent);

[0786] Tween 80 (30189828, National Pharmaceutical Reagent);

[0787] Rat LH ELISA Kit (S-type) was purchased from Japan Shibayagi, with the product number AKRLH-010S, which contains Assay buffer C, Sampledilution buffer G, Washing buffer, biotinylated anti-LH alpha antibody, HRP-conjugated streptavidin and color developing agent Chromogen (TMB).

[0788] 2.3 Experimental animals:

[0789] Bilateral ovariectomy SD rats, 10 weeks old, female, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The animals were raised in SPF level animal room, 5 SD rats per cage. The cages, bedding, feed and water were high temperature sterilized before use, and all animals could freely eat and drink.

[0790] 3. Experimental method:

[0791] Group administration: 10-week-old female SD rats, 3 weeks after bilateral ovariectomy for experiment. Before the experiment, each SD rat was fasted overnight, and then the SD rats were randomly divided into groups before administration, 3 rats per group. Each administration group was orally administered with different test compounds, the administration dose was 30 mg / kg, and the administration volume was 10 mL / kg.

[0792] Sample collection: Before and after administration, 0.2-0.3 mL of whole blood was collected from each group of SD rats at 0, 0.5, 1, 2, 4, 8 hours, placed in EDTA-K2 test tubes, shaken well, centrifuged at 5000 rpm for 5 min at 4°C, then the plasma was separated and stored in an ultra-low temperature freezer (-80±10°C).

[0793] Sample detection: All reagents, samples and ELISA plates were equilibrated at room temperature 20-25℃ for at least 30 min, dissolved, vortexed, centrifuged and ready for use. The standard curve was prepared with Assay buffer C at concentrations of 10, 5, 2.5, 1.25, 0.625, 0.313, 0. The samples were diluted twice with Sample dilution buffer G and incubated at room temperature for 10 min. The samples from the previous step were diluted 2.5 times with Assay buffer C and incubated at room temperature. The 96-well plate was washed 4 times with 1x Washing buffer at 300 μL / well. The standard curve and sample wells were added with 50 μL of the corresponding standard and sample, mixed, sealed and incubated at 20-25℃ for 2 h. 50 μL of 1x biotinylated anti-LHα antibody was added to each well, mixed, sealed and incubated at 20-25℃ for 1 h. The plate was washed 4 times with 1x Washing buffer at 300 μL / well. 50 μL of 1x HRP-conjugated streptavidin was added to each well, mixed, sealed and incubated at 20-25℃ for 0.5 h. The plate was washed 4 times with 1x Washing buffer at 300 μL / well. 50 μL of Chromogen (TMB) was added to each well, mixed and incubated at 20-25℃ for 20 min. 50 μL of Stop solution (1 M H2SO4) was added to each well, mixed and the OD value of each well was read at 450 nm wavelength using a microplate reader.

[0794] 4. Experimental data processing method:

[0795] The standard curve was drawn using Graphpad and the sample concentration was calculated. If the sample detection was diluted, the final calculation needed to be multiplied by the corresponding dilution factor, which was the actual concentration of the sample.

[0796] 5. Experimental results:

[0797] Table 10: Effect of compounds on the content of luteinizing hormone (LH) in the plasma of ovariectomized rats (OVX)

[0798]

[0799] Note: The data in parentheses indicate that the example corresponds to the Vehicle group (i.e. control group)

[0800] 6. Experimental conclusion:

[0801] As can be seen from the data in the table, the compound of the embodiment of the application can significantly reduce the content of LH in the plasma of ovariectomized rats (OVX).

[0802] Test Example 6, Pharmacodynamic study of the test compound on the senktide-induced bilateral ovariectomized rat tail temperature model

[0803] 1. Purpose of the experiment:

[0804] To evaluate the effect of the test compound on the senktide-induced tail temperature of bilateral ovariectomized rats.

[0805] 2. Experimental instruments and reagents:

[0806] 2.1 Instruments:

[0807] Balance (BSA2202s-CW, Sartorius);

[0808] Thermometer (BAT-10, Physitemp);

[0809] Probe (SST-1, Physitemp);

[0810] 2.2 Reagents

[0811] Senktide (106128-89-6, MCE);

[0812] NaCl (10019318, National Reagent);

[0813] DMSO (D2650-100ML, Sigma);

[0814] CMCNa (30036365, National Reagent);

[0815] Tween 80 (30189828, National Reagent).

[0816] 2.3 Experimental animals

[0817] Bilateral ovariectomized SD rats, 10 weeks old, female, purchased from Beijing VitoLihua Experimental Animal Technology Co., Ltd. The animals were raised in SPF animal room, 5 SD rats per cage. The cage, bedding, feed and water were high-temperature sterilized before use, and all animals could freely eat and drink.

[0818] 2.4 Test compound:

[0819] The compound of the embodiment of the application is self-made.

[0820] 3 Experimental operation:

[0821] Ten-week-old female SD rats, two weeks after bilateral ovariectomy and recovery, were randomly divided into a negative control group, a model group, and a drug treatment group, with eight rats in each group. A probe was fixed to the dorsal side of the rat's tail using medical tape, positioned 1-2 cm from the base of the tail.

[0822] The negative control group and the model group were given the solvent orally, and each treatment group was given a different test compound orally. The dosage was 30 mg / kg and the volume was 10 mL / kg.

[0823] Thirty minutes after oral administration of the solvent or test compound, the negative control group received a subcutaneous injection of physiological saline (5 mL / kg); the model group and all treatment groups received a subcutaneous injection of 0.2 mg / mL Senktide (5 mL / kg) to induce hot flash-like symptoms. Tail skin temperature (TST) was measured and recorded at minute 0 before injection; measurements were taken every 5 minutes after injection, for a total of 75 minutes.

[0824] 4. Data Processing:

[0825] Calculate the tail temperature change (ΔTST) at each time point relative to 0, plot the tail temperature change ΔTST-time curve, and calculate the area under the curve (AUC). ΔTST ). ΔTST=TST n -TST0, where TST0 is the tail temperature at 0 minutes prior to subcutaneous injection of saline or Senktide; TST n The tail temperature at the nth minute after subcutaneous injection.

[0826] AUC ΔTST =∑(ΔTST) n +ΔTST n+5 )*5 / 2

[0827] 5. Experimental Results:

[0828] Table 11: Efficacy data of OVX rat tail temperature model

[0829]

[0830] Note: The data in parentheses indicates that this embodiment corresponds to the Vehicle / Senktide group (i.e., the control group).

[0831] 6. Experimental Conclusion:

[0832] As can be seen from the data in the table, the compound of the present invention can effectively inhibit hot flashes induced by Senktide in ovariectomized rats.

[0833] II. Study on the salts and crystal forms of compounds

[0834] 1. Terminology

[0835] The term "pharmaceutically acceptable" as used herein means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0836] The term "substantially pure" as used herein means that the crystalline form structure of the compound of Formula I in certain preferred embodiments of the present application is in a substantially pure form, having an HPLC purity or crystalline form purity of substantially greater than 90% (inclusive), preferably greater than 95%, more preferably greater than 98%, and most preferably greater than 99.5%.

[0837] "Crystal form" or "crystal form modification" as used herein means a crystalline form having the same chemical composition but a different spatial arrangement of the molecules, atoms, and / or ions making up the crystal. Although crystal forms, crystal form modifications, have the same chemical composition, they differ in their packing and geometric arrangement and can exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Two polymorphs can be enantiotropic or monotropic with respect to their temperature-stability relationships. For monotropic systems, the relative stabilities of the two solid phases remain the same upon a change in temperature. In contrast, in enantiotropic systems, there is a transition temperature at which the stabilities of the two phases switch (Theory and Origin of Polymorphismin "Polymorphismin Pharmaceutical Solids" (1999) ISBN: 0-8247-0237).

[0838] The crystalline form samples of the application can be provided with substantial phase homogeneity, meaning that a dominant amount of a single crystalline form structure is present and optionally a minor amount of one or more other crystalline form structures. The presence of more than one crystalline form structure of the application in a sample can be determined by techniques such as powder X-ray diffraction (XRPD) or solid state nuclear magnetic resonance spectroscopy (SSNMR). For example, the presence of additional peaks in a experimentally determined XRPD pattern (observed) compared to a simulated XRPD pattern (calculated) can indicate more than one crystalline form structure in a sample. Simulated XRPD can be calculated from single crystal X-ray data (see Smith, D. K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196, April 1963; also see Yin, S., Scaringe, R. P., DiMarco, J., Galella, M and Gougoutas, J. Z., American Pharmceutical Review. 2003. 6.2. 80). Preferably, the crystalline form structure has substantial phase homogeneity as indicated by less than 10%, preferably less than 5%, more preferably less than 2% of the total peak area resulting from additional peaks in an experimentally determined XRPD pattern that are not present in the simulated XRPD pattern. Most preferably, the crystalline form structure of the application has substantial phase homogeneity of less than 1% of the total peak area resulting from additional peaks in an experimentally determined XRPD pattern that are not present in the simulated XRPD pattern.

[0839] The various crystalline form structures of the application described herein can be distinguished from one another using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, solid state nuclear magnetic resonance (SSNMR) spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0840] The crystalline form structures of the application can be prepared by various methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet-spray. Techniques for crystallization or recrystallization of a crystalline form structure from a solvent mixture include, for example, solvent evaporation, lowering the temperature of the solvent mixture, seeding of the solvent mixture with the molecule and / or salt in a supersaturated state, lyophilization of the solvent mixture, addition of an antisolvent (anti-solvent) to the solvent mixture. The crystalline form structures, including polymorphs, can be prepared using high throughput crystallization techniques.

[0841] Pharmaceutical crystals, including polymorphs, methods of making and characterizing pharmaceutical crystals are disclosed in Solid-State Chemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, 2ndEdition, SSCI, West Lafayette, Indiana, 1999.

[0842] Seed crystals can be added to any crystallization mixture to promote a crystalline form. As will be apparent to the skilled artisan, seed crystals are used as a means of controlling the growth of a particular crystalline form or as a means of controlling the particle size distribution of the crystalline product. Accordingly, 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 desired size of the average product particle. In general, small size seed crystals are required to effectively control the growth of crystals in the batch. Small size seed crystals can be produced by sieving, grinding or micronizing larger crystals or by microcrystallization of a solution. It should be noted that grinding or micronizing of crystals cannot cause any change in the degree of crystallinity of the desired crystal structure (i.e., to amorphous or to another polymorph).

[0843] Crystal structures disclosed or claimed herein can exhibit similar, but not identical, analytical characteristics within a reasonable error range depending on the conditions of testing, purity, equipment, and other variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made in the present application without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the application indicated by the following claims.

[0844] As used herein, the term "room temperature" or "RT" refers to ambient temperature of 20 to 25 °C (68-77 0 F).

[0845] 2. Experimental Materials

[0846] The reagents used in the examples of the present application are commercially available, industrial grade or analytical grade reagents, and the compounds are prepared according to the methods described in the following examples.

[0847] 3. Analytical Methods

[0848] 3.1. X-ray Powder Diffraction

[0849] Those skilled in the art will recognize that powder X-ray diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used. In particular, it is generally known that the intensity in an X-ray powder diffraction pattern can fluctuate with the material conditions used. It should be further understood that the relative intensity can also vary with experimental conditions, and accordingly, the exact intensity should not be taken into account. Furthermore, the measurement error of conventional powder X-ray diffraction angles is typically about 5% or less, and this degree of measurement error should be considered within the aforementioned diffraction angle range. Therefore, it is to be understood that the crystal structure of the present invention is not limited to crystal structures that provide X-ray diffraction patterns that are exactly the same as those depicted in the accompanying drawings. Any crystal structure that provides substantially the same powder X-ray diffraction patterns as those disclosed in the drawings falls within the scope of the present invention. The ability to determine substantially the same X-ray powder diffraction patterns is within the capabilities of those skilled in the art. Other suitable standard calibrations known to those skilled in the art are also available. However, relative intensity may vary with crystal size and shape.

[0850] The polymorphisms of Formula I compounds are characterized by their X-ray powder diffraction patterns. Therefore, in the case of Cu Kα radiation... X-ray powder diffraction patterns of the salt were acquired using a Bruker D8 Advance X-ray powder diffractometer operating in reflection mode (GADDS CS). The tube voltage and current were set to 40 kV and 25 mA, respectively, for acquisition scans. The sample was scanned for 180 seconds within the 2θ range of 4.0° to 40°. The diffractometer was calibrated using corundum standards for the peak positions indicated by 2θ. All analyses were performed at room temperature, typically 20°C–30°C. Data were acquired and integrated using DIFFRAC.COMMANDER. The diffraction patterns were analyzed using jade6 software. XRPD sample preparation involved placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass slide or equivalent to ensure a flat surface and appropriate height. The sample holder was then placed in the Bruker XRPD instrument, and powder X-ray diffraction patterns were acquired using the instrument parameters described above. Measurement discrepancies associated with these types of X-ray powder diffraction analysis results are caused by a number of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including those occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in all peaks in the same direction. Generally, this calibration factor will ensure that the measured peak positions are consistent with the expected peak positions and can be within the expected 2θ value ± 0.2°.

[0851] The 2-theta (°) values and intensity values (as % of the highest peak) for each polymorph obtained in the examples of the present application are listed in Tables 1-6.

[0852] 3.2. Differential Scanning Calorimetry

[0853] Differential scanning calorimetry (DSC) experiments were performed on a NETZSCH DSC 214 polyma instrument. The sample (approximately 1-6 mg) was weighed in an aluminum pan and recorded to the nearest 1 mg, and transferred to the DSC. The instrument was purged with nitrogen at 40 mL / min. Data were collected between 25 and 300 °C at a heating rate of 10 °C / min. The plot was drawn with the endothermic peak facing down. However, one skilled in the art will note that there is some variability in the onset and maximum temperatures measured in DSC measurements depending on the heating rate, crystal shape and purity, and other measurement parameters.

[0854] The specific examples and methods of preparation provided below will further illustrate certain aspects of the embodiments of the present application. The scope of the following examples will not limit the scope of the application in any way.

[0855] Example 1

[0856] Weigh 40 mg of the free base of compound 3, add 10 mL of methanol, heat to 60 °C to dissolve, filter, stir at room temperature overnight, filter, and dry the solid at 50 °C under vacuum for 24 h to obtain (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone free base Form A.

[0857] The obtained compound 3 free base Form A was analyzed by X-ray powder diffractometer (XRPD) and differential scanning calorimeter (DSC), respectively. The XRPD instrument used was a BRUKER D8 ADVANCE, and the DSC instrument used was a NETZSCH DSC 214 polyma. The XRPD analysis method parameters were as follows: Cu K radiation (40 kV, 25 mA), scanning step length of 0.02° / S (2 theta value), scanning speed of 12° / min (2 theta value), and scanning range of 4°-40° (2 theta value). The DSC analysis method parameters were as follows: temperature range of 25 °C to 300 °C, scanning rate of 10 °C per minute, and protective gas of nitrogen (flow rate of 40 mL / min). The XRPD analysis chart is shown in Figure 1 , and the DSC analysis chart is shown in Figure 7 .

[0858] Example 2

[0859] Take 100 mg of compound 3 free base Form A, add 2 mL of ethyl acetate, add 1 mol / L methanolic hydrochloric acid solution to it at a 1 : 1.2 molar ratio, turbid, stir at room temperature for 24 hours, then filter, and dry the solid at 50°C under vacuum overnight to obtain compound hydrochloride salt solid, which has an XRPD pattern as shown in Figure 2 .

[0860] Example 3

[0861] Take 50 mg of compound 3 free base Form A, add 400 μL of tetrahydrofuran, add 1 mol / L methanolic methanesulfonic acid solution to it at a 1 : 1.2 molar ratio, the resulting clear solution is left to evaporate the solvent at room temperature, to obtain a gel, add 400 μL of ethyl acetate to it, stir at room temperature for 8 hours, then filter, and dry the solid obtained at 50°C under vacuum for 24 h to obtain compound methanesulfonic acid salt solid, which has an XRPD pattern as shown in Figure 3 .

[0862] Example 4

[0863] Take 50 mg of compound 3 free base Form A, add 400 μL of tetrahydrofuran, add 1 mol / L methanolic nitric acid solution to it at a 1 : 1.2 molar ratio, the resulting clear solution is left to evaporate the solvent at room temperature, to obtain a gel, add 400 μL of ethyl acetate to it, stir at room temperature for 8 hours, then filter, and dry the solid obtained at 50°C under vacuum for 24 h to obtain compound nitrate salt solid, which has an XRPD pattern as shown in Figure 4 .

[0864] Example 5

[0865] Take 100 mg of compound 3 free base Form A, add 2 mL of ethyl acetate, add 1 mol / L methanolic sulfuric acid solution to it at a 1 : 1.2 molar ratio, turbid, stir at room temperature for 24 hours, then filter, and dry the solid at 50°C under vacuum overnight to obtain compound sulfate salt solid, which has an XRPD pattern as shown in Figure 5 .

[0866] Example 6

[0867] Take 100 mg of compound 3 free base Form A, add 2 mL of ethyl acetate, add 1 mol / L methanolic hydrobromic acid solution to it at a 1 : 1.2 molar ratio, turbid, stir at room temperature for 24 hours, then filter, and dry the solid at 50°C under vacuum overnight to obtain compound hydrobromide salt solid, which has an XRPD pattern as shown in Figure 6 .

[0868] Example 7: Stability test study of Form A sample

[0869] Take the free base crystal form A of compound 3 to prepare samples, and place them in light 5000lx, high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH conditions, and investigate the stability for 5 days and 10 days, determine the content by HPLC external standard method, and calculate the change of related substances by chromatographic peak area normalization method. The experimental results are shown in Table 12:

[0870] Table 12: Stability experiment results of crystal form A samples

[0871]

[0872]

[0873] Conclusion: The total amount of impurities and single impurities of free base crystal form A do not increase significantly after being placed under light, high temperature and / or high humidity conditions for 10 days, and the stability is good.

[0874] Example 8: Hygroscopicity experiment research of crystal form A samples

[0875] The free base crystal form A of compound 3 is placed in saturated water vapor of different relative humidity, so that the compound reaches dynamic equilibrium with water vapor, and the percentage of weight gain of the compound after equilibrium is calculated.

[0876] Conclusion: The free base crystal form A has a weight gain of about 0.2720% under RH 80% conditions, and has slight hygroscopicity. After 2 cycles of hygroscopicity and desorption under 0-95% relative humidity conditions, the XRPD spectrum of the free base crystal form A does not change, i.e. the crystal form does not change.

[0877] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, and they should be covered in the scope of the claims of the present application.

Claims

1. A free base crystalline form of the compound (R)-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl-3-d) methanone, the powder X-ray diffraction pattern of which comprises at least 2-4 peaks at 2-theta of 16.8±0.2°, 18.6±0.2°, 19.8±0.2° or 20.2±0.2°, and further comprises 2-5 peaks at 2-theta of 9.3±0.2°, 10.0±0.2°, 12.0±0.2°, 12.8±0.2° and 22.5±0.2°.

2. The morphic form of claim 1, characterized by, the powder X-ray diffraction pattern of the free base crystalline form comprises at least peaks at the following diffraction angles (2-theta): 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°； 12.8±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°; 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°。 3. The morphic form of claim 2, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. the powder X-ray diffraction pattern of the free base crystalline form optionally further comprises one or more peaks at 2-theta of 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°.

4. The morphic form of claim 2, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. the powder X-ray diffraction pattern of the free base crystalline form comprises at least peaks at the following diffraction angles (2-theta): 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°; or 15.8±0.2°、24.2±0.2°、25.4±0.2°、27.5±0.2°、27.8±0.2°、28.9±0.2°。 5. The morphic form of claim 1, characterized by, the powder X-ray diffraction pattern of the free base crystalline form is substantially as shown in Figure 1 and the DSC pattern thereof is substantially as shown in Figure 7.

6. Acid 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, characterized by the acid in the acid salt 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, acetyloxyhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, octanoic 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, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic 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-naphthalene disulfonic 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, pantothenic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluene sulfonic acid or L-malic acid.

7. The acid salt of claim 6, wherein, a crystalline form of a hydrochloride salt form having a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 8. The crystalline form of the acid salt of claim 7, characterized by, a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 9. The crystalline form of the acid salt of claim 7, characterized by, a powder X-ray diffraction pattern substantially as shown in Figure 2.

10. The acid salt of claim 6, wherein, a crystalline form of a methanesulfonic acid salt form having a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 11. The crystalline form of the acid salt of claim 10, characterized by, a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 12. The crystalline form of the acid salt of claim 10, characterized by, a powder X-ray diffraction pattern substantially as shown in Figure 3.

13. The acid salt of claim 6, wherein, a crystalline form of a nitrate salt form having a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 14. The crystalline form of the acid salt of claim 13, characterized by, a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 15. The crystalline form of the acid salt of claim 13, characterized by, a powder X-ray diffraction pattern substantially as shown in Figure 4.

16. The acid salt of claim 6, wherein, a crystalline form of a sulfate salt form having a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 17. The crystalline form of the acid salt of claim 16, characterized by, a powder X-ray diffraction pattern comprising at least the following peaks at diffraction angles (2Θ): 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°; 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°。 18. The crystalline form of the acid salt of claim 16, characterized by, The powder X-ray diffraction pattern thereof is substantially as shown in Figure 5.

19. The acid salt of claim 6, wherein, The crystalline form is an acid salt, and the crystalline form is a hydrobromide salt, and the crystalline form has a powder X-ray diffraction pattern comprising at least peaks at the following diffraction angles (2Θ): 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°; 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°。 20. The crystalline form of the acid salt of claim 19, characterized by, The powder X-ray diffraction pattern thereof further comprises at least peaks at the following diffraction angles (2Θ): 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°; 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°。 21. The crystalline form of the acid salt of claim 19, characterized by, The powder X-ray diffraction pattern thereof is substantially as shown in Figure 6.

22. The acid salt or a crystalline form thereof according to any one of claims 6-21, wherein, The number of acids is 0.2-3.

23. The acid salt or a crystalline form thereof of claim 22, wherein, The number of acids is 1.

24. The acid salt or a crystalline form thereof according to any one of claims 6-21, wherein, The salt is a hydrate or an anhydrate; when the salt is a hydrate, the number of waters is 0.2-3.

25. The acid salt or crystal form thereof of claim 24, wherein, When the salt is a hydrate, the number of waters is 0.5, 1, 2 or 3.

26. A method for preparing the crystalline form of any one of claims 1-5, wherein, a) a proper amount of the compound is weighed and dissolved in an organic solvent, and the solution is cleared, b) the target product is obtained by stirring, filtering and drying; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methylethyl 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 combination thereof.

27. A process for preparing the acid salt of any one of claims 6-21 or a crystalline form thereof, characterized in that, comprising the following steps: a) a proper amount of the free base crystalline form of the compound is weighed and added into an organic solvent; b) a proper amount of the acid is weighed and dissolved in an organic solvent, and the target product is obtained by filtering after stirring or by volatilizing after dissolving to obtain a gel, stirring and filtering after adding an anti-solvent to the gel, and vacuum drying; wherein: the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methylethyl 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 combination thereof; the anti-solvent is selected from ethyl acetate, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether or a combination thereof; said acid is selected from the group consisting of mineral acids or organic acids, wherein said mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; and said organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetyloxyurea acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic 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-naphthalene disulfonic 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, pantothenic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluene sulfonic acid or L-malic acid.

28. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form, acid salt or a crystalline form thereof according to any one of claims 1-21, and a pharmaceutically acceptable carrier.

29. The crystalline form, acid salt or crystalline form thereof of any one of claims 1-21, and the pharmaceutical composition of claim 28, wherein, said therapeutically effective amount comprises 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%.

30. Use of a crystalline form, acid salt or a crystalline form thereof according to any one of claims 1-21, and a pharmaceutical composition according to claim 28, for the manufacture of a medicament for the treatment and / or prevention of a NK3 inhibitor related disorder.

31. The use according to claim 30, wherein said use is for the manufacture of a medicament for the treatment and / or prevention of a psychotic disorder, a cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, an inflammatory disease, emesis, pre-eclampsia, an airway related disease, a reproductive disorder, a sex hormone dependent disease or a gynaecological related disease.

32. The use according to claim 30, wherein said use is for the manufacture of a medicament for the treatment and / or prevention of a menopausal syndrome related disease, said menopausal syndrome comprising hot flushes, sweating, palpitations, dizziness and obesity symptoms.

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