Free base crystalline form of polycyclic compound containing nitrogen heterocycle and method for producing same

Abstract

The present invention relates to a free base crystalline form of a polycyclic compound containing a nitrogen heterocycle and a method for preparing the same, in particular to a crystalline form having the free base of the compound of general formula (I), a method for preparing the same, a pharmaceutical composition containing a therapeutically effective amount of the crystalline form, and its use as an orexin receptor antagonist in the manufacture of related drugs for treating nervous system diseases. [Formula 1] JPEG2025531050000055.jpg35133

Description

[Technical Field]

[0001] The present invention relates to the field of drug synthesis, specifically to the crystalline form of a polycyclic compound containing a nitrogen heterocycle, and its preparation method and application. [Background technology]

[0002] The hypothalamus is the center regulating feeding and energy balance. Orexin is a neuropeptide synthesized and secreted by lateral hypothalamic (LH) orexin neurons. Named for its potent appetite-stimulating effects, orexin is divided into orexin A and orexin B. Both orexin A and orexin B act on the G protein-coupled receptors OX1R and OX2R, respectively. OX1R and OX2R are widely expressed throughout the central nervous system. OX1R binds more strongly to orexin B than to orexin A, while OX2R binds to both orexin A and B. There is a complex relationship between orexin and other neuropeptides that affect feeding, and orexin has a wide range of effects on feeding, water intake, sleep-wake cycle regulation, reproduction, body temperature, blood pressure, and sensation. For example, orexin regulates wakefulness and arousal by regulating two distinct G protein-coupled receptors, OX1R and OX2R. Orexin receptor antagonists have potential therapeutic advantages in the treatment of neurological disorders, including insomnia, depression, anxiety, and drug addiction.

[0003] OX1R and OX2R mediate intracellular Ca transport via phospholipase C. 2+ OX2R further couples with Gi / Go and inhibits adenylate cyclase, thereby inhibiting cAMP production. Research has shown that of OX1R and OX2R, OX2R is preferentially expressed in the paraventricular nucleus of the hypothalamus and is involved in regulating the HPA axis. Nocturnal hyperexcitation of the hypothalamic-pituitary-adrenal (HPA) axis is the greatest differentiator between depressed patients and healthy controls, and downregulation of hyperexcitation of the HPA axis contributes to the improvement of depressive symptoms.

[0004] Currently, there are several drugs targeting OX1 / 2R that are in clinical trials or already on the market, such as Merck's Suvoraxant and Eisai's Lemborexant. However, these drugs, which are Orexin 1 / 2 antagonists, have antagonistic effects on both OX1R and OX2R receptors. When they act on OX1R, they cause changes in the normal physiological structure of rapid eye movement sleep (NEM, brain activity is the same as during wakefulness) and non-rapid eye movement sleep (NEREM, deep sleep), resulting in the sacrifice of NREM time, the extension of REM time, and an increased risk of lethargy. OX1R also fails to exert its antidepressant effects.

[0005] OX2R antagonists can exert antidepressant effects, and OX2R monoreceptor antagonists can also exert sufficient therapeutic effects on insomnia. Therefore, selective OX2R antagonists can avoid various side effects, such as lethargy, caused by acting on OX1R. Currently, the only OX2R antagonist in clinical trials is Seltorexant, developed by Janssen Pharmaceuticals, Inc., and its main indications include major depressive disorder (MDD) and primary and secondary insomnia.

[0006] Selective OX2R antagonists have the potential to treat neurological disorders such as insomnia, depression, and anxiety, and there is a huge clinical demand for them. Selective OX2R antagonists have good application prospects in the pharmaceutical industry as drugs.

[0007] The PCT patent (application number: PCT / CN2022 / 080829) discloses the structure of a series of polycyclic compounds containing nitrogen heterocycles. In subsequent research and development, the present invention has conducted comprehensive research on the free base crystalline form of the above compound in order to find a suitable crystalline form that can facilitate the processing, filtration and drying of the product, is easy to store, and ensures long-term stability of the product. Summary of the Invention

[0008] The entire contents of patent PCT / CN2022 / 080829 are incorporated herein by reference.

[0009] The object of the present invention is to provide a crystalline form of a compound represented by general formula (I), the structure of which is as shown in formula (I): [ka] where: X1 is CR6 or N; X2 is CR6 or absent, R1 is selected from halogen; R2, R3, R4 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, mercapto, cyano, carboxyl, sulfonic acid, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R2, R3, R4, and R6 are each independently preferably hydrogen, deuterium, a halogen, an amino group, a nitro group, a hydroxy group, a mercapto group, a cyano group, a carboxyl group, a sulfonic acid group, an oxo group, a thio group, or C 1-8 Alkyl group, C 1-8 Deuterated alkyl groups, C 1-8 Haloalkyl group, C 1-8 Hydroxyalkyl group, C 1-8 Alkoxy group, C 1-8 Haloalkoxy group, C 1-8 Hydroxyalkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-12Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-8 Alkyl group, C 1-8 Deuterated alkyl groups, C 1-8 Haloalkyl group, C 1-8 Hydroxyalkyl group, C 1-8 Alkoxy group, C 1-8 Haloalkoxy group, C 1-8 Hydroxyalkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino group, nitro group, hydroxy group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, C 1-8 Alkyl group, C 1-8 Deuterated alkyl groups, C 1-8 Haloalkyl group, C 1-8 Hydroxyalkyl group, C 1-8 Alkoxy group, C 1-8 Haloalkoxy group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, amino group, nitro group, hydroxy group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; or any two or more of R, R, and R are joined to the atoms to which they are connected to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R5 is selected from a hydroxyalkyl group or a haloalkyl group, which may optionally be further substituted, and the hydroxyalkyl group is preferably [ka] and the haloalkyl group is preferably [ka] and X' is a halogen; R7 is independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted, and is preferably hydrogen, deuterium, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, and optionally deuterium, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy groups and C 1-6 It may be further substituted with one or more substituents of haloalkoxy groups, more preferably hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy groups and C 1-6 haloalkoxy groups, and more preferably hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy groups and C 1-3haloalkoxy group, more preferably hydrogen, deuterium, C 1-3 It is an alkyl group.

[0010] A preferred embodiment of the present invention provides a crystalline form of a compound as shown in general formula (II): [ka] where: X1 is CH or N; X2 is CH or absent; R2, R3, and R4 each independently represent hydrogen, deuterium, a halogen, an amino group, a hydroxy group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 haloalkoxy group or C 1-3 hydroxyalkoxy groups, R5 is [ka] is selected from.

[0011] When X2 is absent, the substituent R2 is preferably a halogen, said halogen being preferably located in the ortho or meta position of the triazole, more preferably in the ortho position; The halogen is preferably fluorine; When X2 is CR6, the substituent R2 is preferably a halogen, said halogen being preferably located at the ortho or meta position of the pyrimidine, more preferably at the meta position of the pyrimidine and / or at the ortho position linking the carbonyl group; The halogen is preferably fluorine.

[0012] A preferred embodiment of the present invention is a compound represented by the general formula (I): [ka] The object is to be selected from the above.

[0013] In a preferred embodiment of the present invention, there is provided a crystalline form of ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone (Compound 9), the structure of which is [ka] is.

[0014] The powder X-ray diffraction pattern of the crystalline form I has a diffraction peak at 8.6±0.2° 2θ, or a diffraction peak at 9.2±0.2° 2θ, or a diffraction peak at 10.2±0.2° 2θ, or a diffraction peak at 10.8±0.2° 2θ, or a diffraction peak at 12.0±0.2° 2θ, or a diffraction peak at 12.8±0.2° 2θ, or a diffraction peak at 13.7±0.2° 2θ, or a diffraction peak at 14.2±0.2° 2θ, or a diffraction peak at 15.5±0.2° 2θ, or a diffraction peak at 16.6±0.2° 2θ. or a diffraction peak at 17.3±0.2 degrees 2θ, or a diffraction peak at 18.4±0.2 degrees 2θ, or a diffraction peak at 19.0±0.2 degrees 2θ, or a diffraction peak at 19.5±0.2 degrees 2θ, or a diffraction peak at 20.5±0.2 degrees 2θ, or a diffraction peak at 21.3±0.2 degrees 2θ, or a diffraction peak at 26.5±0.2 degrees 2θ, or a diffraction peak at 28.6±0.2 degrees 2θ, preferably at any of 2, 4, 6, 8 or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least diffraction peaks located at one or more positions where 2θ is 9.2±0.2°, 10.2±0.2°, 16.6±0.2° or 18.4±0.2°, preferably 2 to 4 of these positions, more preferably 3 to 4 positions, most preferably 4 positions, and optionally may further comprise diffraction peaks located at one or more positions where 2θ is 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2° or 26.5±0.2°, preferably 2, 3, 4 or 5 of these positions, for example 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 18.4±0.2°, 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 9.2±0.2°, 12.8±0.2°, 16.6±0.2°, 18.4±0.2°, 9.2±0.2°, 10.2±0.2°, 17.3±0.2°, 19.0±0.2°, 9.2±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 21.3±0.2°, 10.2±0.2°, 12.8±0.2°, 16.6±0.2°, 17.3±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 18.4±0.2°, 19.0±0.2°, 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 19.0±0.2°, 9.2±0.2°, 12.8±0.2°, 16.6±0.2°, 18.4±0.2°, 19.0±0.2°, 9.2±0.2°, 10.2±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 9.2±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 21.3±0.2°, 26.5±0.2°, 10.2±0.2°, 12.8±0.2°, 16.6±0.2°, 17.3±0.2°, 19.0±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 26.5±0.2°, 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 18.4±0.2°, 19.0±0.2°, 21.3±0.2°, 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 9.2±0.2°, 12.8±0.2°, 16.6±0.2°, 18.4±0.2°, 19.0±0.2°, 21.3±0.2°, 9.2±0.2°, 10.2±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 26.5±0.2°, 9.2±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, 26.5±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 18.4±0.2°, 21.3±0.2°, 26.5±0.2°, 10.2±0.2°, 12.8±0.2°, 16.6±0.2°, 17.3±0.2°, 18.4±0.2°, 19.0±0.2°, 12.8±0.2°, 17.3±0.2°, 18.4±0.2°, 19.0±0.2°, 21.3±0.2°, and 26.5±0.2°. More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more positions where 2θ is 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, or 28.6±0.2°, preferably including any 2 to 4 positions, or 5 to 6 positions, more preferably including any 4 or 6 positions, among them, for example: 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 14.2±0.2°, 8.6±0.2°, 10.8±0.2°, 14.2±0.2°, 28.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 28.6±0.2°, 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 14.2±0.2°, 28.6±0.2°, 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, and 28.6±0.2°. The X-ray powder diffraction pattern of crystalline Form I has characteristic peaks at 9.2±0.2° and 18.4±0.2° 2θ, preferably further characteristic peaks at 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, and 19.0±0.2° 2θ, more preferably further characteristic peaks at 12.8±0.2° and 21.3±0.2° 2θ, even more preferably Preferably, the optical isotropy further comprises characteristic peaks at 2θ of 26.5±0.2° and 28.6±0.2°, and even more preferably, the optical isotropy further comprises characteristic peaks at 2θ of 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 15.5±0.2°, 19.5±0.2°, 20.5±0.2°, 23.1±0.2°, 27.8±0.2°, and 32.1±0.2°.

[0015] Using Cu-Kα radiation, the characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacing values, are shown in Table 1.

[0016] [Table 1-1] [Table 1-2]

[0017] For crystalline form I of compound 9 according to the present invention, its X-ray powder diffraction pattern is substantially as shown in FIG. 1, its DSC pattern is substantially as shown in FIG. 2, and its TGA pattern is substantially as shown in FIG. 3.

[0018] The crystalline form I of compound 9 according to the present invention is an anhydrate crystalline form.

[0019] The powder X-ray diffraction pattern of the crystalline form II has a diffraction peak at 2θ of 9.9±0.2 degrees, or a diffraction peak at 2θ of 10.8±0.2 degrees, or a diffraction peak at 2θ of 13.2±0.2 degrees, or a diffraction peak at 2θ of 14.9±0.2 degrees, or a diffraction peak at 2θ of 16.4±0.2 degrees, or a diffraction peak at 2θ of 17.1±0.2 degrees, or a diffraction peak at 2θ of 17.9±0.2 degrees, or a diffraction peak at 2θ of 19.3±0.2 degrees, or a diffraction peak at 2θ of 19.8±0.2 degrees. or a diffraction peak at 20.2±0.2 degrees 2θ, or a diffraction peak at 20.5±0.2 degrees 2θ, or a diffraction peak at 21.0±0.2 degrees 2θ, or a diffraction peak at 21.9±0.2 degrees 2θ, or a diffraction peak at 25.8±0.2 degrees 2θ, or a diffraction peak at 26.5±0.2 degrees 2θ, or a diffraction peak at 27.5±0.2 degrees 2θ, preferably at any 2, 4, 6, 8 or 10 positions therein; Preferably, the powder X-ray diffraction pattern comprises at least diffraction peaks located at one or more positions where 2θ is 16.4±0.2°, 17.1±0.2°, 17.9±0.2° or 25.8±0.2°, preferably 2 to 4 of these positions, more preferably 3 to 4 positions, most preferably 4 positions, and optionally may further comprise diffraction peaks located at one or more positions where 2θ is 10.8±0.2°, 14.9±0.2°, 19.3±0.2°, 21.9±0.2° or 26.5±0.2°, preferably 2, 3, 4 or 5 of these positions, for example 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 25.8±0.2°, 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 26.5±0.2°, 16.4±0.2°, 17.1±0.2°, 25.8±0.2°, 26.5±0.2°, 10.8±0.2°、14.9±0.2°、17.9±0.2°、25.8±0.2°、 10.8±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°、 10.8±0.2°、16.4±0.2°、17.1±0.2°、19.3±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°、26.5±0.2°、 16.4±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°、26.5±0.2°、 10.8±0.2°、14.9±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°、 10.8±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°、26.5±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°、25.8±0.2°、 10.8±0.2°、16.4±0.2°、17.1±0.2°、19.3±0.2°、21.9±0.2°、 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°、 14.9±0.2°、16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°、 14.9±0.2°、16.4±0.2°、17.1±0.2°、17.9±0.2°、26.5±0.2°、26.5±0.2°、 14.9±0.2°、16.4±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°、26.5±0.2°、 10.8±0.2°, 14.9±0.2°, 17.9±0.2°, 21.9±0.2°, 25.8±0.2°, 26.5±0.2°, 10.8±0.2°, 17.1±0.2°, 19.3±0.2°, 21.9±0.2°, 25.8±0.2°, 26.5±0.2°, 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 21.9±0.2°, 25.8±0.2°, 26.5±0.2°, 10.8±0.2°, 14.9±0.2°, 16.4±0.2°, 17.1±0.2°, 19.3±0.2°, 21.9±0.2°, 10.8±0.2°, 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 25.8±0.2°, and 26.5±0.2°. More preferably, the powder X-ray diffraction pattern optionally further comprises diffraction peaks located at one or more positions where 2θ is 9.9±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, or 21.0±0.2°, preferably including any 2 to 4 positions, or 5 to 6 positions, more preferably including any 4 or 6 positions, among them, for example: 9.9±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 9.9±0.2°, 13.2±0.2°, 19.8±0.2°, 20.5±0.2°, 9.9±0.2°, 13.2±0.2°, 20.5±0.2°, 21.0±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 9.9±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 21.0±0.2°, 9.9±0.2°, 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2° or 21.0±0.2°, In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of crystalline Form II has characteristic peaks at 16.4±0.2° and 25.8±0.2° 2θ, preferably further including characteristic peaks at 17.1±0.2°, 17.9±0.2°, 21.9±0.2°, and 26.5±0.2° 2θ, more preferably further including characteristic peaks at 10.8±0.2° and 14.9±0.2° 2θ, even more preferably further including characteristic peaks at 9.9±0.2° and 19.3±0.2° 2θ, and even more preferably further including characteristic peaks at 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 21.0±0.2°, and 27.5±0.2° 2θ.

[0020] Using Cu-Kα radiation, the characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacing values, are shown in Table 2.

[0021] [Table 2-1] [Table 2-2]

[0022] For crystalline form II of compound 9 according to the present invention, its X-ray powder diffraction pattern is substantially as shown in FIG. 4, its DSC pattern is substantially as shown in FIG. 5, and its TGA pattern is substantially as shown in FIG. 6.

[0023] For the crystalline form II (monohydrate) of compound 9 according to the present invention, the water content measured by KF is 3.1% (API:water=1:0.83, molar ratio).

[0024] The present invention further provides a method for preparing a crystalline form of the compound of general formula (I), specifically, Step 1) weighing out an appropriate amount of the free base and suspending it in an antisolvent; Step 2) shaking the suspension obtained above; and step 3) rapidly centrifuging the suspension, removing the supernatant, and drying the solid to a constant weight to obtain the target product. where: The anti-solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water, heptane, and n-pentane, and isopropyl acetate, toluene, methyl tert-butyl ether, water, heptane, and n-pentane are preferred.

[0025] In a preferred embodiment of the present invention, the suspension density in step 1) is 50 to 200 mg / mL.

[0026] In a preferred embodiment of the present invention, the temperature in step 2) is 0 to 50°C.

[0027] In a preferred embodiment of the present invention, the shaking time in step 2) is selected from 1 to 10 days.

[0028] The present invention further provides a method for preparing a crystalline form of the compound of general formula (I), specifically, Step 1) weighing an appropriate amount of free base and dissolving it in a good solvent; Step 2) adding a poor solvent to the solution obtained above and stirring until a solid is precipitated; and step 3) rapidly centrifuging the suspension, removing the supernatant, and drying the remaining solid to a constant weight to obtain the target product. where: The good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, and 3-pentanone, and is preferably methanol, dichloromethane, or ethyl acetate.

[0029] The anti-solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane, isopropyl acetate.

[0030] In a preferred embodiment of the present invention, the temperature in step 2) is 0 to 25°C.

[0031] The present invention further provides a method for preparing a crystalline form of the compound of general formula (I), specifically, Step 1) weighing an appropriate amount of free base and dissolving it in a good solvent by heating; Step 2) rapidly placing the solution obtained above at a low temperature and stirring until a solid precipitates; and step 3) rapidly centrifuging the suspension, removing the supernatant, and placing the remaining solid in a drying box and drying it to a constant weight to obtain the target product. where: The good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, and tetrahydrofuran, and is preferably acetone.

[0032] In a preferred embodiment of the present invention, the temperature in step 2) is 0 to 25°C.

[0033] Another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound described above and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0034] The present invention further relates to the use of the crystalline form of any one of the compounds or the pharmaceutical composition of the present invention in the preparation of an orexin receptor antagonist, preferably an OX2R selective receptor antagonist.

[0035] The present invention further relates to the use of any one of the crystalline forms of the compounds or the pharmaceutical composition of the present invention in the manufacture of a medicament for treating nervous system diseases, preferably insomnia, depression, anxiety, and drug addiction, more preferably major depressive disorder (MDD), primary and secondary insomnia, and depression accompanied by insomnia.

[0036] The present invention further relates to a method for treating a nervous system disorder, comprising using said crystalline form of any one of the further compounds of the present invention or the pharmaceutical composition of the present invention, wherein said nervous system disorder is preferably insomnia, depression, anxiety, or drug addiction, more preferably major depressive disorder (MDD), primary and secondary insomnia, or depression accompanied by insomnia. [Brief explanation of the drawings]

[0037] [Figure 1] 1 is an XRPD pattern of the free base crystalline form I of Compound 9. [Figure 2] 1 is a DSC pattern of the free base crystalline form I of Compound 9. [Figure 3] 1 is a TGA pattern of the free base crystalline form I of Compound 9. [Figure 4] 1 is an XRPD pattern of the free base crystalline form II of Compound 9. [Figure 5] 1 is a DSC pattern of the free base crystalline form II of Compound 9. [Figure 6] 1 is a TGA pattern of the free base crystalline form II of Compound 9. DETAILED DESCRIPTION OF THE INVENTION

[0038] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0039] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl groups. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

[0040] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available bonding site. The substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups. In the present invention, the substituent is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a haloalkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, or an alkyl group substituted with a hydroxy group. The alkyl group substituted with a hydroxy group may be a 2-hydroxyisopropyl group or a 1-hydroxyethyl group.

[0041] In the present invention, the cycloalkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms.

[0042] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl groups, and the like; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0043] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, heteroaryl group, or heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups.

[0044] In the present invention, a heterocyclyl group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclyl group, which contains 3 to 20 ring atoms, wherein one or more ring atoms are nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 2), but does not include a ring moiety of -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 10 ring atoms, and even more preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, pyrrolidone, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 4,5-dihydropyridazin-3(2H)-one, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, [ka] and the like, and preferably a pyrrolidinyl group, a pyrrolidone group, a piperidin-2-one group, a 3,4-dihydropyridin-2(1H)-one group, a 4,5-dihydropyridazin-3(2H)-one group, an azetidinyl group, an oxetanyl group, a dihydropyrrolyl group, a tetrahydrofuryl group, a pyrazolidinyl group, a morpholinyl group, [ka] A piperazinyl group and a pyranyl group are more preferred, and a dihydropyrrolyl group, a pyrrolidinyl group, a pyrrolidone group, a piperidin-2-one group, a 3,4-dihydropyridin-2(1H)-one group, a 4,5-dihydropyridazin-3(2H)-one group, an azetidinyl group, an oxetanyl group, an oxanyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, [ka] Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, which are optionally linked to other groups via a single bond or further linked in a tandem ring to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0045] Heterocyclyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0046] In the present invention, the term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as a phenyl group and a naphthyl group. The ring of the aryl group, which is preferably a phenyl group, can be fused to the ring of a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, where the ring connected to the basic skeleton is the ring of the aryl group, and non-limiting examples thereof include: [ka] Includes.

[0047] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0048] In the present invention, the heteroaryl group refers to a heteroaromatic group containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5 or 6-membered, such as pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, and pyrazinyl, and preferably pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazole, and pyridine. The ring of the heteroaryl group can be fused onto the ring of an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring connected to the base skeleton is the ring of the heteroaryl group, non-limiting examples of which include: [ka] Includes.

[0049] Heteroaryl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0050] In the present invention, the term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of "alkyl group" is as defined above. Preferably, it is an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, and carboxylate groups. Further non-limiting examples of alkoxy groups include propane-2-oxy groups and the like.

[0051] In the present invention, a haloalkyl group refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of haloalkyl groups include a trifluoromethyl group, a trifluoroethyl group, Non-limiting examples of haloalkyl groups further include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0052] In the present invention, a haloalkoxy group refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above; The haloalkoxy group may be perhalogenated or partially halogenated, and the number of halogen atoms may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., and the halogen atom is preferably F, Cl, Br, or I, such as a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2-tetrafluoroethoxy group, or a perfluoroethoxy group.

[0053] In the present invention, a hydroxyalkyl group refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.

[0054] In the present invention, the term "alkenyl group" refers to a chain-like alkenyl group, also known as an olefin group. Preferably, the alkenyl group contains 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and most preferably 2 to 3 carbon atoms. Non-limiting examples of the alkenyl group include a vinyl group and a propenyl group. Here, the alkenyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0055] In the present invention, the term "alkynyl group" refers to a chain-like alkynyl group, also known as an alkyne group, and refers to an unsaturated hydrocarbon group containing -C≡C-, preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms, even more preferably an alkynyl group containing 2 to 4 carbon atoms, and most preferably an alkynyl group containing 2 to 3 carbon atoms. Here, the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0056] In the present invention, a haloalkyl group refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0057] In the present invention, a haloalkoxy group refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0058] In the present invention, a hydroxyalkyl group refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.

[0059] "Hydroxy" refers to an -OH group.

[0060] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0061] An "amino group" refers to -NH2.

[0062] A "cyano group" refers to -CN.

[0063] A "nitro group" refers to -NO2.

[0064] "THF" refers to tetrahydrofuran.

[0065] "DMSO" refers to dimethyl sulfoxide.

[0066] "IPA" refers to isopropanol.

[0067] "MeOH" refers to methanol.

[0068] "EtOH" refers to ethanol.

[0069] "DMF" refers to N,N-dimethylformamide.

[0070] "DIPEA" refers to N,N-diisopropylethylamine.

[0071] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0072] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be any one or more of A, B, and C.

[0073] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and the description includes cases where the event or circumstance has or has not occurred.

[0074] "Substituted" refers to the fact that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0075] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0076] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0077] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting biological activity.

[0078] An X-ray powder diffraction pattern (XRPD) refers to an experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak positions (abscissa) and peak intensities (ordinate). As those skilled in the art will appreciate, experimental error therein is dependent on instrument conditions, sample preparation, and sample purity. In particular, as those skilled in the art will appreciate, X-ray diffraction patterns typically vary depending on instrument conditions. As those skilled in the art will appreciate, suitable error limits for XRPD may be 2θ±0.5°, 2θ±0.4°, 2θ±0.3°, or 2θ±0.2°. It should be noted that the relative intensities of an X-ray diffraction pattern may also vary depending on experimental conditions, and therefore the order of peak intensities is not the only or decisive factor. Furthermore, experimental factors such as sample height may affect the overall peak angle, and a certain deviation is usually acceptable. Therefore, as those skilled in the art will appreciate, any crystalline form having characteristic peaks that are the same as or similar to those of the patterns of the present invention is within the scope of the present invention.

[0079] "TGA" refers to thermogravimetric analysis (TGA) experiments.

[0080] "DSC" refers to differential scanning calorimetry (DSC) experiments.

[0081] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0082] "PK" refers to pharmacokinetic (PK) studies.

[0083] "KF" refers to Karl Fischer moisture determination (KF) experiment.

[0084] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0085] Example Preparation of intermediates: Intermediate 1: Preparation of 2-(2-chloro-6-methylpyrimidin-4-yl)propanol [ka]

[0086] A solution of Intermediate 1a (674 mg, 3.6 mmol) in THF (5 mL) was added to methylmagnesium bromide (5 mL, 1 M in THF) at -78 °C, and the mixture was stirred at -78 °C for 2 h, followed by stirring at room temperature for 12 h. The reaction mixture was quenched by slowly adding saturated ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, dried, and concentrated, and the residue was purified using silica gel column chromatography (petroleum ether / ethyl acetate system) to give Intermediate 1 (362 mg, colorless oil) in 53.7% yield. MS m / z (ESI): 187.1[M+1]

[0087] Preparation of Intermediate 2: 2-(5-fluoro-2-(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidin-4-yl)-propan-2-ol [ka]

[0088] Step 1 Under nitrogen protection, tributyl-(1-ethoxy-vinyl)-stannane (2.7 mL, 7.99 mmol) and dichlorobis(triphenylphosphine)palladium(II) (100 mg, 0.142 mmol) were added to a solution of intermediate 2a (1.3 g, 7.18 mmol) in anhydrous DMF (15 mL). The mixture was heated at 100 °C for 16 h, cooled, and a saturated solution of potassium fluoride (aq) was added. The mixture was stirred at room temperature for 1 h. After filtration through diatomaceous earth, the organic phase was thoroughly washed with water, extracted with ethyl acetate, and concentrated. The crude product was passed through a column (PE:EA = 10:1) to give intermediate 2b (1.3 g, 83.5%). MS m / z (ESI): 217.0 [M+1]

[0089] Step 2 Intermediate 2b (1.3 g, 6.00 mmol) was dissolved in THF (10 mL) and 3N HCl (5 mL) was added. The mixture was stirred at room temperature for 1 h. After completion of the reaction was monitored by LCMS, the mixture was adjusted to pH 7-8 with saturated NaHCO3, extracted with ethyl acetate, and the organic phase was concentrated to give intermediate 2c (1.1 g, 97.2%), which was used directly in the next step. MS m / z (ESI): 189.0[M+1] 1H NMR (400MHz, Chloroform-d) δ 2.69 (s,3H),2.62 (d,J=2.8Hz,3H).

[0090] Step 3 Intermediate 2c (1.9 g, 10.07 mmol) and MeMgBr (3 M, 4.37 mL) were added to THF (40 mL) at 0° C. The reaction solution was stirred at 25° C. for 1 hour, saturated NH4Cl (20 mL) was added, extracted with ethyl acetate (40 mL), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA = 3:1) to give intermediate 2d (1.4 g, 67.9% yield). MS m / z (ESI): 205.0[M+1]

[0091] Step 4 tert-Butyl rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (500 mg, 2.36 mmol), intermediate 2d (530.16 mg, 2.59 mmol), and cesium carbonate (1.55 g, 4.76 mmol) were added to DMF (10 mL). The reaction mixture was stirred at 100 °C for 3 h, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL). The combined extracts were dried over NaSO, spun dry, and the crude product was passed through a column (PE:EA = 3:1) to give intermediate 2e (720 mg, 80.3% yield). MS m / z (ESI): 381.2[M+1]

[0092] Step 5 Intermediate 2e (1 g, 2.63 mmol), trifluoroacetic acid (2.69 mmol, 2 mL) were added to DCM (3 mL), and the reaction solution was stirred at 25° C. for 3 hours and then spun to dryness to give Intermediate 2 (700 mg, 95.0% yield). MS m / z (ESI): 281.2[M+1]

[0093] Preparation of Intermediate 3: 2-(6-(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1h)-yl)-4-methylpyridin-2-yl)propan-2-ol [ka]

[0094] The preparation of Intermediate 3 was carried out in accordance with the preparation methods of Steps 3, 4, and 5 of Intermediate 2, except that 6-chloro-4-methyl-2-acetyl-pyridine was used instead of Intermediate 2c to obtain Intermediate 3 (1.2 g, colorless oil, 53.7%). MS m / z (ESI): 262.2[M+1]

[0095] Example 1 Preparation of Compound 1: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0096] Step 1 To a solution of 1a (300 mg, 1.42 mmol) and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (310 mg, 1.50 mmol) in DMF (5.0 mL), HATU (809 mg, 2.13 mmol) and DIPEA (550 mg, 4.26 mmol) were slowly added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 30 mL of ethyl acetate and washed with water (30 mL * 3). The organic phases were combined, dried, and concentrated. The residue was purified using silica gel column chromatography (petroleum ether / ethyl acetate system) to give tert-butyl (3aR,6aS)-5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Compound 1b) (452 ​​mg, pale yellow solid, 79.7%). MS m / z (ESI): 402.1[M+1]

[0097] Step 2 To a solution of 1b (450 mg, 1.12 mmol) in DCM (6 mL) was slowly added TFA (3 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Compound 1c) (330 mg, pale yellow oil), which was used directly in the next step. MS m / z (ESI): 302.0[M+1]

[0098] Step 3 Intermediate 1 (61.5 mg, 0.33 mmol), 1c (100 mg, 0.33 mmol), Pd(dba) (18 mg, 0.02 mmol), BINAP (25 mg, 0.04 mmol), cesium carbonate (215 mg, 0.66 mmol), and dioxane (2 mL) were added to a round-bottom flask, and the mixture was stirred at 100 °C for 12 h under nitrogen gas protection. After the reaction was cooled, it was quenched by adding water (5 mL) and extracted with dichloromethane (10 mL*3). The organic phases were combined, dried and concentrated, and the residue was purified by preparative HPLC to give (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 1) (32.4 mg, white solid, 21.8%). MS m / z (ESI): 452.2[M+1] 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.94 (s,1H),7.80 (dd,J=17.2,8.2Hz,1H),7.66 (td,J=8.3,6.1Hz,1H),7.44 (dt,J=12.0,8.6Hz,1H),6.74 (d,J=4.1Hz,1H),5.10 (d,J=4.0Hz,1H),3.73 (dtd,J=22.4,7.2,6.5,3.6Hz,2H),3.59-3.41 (m,4H),3.35 (d,J=4.8Hz,1H),3.16-2.90 (m,3H),2.28 (d,J=3.5Hz,3H),1.36 (d, J = 3.3 Hz, 6 H).

[0099] Example 2 Preparation of Compound 2: ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone [ka]

[0100] The synthesis method of Compound 2 was the same as that of Example 1. MS m / z (ESI): 470.2[M+1].

[0101] Example 3 Preparation of Compound 3: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3aR,6aS)-5-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0102] 2-Fluoro-6-pyrimidin-2-ylbenzoic acid (50 mg, 0.23 mmol) and intermediate 3 (65.88 mg, 0.25 mmol) were added to MeCN (5 mL). Tetramethylchlorourea hexafluorophosphate (128.33 mg, 0.46 mmol) and 1-methylimidazole (56.45 mg, 0.69 mmol) were added at 25 °C. The reaction solution was stirred at 25 °C for 2 hours, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL * 2). The combined extracts were dried over Na2SO4 and spin-dried. The crude product was purified by preparative HPLC to give compound 3 (64 mg, 60.5% yield). MS m / z (ESI): 462.2[M+1] 1H NMR (400MHz,DMSO-d6) δ 8.93 (d,J=4.9Hz,1H),8.82 (d,J=4.9Hz,1H),8.05 (dd,J=25.0,7.8Hz,1H),7.62 (q,J=7.7Hz,1H),7.54-7.38 (m,2H),6.85 (d,J=9.8Hz,1H),6.68 (d,J=22.0Hz,1H),3.80 (ddd,J=37.8,12.6,7.8Hz,4H),3.61-3.51 (m,3H),3.18 (dt,J=10.8,5.1Hz,3H),2.36 (d,J=3.4Hz,3H),1.50 (d,J=5.2Hz,6H).

[0103] Example 4 Preparation of Compound 4: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3aR,6aS)-5-(6-(2-fluoropropan-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0104] Compound 3 (45 mg, 0.1 mmol) and DAST (23.57 mg, 0.15 mmol) were added to DCM (5 mL) at 0° C. The reaction solution was stirred at 25° C. for 0.5 hours. After the reaction was completed, water (20 mL) was added, followed by extraction with dichloromethane (30 mL * 2). The organic phases were combined, dried over Na2SO4, spin-dried, and the crude product was purified by preparative HPLC to give compound 4 (31 mg, yield 68.6%). MS: m / z (ESI): 464.2[M+1]. 1H NMR (400MHz,DMSO-d6) δ 8.92 (d,J=4.9Hz,1H),8.76 (d,J=4.9Hz,1H),8.03 (dd,J=31.4,7.8Hz,1H),7.67-7.33 (m,3H),6.56 (d,J=3.8Hz,1H),6.20 (d,J=5.4Hz,1H),3.85-3.65 (m,2H),3.59-3.47 (m,3H),3.27-2.90 (m,5H),2.23 (s,3H),1.60 (dd,J=22.0,3.0Hz,6H).

[0105] Example 5 Preparation of Compound 5: ((3aR,6aS)-5-(5-fluoro-4-(2-fluoropropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone [ka]

[0106] The synthesis method of Compound 5 was the same as that of Example 4, and Compound 2 was used as a starting material in place of Compound 3 to obtain Compound 5 (30 mg, yield 66%). MS: m / z (ESI): 472.2[M+1]. 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.96 (s,1H),7.80 (dd,J=14.7,8.2Hz,1H),7.66 (td,J=8.3,6.0Hz,1H),7.44 (q,J=9.2Hz,1H),3.76-3.64 (m,2H),3.53 (ddd,J=23.2,11.1,7.2Hz,5H),3.17-2.94 (m,3H),2.36-2.23 (m,3H),1.67 (dd,J=21.9,4.0Hz,6H).

[0107] Example 6 Preparation of Compound 6: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0108] Step 1 Compound 6-1 (100.00 mg, 539.08 μmol) was dissolved in tetrahydrofuran (5.0 mL), and then methylmagnesium bromide (3 M, 538.77 μL) was added to the reaction solution. The reaction solution was stirred at 0 ° C for 0.5 h. Saturated ammonium chloride (5 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 * 10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain the product 2-(6-chloro-4-methylpyridin-2-yl)propan-2-ol (compound 6-2) (90 mg, 90.0%). MS m / z (ESI): 186.1[M+1]

[0109] Step 2 Compound 6-2 (65.95 mg, 0.36 mmol), compound 3c (100 mg, 0.33 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.22 mg, 59.20 μmol), and palladium acetate (6.63 mg, 29.61 μmol) were dissolved in 1,4-dioxane (2 mL). Potassium tert-butoxide (33.16 mg, 296.07 μmol) was then added to the reaction mixture, and the mixture was stirred at 100°C under microwave conditions for 1 hour. Saturated brine (10 ml) was added to the reaction solution, and extracted with dichloromethane (3 * 10 mL). The organic phases were combined, dried, and concentrated to give the crude product, which was purified by preparative separation to give (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 6) (8 mg, 6.00% yield). MS m / z (ESI): 451.1[M+1]. 1 H NMR (400MHz,DMSO) δ 7.95 (s,1H),7.80 (dd,J=18.7,8.2Hz,1H),7.73-7.55 (m,1H),7.40 (m,1H),7.02 (dd,J=58.3,50.0Hz,2H),6.66 (d,J=6.9Hz,1H),6.11 (s,1H),3.87-3.48 (m,7H),3.27-2.90 (m,3H),2.21 (d,J=4.9Hz,3H),1.38 (d,J=6.3Hz,6H).

[0110] Example 7 Compound 7: Preparation of ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone [ka]

[0111] Step 1 Tributyl(1-ethoxyvinyl)stannane (11.90 g, 32.95 mmol) and compound 7a (5 g, 29.95 mmol) were dissolved in DMF (5 mL), followed by the addition of bistriphenylphosphine palladium(II) chloride (1.05 g, 1.50 mmol). The reaction mixture was stirred at 100 ° C for 2 hours. After the reaction was completed, saturated aqueous potassium fluoride (10 mL) was added, the mixture was stirred for 1 hour, filtered, and the filter cake was washed with dichloromethane (10 mL * 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain compound 7b (5.6 g, 92.3% yield). MS m / z (ESI): 203.0 [M+1]

[0112] Step 2 Compound 7b (5.6 g, 27.64 mmol) was dissolved in tetrahydrofuran (2 mL), and then hydrochloric acid (2 mL, 27.64 mmol) was added to the reaction mixture. The reaction mixture was then stirred at 50 ° C for 2 h, saturated sodium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain compound 7c (4.4 g, yield 91.2%). MS m / z (ESI): 175.0[M+1]

[0113] Step 3 Compound 7c (4.4 g, 25.21 mmol) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (3 M, 9.24 mL) was added to the reaction mixture at −78° C. The mixture was then stirred at −78° C. for 15 minutes, saturated ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate system) to obtain 7d (2.2 g, yield 45.8%). MS m / z (ESI): 191.0[M+1]

[0114] Step 4 The synthesis method of Compound 7 was the same as that of Compound 6, and Compound 1c and Compound 7d were used as raw materials to obtain Compound 7 (38 mg, yield 42.6%). MS: m / z (ESI): 456.2[M+1] 1 H NMR (400MHz,DMSO) δ 8.21 (t,J=23.7Hz,1H),7.99 (d,J=73.9Hz,2H),7.73 (dd,J=17.8,8.2Hz,1H),7.59 (dd,J=14.6,8.1Hz,1H),7.37 (dd,J=19.5,8.8Hz,1H),5.13 (d,J=9.5Hz,1H),3.91-3.34 (m,7H),3.14-2.87 (m,3H),1.39 (d,J=4.2Hz,6H).

[0115] Example 8 Preparation of Compound 8: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropan-2-yl)-5-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0116] Step 1 Compound 8-1 (0.2 g, 1.75 mmol), methyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (586.94 mg, 2.10 mmol), and potassium phosphate (1.11 g, 5.24 mmol) were dissolved in 1,4-dioxane (4.0 mL) and HO (1.0 mL). Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (142.49 mg, 174.62 μmol) was added to the reaction mixture, and the mixture was stirred at 100°C for 16 hours. Saturated brine (10 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, dried, and concentrated to give a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate system) to give methyl 2-fluoro-6-(pyrimidin-2-yl)benzoate (compound 8-2) (0.2 g, 49.1%). MS m / z (ESI): 233.1[M+1]

[0117] Step 2 Compound 8-2 (0.8 g, 3.45 mmol) was dissolved in water (2 mL) and methanol (2 mL). Sodium hydroxide (413.39 mg, 10.33 mmol) was then added to the reaction mixture, which was then stirred at 70 °C for 16 h. The reaction mixture was then adjusted to an acidic pH by adding 2 mol / L hydrochloric acid (10 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried and concentrated to give crude 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (compound 8-3) (260 mg, 34.6%). The crude product was used directly in the next step without further purification. MS m / z (ESI): 219.1[M+1]

[0118] Step 3 Compound 8-3 (0.2 g, 917.43 μmol) and N,N-dimethylformamide (0.1 mL) were dissolved in dichloromethane (2 mL). Oxalyl chloride (232.70 mg, 1.83 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 0.5 h and then concentrated to give the crude product. The crude product, tert-butyl (3R,6S)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (192.88 mg, 909.81 μmol), was dissolved in dichloromethane (2 mL). N-ethyl-N-isopropylpropan-2-amine (352.29 mg, 2.73 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. Saturated brine (10 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 * 10 mL). The organic phases were combined, dried, and concentrated to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate system) to give tert-butyl (3R,6S)-5-(2-fluoro-6-(pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (compound 8-4) (0.2 g, 53.4%). MS m / z (ESI): 413.2[M+1]

[0119] Step 4 Compound 8-4 (200.00 mg, 485.43 μmol) was dissolved in hydrochloric acid / 1,4-dioxane (4 M, 2 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, and the filter cake was collected and dried to give (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3R,6S)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 8-5) (120 mg, 79.2%). MS m / z (ESI): 313.2[M+1]

[0120] Step 5 The synthesis method of compound 8 was the same as that of compound 6, and compound 8-5 and compound 2-(6-chloro-3-methylpyridin-2-yl)-propan-2-ol were used as raw materials to obtain (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropan-2-yl)-5-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 8) (1.8 mg, 2.6%). MS: m / z (ESI): 462.2[M+1]

[0121] Example 9 Preparation of Compound 9: ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone [ka]

[0122] The synthesis method of compound 9 was the same as that of compound 6, and compound 9 (22 mg, yield 28.6%) was obtained using compounds 8-5 and 7d as starting materials. MS: m / z (ESI): 467.2[M+1] 1 H NMR (400MHz,DMSO) δ 8.86 (dd,J=48.0,4.9Hz,2H),8.32 (s,1H),8.02 (dd,J=35.7,7.8Hz,1H),7.60 (dd,J=14.0,7.9Hz,1H),7.44 (ddd,J=26.7,12.9,4.9Hz,2H),5.33-5.10 (m,1H),3.89-3.46 (m,7H),3.23-2.95 (m,3H),1.46 (s,6H).

[0123] Example 10 Preparation of Compound 10: (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0124] Intermediate 2 (80 mg, 0.285 mmol) was dissolved in acetonitrile (2 mL), and 4-fluoro-2-(triazol-2-yl)benzoic acid (59 mg, 0.285 mmol), N-methylmorpholine (36 mg, 0.356 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (120 mg, 0.428 mmol) were added. The reaction mixture was incubated at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC chromatography (acetonitrile / water system) to give compound 10 (16.3 mg, 12.2% yield). MS m / z (ESI): 470.2[M+1] 1 H NMR (400MHz,DMSO-d6) δ 8.03 (s,2H),7.74 (dd,J=9.6,2.0Hz,1H),7.60 - 7.56 (m,1H),7.43 - 7.38 (m,1H),5.17 (s,1H),3.75 - 3.65 (m,2H),3.60 - 3.56 (m,1H),3.48 - 3.44 (m,3H),3.34 - 3.29 (m,1H),3.02 - 2.93 (m,3H),2.31 (s,3H),1.46 (s,6H).

[0125] Example 11 Preparation of Compound 11: (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0126] Step 1 2,3-Difluorobenzonitrile (12.0 g, 86.3 mmol) was dissolved in N,N-dimethylformamide (100 mL), 1,2,3-triazole (5.96 g, 86.3 mmol) and cesium carbonate (28.1 g, 86.3 mmol) were added, and the reaction mixture was heated to 120 °C and reacted for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into 200 mL of water, and extracted with methyl tert-butyl ether (100 mL * 2). The combined organic phases were washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to give compound 11a (6.5 g, 40.0% yield). MS m / z (ESI): 189.0[M+1] 1 H NMR (400MHz,CDCl3) δ 8.00 (s,2H),7.67 - 7.65 (m,1H),7.62 - 7.55 (m,2H).

[0127] Step 2 Compound 11a (1.5 g, 7.97 mmol) was dissolved in 1,4-dioxane (10 mL) and water (30 mL), sodium hydroxide (3.19 g, 79.8 mmol) was added, and the mixture was heated to 110 °C and reacted for 4 hours. The reaction mixture was cooled to 0 °C, adjusted to approximately pH 1 with dilute hydrochloric acid, and extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 11b (1.5 g, 90.8% yield). MS m / z (ESI): 208.0[M+1] 1 H NMR (400MHz,CDCl3) δ 7.89 (s,2H),7.87 (d,J=7.6Hz,1H),7.63 - 7.58 (m,1H),7.52 - 7.49 (m,1H).

[0128] Step 3 (cis)-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (120 mg, 0.565 mmol) was dissolved in anhydrous acetonitrile (2 mL), and compound 11b (117 mg, 0.565 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (238 mg, 0.848 mmol), and N-methylmorpholine (86 mg, 0.850 mmol) were added and reacted at room temperature for 2 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to give compound 11c (210 mg, 92.6% yield). MS m / z (ESI): 402.2[M+1] 1H NMR (400MHz,DMSO-d6) δ 8.07 (s,2H),7.71 - 7.66 (m,1H),7.63 - 7.58 (m,1H),7.42 (d,J=7.6Hz,1H),3.49 - 3.42 (m,3H),3.40 - 3.36 (m,1H),3.23 - 3.19 (m,1H),3.16 - 3.01 (m,3H),2.87 - 2.78 (m,2H),1.41 (s,9H).

[0129] Step 4 Compound 11c (80 mg, 0.199 mmol) was dissolved in anhydrous dichloromethane (2 mL), and a solution of hydrochloric acid in dioxane (4 M, 2 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 11d (60 mg, 99.9% yield). MS m / z (ESI): 302.1[M+1]

[0130] Step 5 Compound 11d (60 mg, 0.199 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and intermediate 2d (45 mg, 0.220 mmol) and cesium carbonate (130 mg, 0.399 mmol) were added. The mixture was heated to 110 °C and reacted for 2 hours. The reaction mixture was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC chromatography (acetonitrile / water system) to give compound 11 (31.3 mg, 33.5% yield). MS m / z (ESI): 470.2[M+1] 1H NMR (400MHz,DMSO-d6) δ 8.00 (s,2H),7.70 - 7.65 (m,1H),7.62 - 7.57 (m,1H),7.42 (d,J=7.6Hz,1H),5.16 (s,1H),3.73 - 7.69 (m,1H),3.64 - 3.59 (m,1H),3.57 - 3.49 (m,2H),3.43 - 3.34 (m,2H),3.29 - 3.25 (m,1H),3.13 - 3.09 (m,1H),2.99 - 2.93 (m,2H),2.32 (d,J=2.8Hz,3H),1.46 (s,6H).

[0131] Example 12 Preparation of Compound 12: ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyridin-2-yl)phenyl)methanone [ka]

[0132] Step 1 Under N2 protection, CuI (653.81 mg, 3.43 mmol), Pd(PPh3)4 (1.98 g, 1.71 mmol), and CsF (5.21 g, 34.30 mmol) were added to a solution of compound 12a (4 g, 17.16 mmol) and 2-(tributylstannyl)pyridine (6.97 g, 18.93 mmol) in DMF (60 mL). The reaction was carried out at 120 °C for 5 h. After cooling to room temperature, 150 mL of water was added and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified to give compound 12b (2.8 g, 70.5% yield). MS m / z (ESI): 232.1[M+1]

[0133] Step 2 To a mixture of compound 12b (800 mg, 3.46 mmol) in water (5.0 mL) and methanol (5.0 mL), sodium hydroxide (688.98 mg, 17.22 mmol) was added. The mixture was allowed to react at 25°C for 3 hours. 2 N HCl was added until the pH reached 2, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give compound 12c (650 mg, 86.5% yield). MS m / z (ESI): 218.0[M+1]

[0134] Step 3 To a solution of 12c (100 mg, 0.46 mmol) and intermediate 2 (129 mg, 0.46 mmol) in acetonitrile (3.0 mL), tetramethylchlorourea hexafluorophosphate (257 mg, 0.92 mmol) and N-methylimidazole (188 mg, 2.29 mmol) were added. The mixture was stirred at 25 °C for 30 minutes. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative HPLC to give compound 12 (40 mg, 18.1% yield). MS m / z (ESI): 480.2[M+1] 1 H NMR (400MHz,DMSO-d6) δ 8.64-8.44 (m,1H),7.87 (dq,J=21.9,7.1,6.6Hz,1H),7.76-7.48 (m,3H),7.43-7.19 (m,2H),5.16 (s,1H),3.67 (dddd,J=38.5,25.2,11.5,7.2Hz,5H),3.23-2.95 (m,5H),2.32 (dd,J=11.6,2.8Hz,3H),1.46 (d,J=11.0Hz,6H).

[0135] Example 13 Preparation of Compound 13: (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0136] Step 1 5-Fluoro-2-iodobenzoic acid (300 mg, 1.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL), and 1,2,3-triazole (117 mg, 1.69 mmol), cuprous iodide (258 mg, 1.35 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (193 mg, 0.97 mmol), and cesium carbonate (735 mg, 2.26 mmol) were added. The mixture was microwaved at 120 °C for 15 min. The reaction mixture was cooled to room temperature, poured into 50 mL of water, adjusted to pH 5 with dilute hydrochloric acid, and extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 column chromatography (acetonitrile / water system) to give Compound 13a (150 mg, yield 64.2%). MS m / z (ESI): 208.0[M+1].

[0137] Step 2 The preparation of Compound 13 was carried out in accordance with the preparation method of Step 3 of Compound 12, except that Compound 12c was replaced with Compound 13a to obtain Compound 13 (60 mg, yield 30%). MS m / z (ESI): 470.2[M+1]. 1H NMR (400MHz,DMSO-d6) δ 7.98 (s,2H),7.93 - 7.89 (m,1H),7.49 - 7.46 (m,1H),7.37 - 7.35 (m,1H),5.16 (s,1H),3.81 - 3.57 (m,3H),3.42 - 3.37 (m,4H),3.04 - 2.94 (m,3H),2.30 (s,3H),1.46 (s,6H).

[0138] Example 14 Preparation of Compound 14: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka]

[0139] Step 1 2-Chloropyrimidine (280 mg, 2.44 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and water (1 mL). 2-Borato-5-fluorobenzoic acid (300 mg, 1.63 mmol), tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol), and cesium carbonate (451 mg, 1.38 mmol) were added and the mixture was heated to 100 °C under nitrogen gas protection for 2 h. The reaction mixture was cooled to room temperature, 15 mL of water was added, filtered, and the filtrate was concentrated under reduced pressure. 10 mL of ethanol was added, filtered to remove inorganic salts, and the filtrate was concentrated under reduced pressure to give crude compound 14a (260 mg, 73.1% yield), which was used directly in the next step. MS m / z (ESI): 219.1[M+1].

[0140] Step 2 The method for producing compound 14b was the same as that for producing compound 11c. MS m / z (ESI): 413.2[M+1].

[0141] Step 3 The preparation of compound 14c was carried out in accordance with the preparation method of compound 11d. MS m / z (ESI): 313.1[M+1].

[0142] Step 4 The production method of Compound 14 was the same as that of Compound 11. MS m / z (ESI): 481.2[M+1]. 1 H NMR (400MHz,DMSO-d6) δ 8.81 (d,J=4.8Hz,2H),8.19 (dd,J=8.8,5.6Hz,1H),7.42 - 7.37 (m,2H),7.31-7.29 (m,1H),5.16 (s,1H),3.78 - 3.67 (m,2H),3.62 - 3.46 (m,5H),3.09 - 2.95 (m,3H),2.31 (d,J=2.4Hz,3H),1.46 (s,6H).

[0143] Example 15 Preparation of Compound 15: ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone [ka]

[0144] Step 1 Under N2 protection, CuI (653.81 mg, 3.43 mmol), Pd(PPh3)4 (1.98 g, 1.71 mmol), and CsF (5.21 g, 34.30 mmol) were added to a solution of compound 15a (4 g, 17.16 mmol) and 2-(tributylstannyl)pyrimidine (6.97 g, 18.88 mmol) in DMF (60 mL). The reaction was carried out at 120 °C for 5 h. After cooling to room temperature, 150 mL of water was added and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified to give compound 15b (2.8 g, 70.3% yield). MS m / z (ESI): 233.1[M+1].

[0145] Step 2 To a mixture of compound 15b (800 mg, 3.45 mmol) in water (5.0 mL) and methanol (5.0 mL), sodium hydroxide (688.98 mg, 17.22 mmol) was added. The mixture was allowed to react at 25°C for 3 hours. 2 N HCl was added until the pH reached 2, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give compound 15c (650 mg, 86.5% yield). MS m / z (ESI): 219.0[M+1].

[0146] Step 3 To a solution of 106c (100 mg, 0.46 mmol) and intermediate 2 (129 mg, 0.46 mmol) in acetonitrile (3.0 mL), tetramethylchlorourea hexafluorophosphate (257 mg, 0.92 mmol) and N-methylimidazole (188 mg, 2.29 mmol) were added. The mixture was stirred at 25 °C for 30 minutes. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative HPLC to give compound 15 (40 mg, 18.2% yield). MS m / z (ESI): 481.2[M+1]. 1 H NMR (400MHz,DMSO-d6) δ 8.85 (dd,J=42.9,4.9Hz,2H),8.01 (dd,J=36.2,7.8Hz,1H),7.59 (td,J=8.1,5.8Hz,1H),7.51-7.37 (m,2H),5.15 (s,1H),3.85-3.47 (m,7H),3.09 (dddd,J=36.1,22.9,11.1,7.0Hz,3H),2.36-2.24 (m,3H),1.44 (d,J=3.3Hz,6H).

[0147] Biological Test Evaluation The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0148] 1. Cell function experiments Test Example 1: Measurement of the effect of the compounds of the present invention on calcium flux in cells stably expressing OX1 and OX2 receptors 1. Purpose of the experiment: The inhibitory effects of compounds on calcium flux activity in CHO-K1 / human OX1R and CHO-K1 / human OX2R cells were detected.

[0149] 2. Laboratory equipment and reagents 2.1 Equipment: 384-well cell culture plate (Corning: 3764), Plate reader FLIPR Tetra (Molecular Device).

[0150] 2.2 Reagents: DMEM, high glucose (Gibco:12100), Fetal bovine serum (Biosera: FB-1058 / 500), P / S(Biosera:XC-A4122), 5X Matrigel (Corning:354230), HBSS (Sigma: H1387), HEPES (Invitrogen: 15630080), Fluo-8 AM (AAT Bioquest:21080), Probenecid (Sigma: P8761), Pluronic F-127(Sigma:P2443-250G), 1000X Fluo-8 AM (2 mM): Fluo-8 AM was dissolved in DMSO, shaken for 1-2 minutes, aliquoted, and stored at -20°C. Complete medium: DMEM+10% FBS+1X P / S, Cell inoculation medium: DMEM+10% FBS+1X PS, Experimental buffer: 1X HBSS+20mM HEPES+1mM Probenecid+0.025% Pluronic F-127, 1X Matrigel: Dilute 5X Matrigel in DMEM. Cell lines: CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines.

[0151] 3. Experimental Method: 1) CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines were cultured separately in complete medium at 37°C and 5% CO2 until they reached 70% to 90% confluence. 2) Coat a 384-well cell culture plate with 1X Matrigel, using 5uL per well, for 10-30 minutes at room temperature. 3) The cells were digested and resuspended in cell inoculation medium. The CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines were inoculated into two 384-well cell culture plates at 8,000 cells / well / 20 μL, respectively, and cultured at 37°C, 5% CO2 for 24 hours. 4) Remove the cell culture plate from the CO2 incubator and equilibrate it at room temperature for 10 minutes. 5) Take 1000X Fluo-8 AM and dilute it to 1X Fluo-8 AM at a concentration of 2 μM with Experimental Buffer 1 equilibrated to room temperature. 6) Remove the medium from the cell culture plate, add 20 μL of 1X Fluo-8 AM to each well, centrifuge at 300 rpm for 60 seconds at room temperature, and then incubate at room temperature in the dark for 1 hour. 7) Determination of EC80 of OX1 and OX2 receptor agonists (OX-A for OX1R assays, OX-B for OX2R assays): Prepare working solutions for diluting OX1 and OX2 receptor agonists, respectively, and add the diluted OX1 and OX2 receptor agonists to the experimental wells of a 384-well cell culture plate corresponding to the CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines, respectively, using FLIPR Tetra. Data were read and collected, and the EC80 of OX-A and OX-B were obtained using the following experimental data processing method. 8) Repeat steps 1 to 7 to mix the positive compounds (suvorexant and seltorexant) and the test compounds. Add the diluted compounds (11 concentration points) to the corresponding experimental wells of two 384-well cell culture plates using FLIPR Tetra. After 15 minutes, add OX1 and OX2 receptor agonists to the well plates of the two cell lines based on the previously obtained EC80. Data were read and collected to determine the IC50 of the positive compounds and the test compounds.

[0152] 4. Experimental data processing method: The fluorescence signal values ​​(RFU) were read and collected using FLIPR Tetra, and the maximum RFU value was taken. Based on the readings of the low control (DMSO control) and high control (100 nM positive compound) experimental groups, the inhibition (activation) percentage data {% inhibition (activation) rate = (RFU sample - RFU low control) / (RFU high control - RFU low control) × 100} was calculated. The inhibition (activation) rate percentage and the 11 concentration data were fitted to a parameter nonlinear logical equation using Prism8 to calculate the IC value of the compound. 50 values ​​were calculated. 5. Experimental Results:

[0153] [Table 3]

[0154] The compounds of the present invention showed good inhibitory effects in experiments on calcium flux in cells stably expressing OX2 receptors, and the inhibitory effect of the compounds on OX2 receptors was significantly superior to that on OX1 receptors, with good selectivity.

[0155] 2. Pharmacokinetic evaluation study Pharmacokinetic evaluation study in rats 1. Research purpose: Using SD rats as test animals, the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma) when orally administered at a dose of 5 mg / kg was examined. 2. Experimental plan: 2.1 Experimental Chemicals: Compounds of the present invention examples, self-prepared.

[0156] 2.2 Experimental animals: JPEG2025531050000037.jpg161682.3 Pharmaceutical formulation: Oral drug formulation: 20% HP-β-CD in Water 20 g of HP-β-CD powder was weighed and dissolved in 100 mL of purified water, vortexed, mixed uniformly, and sonicated to obtain a clear solution.

[0157] The compound of the example was weighed and placed in a 20 mL glass bottle, and the solution was added and sonicated for 10 minutes to obtain a clear colorless solution with a concentration of 0.5 mg / mL.

[0158] 2.4 Administration: Three male SD rats were fasted overnight and then po'd. The po dose was 5 mg / kg and the administration volume was 10 mL / kg.

[0159] 2.5 Sampling: Blood collection: 0.2 mL of blood was collected from the jugular vein of each rat before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 6000 rpm at 4°C for 6 minutes to separate the plasma, which was then stored at -80°C and fed 4 hours after administration.

[0160] Brain tissue collection: After euthanizing the experimental animals with CO2, 0.25 Brain tissues were collected at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h, and then rinsed thoroughly with pre-chilled PBS, wiped dry, weighed, and stored at -80°C.

[0161] 2.6 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile to precipitate, mixed, and then centrifuged at 3500 × g for 5 to 20 minutes.

[0162] 2) The treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS, and the LC / MS / MS analysis equipment was AB Sciex API 4000 Qtrap. 2.7 Liquid phase analysis: ● Liquid phase conditions: Shimadzu LC-20AD pump Chromatography column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm) Mobile phase: Solution A was 0.1% formic acid in water, and solution B was acetonitrile. ● Flow rate: 0.4mL / min Elution time: 0 to 4.0 minutes, and the eluate was as follows:

[0163] [Table 4]

[0164] 3. Test Results and Analysis: The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the rat drug experiment results were as follows:

[0165] [Table 5]

[0166] 4. Experimental Conclusion: The data showed that in pharmacokinetic evaluation experiments in rats, the compounds of the examples of the present invention showed high exposure after oral administration, especially in the brain.

[0167] 3. Evaluation of the effects of the compounds of the present invention on rat sleep structure using electroencephalography and electromyography telemetry sleep techniques 1. Purpose of the experiment In this experiment, the effects of the compound of the present invention on the sleep structure of SD rats were detected using an electroencephalogram and electromyography telemetry system manufactured by DSI.

[0168] 2. Laboratory equipment and reagents 2.1. Main equipment DSI Remote Sensing Pressure Measurement System: Implant Model Number: TL11M2-F40-EET, Data Sciences International. HD-S02, Data Sciences International. Data collection software: Ponemah Software 5.0, Data Sciences International. Data analysis software: NeuroScore, Data Sciences International. precision electronic balance electronic balance ultrasound device Thermostatic Magnetic Mixer Vortex mixer 2.2. Main Reagents HP-β-CD

[0169] 3. Experimental process 3.1. Purchasing and acclimatization of experimental animals The SD rats weighed 190-210 g (5-6 wk) when they arrived at the facility. After arriving at the facility, the animals were housed in an animal care room where environmental conditions were strictly controlled, and the acclimation period lasted 7-9 days. During this period, the experimental animals were acclimatized to an environment with alternating 12-hour light and dark periods, and the rhythm was adjusted. The animals' health status was monitored daily.

[0170] 3.2. Grouping All animals arrived at the animal facility according to weight, were adaptively housed, surgically implanted with electrodes, had at least six animals per group, and met the requirements of statistical tests and pharmacodynamic guidelines.

[0171] 3.3. Experimental flow 1) Surgical electrode implantation: Experimental animals were placed in a 12-hour alternating light-dark environment and allowed to acclimate for 7–9 days (lights off: 07:00, lights on: 19:00). On the day of the experiment, the animals were anesthetized with a combination of telazol (ip, 20 mg / kg) and xylazine (ip, 8 mg / kg). After anesthesia, the animals were fixed in a stereotaxic apparatus, the skin was prepared in the surgical area of ​​the head, a hole was drilled in the skull, and the electrodes were implanted. Simultaneously, two electromyographic electrodes were inserted parallel to each other into the neck muscles, and both ends were secured with sutures to prevent contact between the ends. The implant body was then placed subcutaneously on the back, and the surgical wound was sutured and disinfected.

[0172] 2) Postoperative care: After surgery, rats were carefully placed in a clean recovery cage, positioned lateral, and their airways were secured. A 12-hour light-dark cycle was automatically established (lights off: 7:00 AM, lights on: 7:00 PM), with a constant temperature of 20-26°C and a relative humidity of 40-70%. After surgery, the animals were cared for for 3 days. Cephradine powder was administered topically at the surgical incision site, and gentamicin was administered subcutaneously at 4-8 mg / kg and meloxicam was administered subcutaneously at 0.1 ml / animal for 3 consecutive days. After 7-10 days of recovery, the animals were randomly assigned to groups according to their weight for the experiment.

[0173] 3) Administration plan and monitoring indicators: Baseline EEG and EMG recordings were performed 7 to 10 days after surgery, and administration began after these were completed. Administration continued for 7 days. On the first and seventh days of administration, EEG and EMG recordings began at 11:00, 1 hour before administration, and administration began at 12:00. EEG and EMG recordings were then performed 24 hours after administration.

[0174] 4) Experimental endpoints: After administration, the time changes in the latency period of NREM and REM between different groups, and the time changes in Wake, NREM and REM within 24 hours after administration.

[0175] 4. Data Collection and Analysis Raw data were collected using DSI System Ponemah software and analyzed using NeuroScore software and GraphPad Prism software. Experimental data were expressed as mean ± standard error (Mean ± SEM) and analyzed by ANOVA, with P < 0.05 indicating significant differences.

[0176] 5. Experimental Results The distribution of wakefulness / sleep states of animals in the vehicle control group was consistent with the day-night rhythm, the vehicle showed no significant effect on the sleep structure of the animals, and the distribution of different wakefulness / sleep stages was consistent with the reported situations in the literature, indicating that the model was successful and stable.

[0177] For each animal in the vehicle and administration groups, analysis was performed on different sleep stages from 1 h before administration to 1 h after administration, and the average value for each group was taken in 1-h units to analyze the time distribution changes for each group at different sleep stages.

[0178] During the lights-off phase, the total time spent by animals in different sleep stages was statistically recorded 1 h, 3 h, 5 h, and 7 h after administration, and the pharmacological effects of different administration groups were analyzed.

[0179] Regarding the light-on stage, the total time length of the animals in different sleep stages was statistically recorded 1 h, 3 h, 5 h, and 7 h after the lights were turned on, and the drug effects between different administration groups were analyzed.

[0180] 6. Experimental Conclusion The compound of the present invention in the embodiment can significantly reduce the latency period of NREM / REM and the total time length of waking at low dose, significantly increase the total time length of NREM, but do not affect the total time length of REM, and have low risk of lethargy.It can be seen that the compound of the present invention has good sleep-promoting effect on rats, and has low risk of lethargy.

[0181] 4. CYP enzyme single-point inhibition test 1. Purpose of the experiment Using a human liver microsome incubation system, the inhibition of compounds against CYP450 enzyme subtypes was rapidly predicted using a single-point method.

[0182] 2. Experimental steps 2.1 Solution preparation NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed and added to 100 mM phosphate buffer to a final concentration of 2.5 mM. 4 mL of 100 mM phosphate buffer was added to 50 μL of 20 mg / mL microsomes and mixed uniformly to obtain 0.25 mg / mL microsomes.

[0183] Preparation of test compound reaction mixture: The compounds of the examples to be tested were weighed and diluted to 10 mM in DMSO and further diluted to 100 μM in 100 mM phosphate buffer.

[0184] 2.2 Experimental procedure: 1. 40 μL of liver microsomes, 10 μL of substrate, and 10 μL of test compound were added to a 96-well plate and pre-incubated for 3 minutes.

[0185] 2. 40 μL of NADPH was added.

[0186] 3. At 20 min, 300 μL of acetonitrile stop solution containing the internal standard was added.

[0187] 4. Centrifuge and add sample. 3. Experimental Results:

[0188] [Table 6]

[0189] Crystal Form Research 1.1 Experimental equipment 1.1.1 Some parameters of physicochemical detection instruments

[0190] [Table 7]

[0191] [Table 8] 1.1.2 Chromatography conditions

[0192] [Table 9]

[0193] 1. Preparation of different crystalline forms 1.1 Preparation of Free Base Crystalline Form I of Compound 9 Approximately 20 mg of the free base was weighed and placed in a 2 mL glass vial. 100-200 μL of an organic solvent (MeOH, EtOH, EA, Acetone, IPA, IPAc, MEK, 2-Me-THF, MTBE, toluene, cyclohexane, or heptane may be selected as the organic solvent) was added and the mixture was beaten at 50°C for 7 days. The resulting solid was centrifuged, the supernatant removed, and dried under vacuum at 40°C to obtain Form I of the free base. Upon detection and analysis, it had the following XRPD pattern shown in Figure 1, DSC pattern shown in Figure 2, and TGA pattern shown in Figure 3.

[0194] 1.2 Preparation of Free Base Crystalline Form I of Compound 9 (Process Manufacturing Method) 1) 15.3 g of the crude product was dissolved in 20 mL of methanol, 30 mL of water was added dropwise, and the mixture was stirred for 20 minutes to precipitate a solid. Further, 6 mL of water was added dropwise (methanol:water=1:1.8), and the mixture was stirred for 16 hours.

[0195] 2) Filter, mix 4 mL of methanol + 12 mL of water, wash the filter cake and dry at 40°C to obtain a light brown solid; 3) 7.7 g of the solid was added to 23 mL of methanol, heated to an external temperature of 65°C, dissolved, cooled to 20°C, stirred for 0.5 hours to precipitate the solid, and then 23 mL of water was added dropwise and stirred for 4 hours.

[0196] 4) Filter, mix 10 mL of methanol + 30 mL of water, wash the filter cake, and dry at 40 ° C to obtain a light brown solid; 5) 7.3 g of the solid was added to 22 mL (3 V) of EA, heated to reflux, stirred for 1 h, 22 mL (3 V) of n-heptane was added dropwise, stirring was continued for 0.5 h, cooled to 20-24°C, and stirred for 16 h.

[0197] 6) Filtration, mixing 4 mL of EA and 8 mL of n-heptane, washing the filter cake and drying at 40° C. gave 6.5 g of a light brown solid, free base crystalline form I.

[0198] 1.3 Preparation of Free Base Crystalline Form II of Compound 9 Approximately 20 mg of the free base was weighed and placed in a 2 mL glass vial, and 50 to 300 μL of a solvent (ACN, THF, DCM, or water may be used as the solvent) was added. The mixture was then beaten at 50°C for 7 days. The clear solution obtained during this process was evaporated at room temperature, and the resulting solid was centrifuged, the supernatant removed, and dried under vacuum at 40°C to obtain free base crystalline Form II. Upon detection and analysis, it had the following XRPD pattern shown in Figure 4, DSC pattern shown in Figure 5, and TGA pattern shown in Figure 6.

[0199] 2. Solid-state stability experiments 2.1 Experimental Objective: The physicochemical stability of the free base crystalline form I and crystalline form II under conditions of high temperature 60°C, high humidity 92.5% RH, and high temperature and humidity 50°C, 75% RH was examined, providing a basis for the storage of the compounds.

[0200] 2.2 Experimental plan: Approximately 2 mg of free base crystalline Form I and Form II were taken, and the changes in related substances in the crystalline forms were examined for 7 and 14 days under conditions of high temperature 60°C, high humidity 92.5% RH, and high temperature and humidity 50°C, 75% RH. The changes in related substances were calculated using HPLC with the chromatographic peak area normalization method. Chromatography conditions:

[0201] [Table 10]

[0202] 2.3 Experimental results: Physicochemical stability results for free base crystalline Form I:

[0203] [Table 11] Physicochemical stability results for free base crystalline Form II:

[0204] [Table 12]

[0205] These data demonstrate that the free base crystalline Forms I and II of Compound 9 were both stable under all conditions after standing for 7 and 14 days.

[0206] 3 Hygroscopicity experiment 3.1 Experimental Objectives The hygroscopicity of Form I and Form II of Compound 9 under different relative humidity conditions was examined to provide a basis for storage of the compound.

[0207] 3.2 Experimental plan: Form I and Form II of Compound 9 were placed in saturated water vapor at different relative humidities to dynamically equilibrate the compound with water vapor, and the percentage of weight increase due to moisture absorption of the compound after equilibration was calculated.

[0208] 3.3 Experimental results: The free base crystalline form I exhibited slight hygroscopicity, with a weight gain of approximately 0.3263% due to moisture absorption under 80% RH conditions. The XRPD pattern of the free base crystalline form I did not change after two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, indicating that the crystalline form was unchanged.

[0209] The free base crystalline form II exhibited a slight hygroscopicity, with a weight increase of about 0.2053% due to moisture absorption under conditions of 80% RH.

[0210] 4. Solubility experiments in different media 4.1 Experimental Objectives The solubilities of free base Form I and Form II in pH 1.0-8.0 USP buffer, artificial simulated gastric fluid (FaSSGF), fasted artificial simulated intestinal fluid (FaSSIF), non-fasted artificial simulated intestinal fluid (FeSSIF), and pure water were compared to provide a basis for evaluating drug formability.

[0211] 4.2 Experimental plan: Approximately 1 mg of free base crystalline Form I and crystalline Form II were suspended in different media for 2 hours, and the thermodynamic solubility of the compounds at 37°C was measured using HPLC with an external standard method.

[0212] 4.3 Experimental results: As shown in Table 3.

[0213] [Table 13]

[0214] As can be seen from the above experimental results, the thermodynamic solubility of free base crystalline Form I in each vehicle system was higher than that of crystalline Form II, and the solubility of crystalline Form I in each vehicle system satisfied the drug concentration required for local treatment.

[0215] 5. Animal PK research 5.1 Experimental Objective: SD rats were used as test animals, and the pharmacokinetic behavior in the rat body (plasma) of free base crystalline Form I and free base crystalline Form II was investigated after single oral administration, and changes in exposure were compared. The pharmacokinetics of the free base crystalline Form I and free base crystalline Form II after single intravenous administration was investigated, and the oral bioavailability of free base crystalline Form I and free base crystalline Form II was calculated.

[0216] 5.2 Experimental plan: Form I of the free base was suspended in a 0.5% CMCC-Na aqueous solution, and then suspended in a 0.5% HPMC aqueous solution. After homogenization, the suspension was administered intragastrically to rats, with three rats administered in parallel. The dosages were Form I of the free base (5 mg / kg, 30 mg / kg suspension) and Form II of the free base (30 mg / kg suspension). Form I of the free base was dissolved in a 20% HP-β-CD-containing aqueous solution, filtered through a filter membrane, and then administered by injection to three rats, with three rats administered in parallel. 5.3 Experimental Results

[0217] [Table 14]

[0218] As can be seen from the above data, the exposure of free base crystalline Form I was higher than that of free base crystalline Form II, and the exposure of crystalline Form I at 30 mg / kg was obviously higher than that at 5 mg / kg.

Claims

1. The crystalline form of the compound shown by general formula (I) has the following structure: 【Chemistry 1】 Here, X １ CR ６ or N, X ２ CR ６ is or does not exist, R １ It is selected from halogens, R ２ , R ３ , R ４ or R ６ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and said amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, R ２ , R ３ , R ４ or R ６ Each of these is independently preferably hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, C １－８ Alkyl alkyl group, C １－８ Deuterated alkyl groups, C １－８ Haloalkyl group, C １－８ Hydroxyalkyl group, C １－８ Alkoxy group, C １－８ Haloalkoxy group, C １－８ Hydroxyalkoxy group, C ２－８ Alkenyl group, C ２－８ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ The group is an aryl group or a 5- to 14-membered heteroaryl group, and the amino group is C １－８ Alkyl alkyl group, C １－８ Deuterated alkyl groups, C １－８ Haloalkyl group, C １－８ Hydroxyalkyl group, C １－８ Alkoxy group, C １－８ Haloalkoxy group, C １－８ Hydroxyalkoxy group, C ２－８ Alkenyl group, C ２－８ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally composed of deuterium, halogen, amino group, nitro group, hydroxyl group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, and C. １－８ Alkyl alkyl group, C １－８ Deuterated alkyl groups, C １－８ Haloalkyl group, C １－８ Hydroxyalkyl group, C １－８ Alkoxy group, C １－８ Haloalkoxy group, C ２－８ Alkenyl group, C ２－８ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Further substituted with one or more substituents from an aryl group and a 5- to 14-membered heteroaryl group, More preferably, hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, C １－６ Alkyl alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group is an aryl group or a 5-10 membered heteroaryl group, and the amino group is C １－６ Alkyl alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally composed of deuterium, halogen, amino group, nitro group, hydroxyl group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, and C. １－６ Alkyl alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Further substituted with one or more substituents from an aryl group and a 5- to 10-membered heteroaryl group, Or, R ２ , R ３ , R ４ Any two or more of these may be bonded to the linked atom to form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R ５ The hydroxyalkyl group is selected from hydroxyalkyl groups or haloalkyl groups and may be further optionally substituted, wherein the hydroxyalkyl group is preferably 【Chemistry 2】 The haloalkyl group is preferably, 【Transformation 3】 And, X' is a halogen, R ７ Each of the following is independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, mercapto group, cyano group, carboxyl group, sulfonic acid group, oxo group, thio group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, hydroxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted, in the crystalline form of the compound shown in general formula (I).

2. The above general formula (I) is further shown in general formula (II), 【Chemistry 4】 Here, X １ is CH or N, X ２ It is either CH or does not exist. R ２ , R ３ or R ４ are each independently selected from hydrogen, deuterium, halogen, amino group, hydroxy group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ haloalkoxy group or C １－３ hydroxyalkoxy group, R ５ teeth, 【Transformation 5】 The crystal form according to claim 1, which is selected from the following.

3. X ２ When does not exist, the substituent R ２ is preferably halogen, said halogen is preferably located at the ortho-position or meta-position of triazole, more preferably located at the ortho-position, The halogen is preferably fluorine. X ２ CR ６ In this case, substituent R ２ Preferably, the halogen is a halogen, which is preferably located at the ortho or meta position of the pyrimidine, and more preferably at the meta position and / or the ortho position linking the carbonyl group of the pyrimidine. The crystalline form according to claim 1, characterized in that the halogen is preferably fluorine.

4. The above general formula (I) is, 【Transformation 6】 The crystal form according to claim 1, characterized by being selected from the following compounds.

5. ((3aR,6aS)-5-(5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidine-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(2-fluoro-6-(pyrimidine-2-yl)phenyl)methanone is a crystalline form comprising crystalline form I and crystalline form II, where, The powder X-ray diffraction pattern of crystal form I shows diffraction peaks at positions where 2θ is 8.6±0.2°, or at positions where 2θ is 9.2±0.2°, or at positions where 2θ is 10.2±0.2°, or at positions where 2θ is 10.8±0.2°, or at positions where 2θ is 12.0±0.2°, or at positions where 2θ is 12.8±0.2°, or at positions where 2θ is 13.7±0.2°, or at positions where 2θ is 14.2±0.2°, or at positions where 2θ is 15.5±0.2°, or at positions where 2θ is 16.6±0.2°. There is a diffraction peak at the position, or at a position where 2θ is 17.3±0.2°, or at a position where 2θ is 18.4±0.2°, or at a position where 2θ is 19.0±0.2°, or at a position where 2θ is 19.5±0.2°, or at a position where 2θ is 20.5±0.2°, or at a position where 2θ is 21.3±0.2°, or at a position where 2θ is 26.5±0.2°, or at a position where 2θ is 28.6±0.2°, and preferably there are diffraction peaks at any optional 2, 4, 6, 8, or 10 locations included therein. The powder X-ray diffraction pattern of crystal form II shows diffraction peaks at positions where 2θ is 9.9±0.2°, or at positions where 2θ is 10.8±0.2°, or at positions where 2θ is 13.2±0.2°, or at positions where 2θ is 14.9±0.2°, or at positions where 2θ is 16.4±0.2°, or at positions where 2θ is 17.1±0.2°, or at positions where 2θ is 17.9±0.2°, or at positions where 2θ is 19.3±0.2°, or at positions where 2θ is 19.8±0.2°. A crystal form having diffraction peaks at a position where 2θ is 20.2±0.2°, or at a position where 2θ is 20.5±0.2°, or at a position where 2θ is 21.0±0.2°, or at a position where 2θ is 21.9±0.2°, or at a position where 2θ is 25.8±0.2°, or at a position where 2θ is 26.5±0.2°, or at a position where 2θ is 27.5±0.2°, preferably having diffraction peaks at two, four, six, eight, or ten arbitrarily selected locations within it.

6. The powder X-ray diffraction pattern of crystal form I includes at least one or more diffraction peaks located at positions where 2θ is 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, or 18.4±0.2°, preferably 2 to 4 of these, more preferably 3 to 4, most preferably 4, and optionally further including one or more diffraction peaks at positions where 2θ is 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°, or 26.5±0.2°, preferably 2, 3, 4, or 5 of these. The powder X-ray diffraction pattern of crystal form II includes at least one or more diffraction peaks located at positions where 2θ is 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, or 25.8±0.2°, preferably 2 to 4 of these, more preferably 3 to 4, most preferably 4, and optionally further including one or more diffraction peaks at positions where 2θ is 10.8±0.2°, 14.9±0.2°, 19.3±0.2°, 21.9±0.2°, or 26.5±0.2°, preferably 2, 3, 4, or 5 of these, characterized in that the crystal form according to claim 5.

7. The X-ray powder diffraction pattern of crystal form I has characteristic peaks at positions where 2θ is 9.2±0.2° and 18.4±0.2°, preferably further including characteristic peaks at positions where 2θ is 10.2±0.2°, 16.6±0.2°, 17.3±0.2° and 19.0±0.2°, more preferably further including characteristic peaks at positions where 2θ is 12.8±0.2° and 21.3±0.2°, and even more preferably further including characteristic peaks at positions where 2θ is 26.5±0.2° and 28.6±0.2°. More preferably, it further includes characteristic peaks located at 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 15.5±0.2°, 19.5±0.2°, 20.5±0.2°, 23.1±0.2°, 27.8±0.2° and 32.1±0.2°, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 1, its DSC pattern is substantially as shown in Figure 2, and its TGA pattern is substantially as shown in Figure 3. The X-ray powder diffraction pattern of crystal form II has characteristic peaks at positions where 2θ is 16.4±0.2° and 25.8±0.2°, preferably further including characteristic peaks at positions where 2θ is 17.1±0.2°, 17.9±0.2°, 21.9±0.2° and 26.5±0.2°, more preferably further including characteristic peaks at positions where 2θ is 10.8±0.2° and 14.9±0.2°, and even more preferably at positions where 2θ is 9.9±0.2° and 19.3±0.2°. The crystal form according to claim 5, further comprising characteristic peaks located at 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 21.0±0.2° and 27.5±0.2°, most preferably having an X-ray powder diffraction pattern substantially as shown in Figure 4, a DSC pattern substantially as shown in Figure 5, and a TGA pattern substantially as shown in Figure 6.

8. A method for producing a crystalline form of a compound according to any one of claims 1 to 7, specifically, Step 1) involves weighing an appropriate amount of free base, mixing and suspending it in a poor solvent, and ensuring the suspension density is preferably 50 to 200 mg / mL. Step 2) involves shaking the suspension obtained above, then raising the temperature to preferably 0 to 50°C and the time to preferably 1 to 10 days. The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried until a constant weight is obtained to obtain the target product. Here, The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water, heptane or n-pentane, and preferably isopropyl acetate, toluene, methyl tert-butyl ether, water, heptane or n-pentane. Or, Step 1) involves weighing an appropriate amount of free base and dissolving it in a good solvent, Step 2) involves adding a poor solvent to the solution obtained above, stirring until a solid precipitates, and raising the temperature to preferably 0 to 25°C. The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried until a constant weight is obtained to obtain the target product. Here, The good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, or 3-pentanone, and is preferably methanol, dichloromethane, or ethyl acetate. The poor solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane, or isopropyl acetate. Or, Step 1) involves weighing an appropriate amount of free base and dissolving it by heating in a good solvent, Step 2) involves rapidly lowering the solution obtained above to a low temperature and stirring until a solid precipitates, preferably at a temperature of -10 to 5°C. The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried until a constant weight is obtained to obtain the target product. Here, The method wherein the good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol or 2-butanone or tetrahydrofuran, and preferably acetone.

9. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound described in claim 1, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

10. An application of the crystalline form described in any one of claims 1 to 7 or the pharmaceutical composition described in claim 9 in the manufacture of a drug for treating neurological diseases as an orexin receptor antagonist, preferably in the manufacture of an OX2R selective receptor antagonist, More preferably, the neurological disorder is selected from insomnia, depression, anxiety disorder, or drug addiction, and more preferably from major depressive disorder, primary and secondary insomnia, or depression with insomnia, in the application.

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