Free alkali crystal form of polycyclic compound containing nitrogen heterocyclic ring and preparation method of free alkali crystal form

Abstract

The invention relates to a free alkali crystal form of a nitrogen-containing heterocyclic polycyclic compound and a preparation method of the free alkali crystal form. The invention specifically relates to a crystal form of a compound free alkali with a general formula (I), a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and an application of the crystal form as an orexin receptor antagonist in preparation of related drugs for treating nervous system diseases.

Description

Free base crystal form of polycyclic compound containing nitrogen heterocycle and preparation method thereof

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a crystal form of a polycyclic compound containing a nitrogen heterocycle, a preparation method and an application thereof.

[0002] The hypothalamus is the center for regulating diet and energy balance. Orexin is a neuropeptide synthesized and secreted by orexin neurons in the lateral hypothalamus (LH). It is named for its strong appetite-promoting effect. Orexin is divided into orexin A and orexin B. Orexin A and Orexin B both act on the G protein-coupled receptors orexin receptor OX1R and orexin receptor OX2R. OX1R and OX2R are widely expressed throughout the central nervous system. Among them, OX1R has a stronger binding ability with orexin A than orexin B, while OX2R has a similar binding ability with orexin A and orexin B. Orexin has an intricate relationship with other neuropeptides that affect eating. It has a wide range of effects in increasing food intake, drinking, regulating sleep-wake cycles, reproduction, body temperature, blood pressure and sensation. For example, it regulates wakefulness and arousal by regulating two different G protein-coupled receptors OX1R and OX2R. Orexin receptor antagonists have potential therapeutic advantages in the treatment of neurological diseases, including insomnia, depression, anxiety, drug addiction, etc.

[0003] OX1R and OX2R activate intracellular Ca via phospholipase C 2+ OX2R can also couple Gi / Go and inhibit the production of cAMP by inhibiting adenylate cyclase. Studies have found that among OX1R and OX2R, OX2R is preferentially expressed in the paraventricular nucleus of the hypothalamus and participates in the regulation of the HPA axis. Excessive excitement of the hypothalamus-pituitary-adrenal gland (HPA) at night is the biggest difference between patients with depression and normal people. Downregulation of excessive excitement of the HPA system will help improve depressive symptoms.

[0004] Currently, there are several drugs targeting OX1 / 2R that are in the clinical stage or have been launched on the market, such as Merck's Suvoraxant and Eisai's Lemborexant. However, drugs that are orexin 1 / 2 antagonists have antagonistic effects on both OX1R and OX2R receptors. Acting on OX1R will change the normal physiological structure of rapid eye movement sleep (NEM, brain activity is the same as when awake) and non-rapid eye movement sleep (NEREM, deep sleep), that is, sacrificing NREM time and prolonging REM time, thereby increasing the risk of drowsiness, and OX1R cannot have an antidepressant effect.

[0005] OX2R antagonists can have an antidepressant effect, and OX2R single receptor antagonists can also have a sufficient therapeutic effect on insomnia, so selective OX2R antagonists can avoid various side effects such as drowsiness caused by the action on OX1R. At present, the only OX2R antagonist developed by Janssen is Seltorexant in the clinical stage, and its main indications are major depressive disorder (MDD), primary and secondary insomnia, etc.

[0006] Selective OX2R antagonists have the potential to treat neurological diseases such as insomnia, depression, and anxiety, and have huge clinical needs. Selective OX2R antagonists have good application prospects in the pharmaceutical industry as drugs.

[0007] The PCT patent (application number: PCT / CN2022 / 080829) discloses the structures of a series of polycyclic compounds containing nitrogen heterocycles. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term stability, the present invention has conducted a comprehensive study on the free base crystal forms of the above-mentioned compounds.

[0008]

[0009] All contents involved in patent PCT / CN2022 / 080829 are added to the present invention by reference.

[0010] 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 shown in formula (I):

[0011] in:

[0012] X1 is CR6 or N;

[0013] X2 is CR6 or does not exist;

[0014] R1 is selected from halogen;

[0015] R2, R3, R4 or R6 are independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxyl, sulfonic acid, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may be further substituted;

[0016] R2, R3, R4 or R6 are each independently preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfonic acid, oxo, thio, C 1-8Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonate, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents selected from aryl and 5-14 membered heteroaryl;

[0017] More preferably, hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfonic acid, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonate, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0018] Alternatively, any two or more of R2, R3, and R4 are linked to the connected atom to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, and the cycloalkyl, heterocyclic, aryl, and heteroaryl group may be further substituted;

[0019] R5 is selected from hydroxyalkyl or haloalkyl, optionally further substituted, and the hydroxyalkyl is preferably The haloalkyl group is preferably

[0020] X' is a halogen;

[0021] R7 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonic acid, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may be further substituted; preferably hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may be further substituted; preferably hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, may be further substituted by deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy and C 1-6 One or more substituents in the haloalkoxy group are substituted; preferably hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy; further preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy and C 1-3 more preferably hydrogen, deuterium, C 1-3 alkyl.

[0022] A preferred embodiment of the present invention is to provide a crystalline form of a compound represented by general formula (II),

[0023] in,

[0024] X1 is CH or N;

[0025] X2 is CH or does not exist;

[0026] R2, R3 or R4 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 Hydroxyalkoxy;

[0027] R5 is selected from

[0028] When X2 is absent, the substituent R2 is preferably a halogen, which is preferably located at the ortho or meta position of the triazole, more preferably at the ortho position.

[0029] The halogen is preferably fluorine;

[0030] When X2 is CR6, the substituent R2 is preferably a halogen, which is preferably located at the ortho position or meta position of the pyrimidine, more preferably at the meta position of the pyrimidine, and / or at the ortho position of the carbonyl group.

[0031] The halogen is preferably fluorine.

[0032] A preferred embodiment of the present invention is that the general formula (I) is selected from the following compounds:

[0033] In a preferred embodiment of the present invention, 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) is provided, and the structure of the compound is as follows:

[0034] The powder X-ray diffraction spectrum of the crystalline form I has a diffraction peak at 2θ of 8.6±0.2°, or at 2θ of 9.2±0.2°, or at 2θ of 10.2±0.2°, or at 2θ of 10.8±0.2°, or at 2θ of 12.0±0.2°, or at 2θ of 12.8±0.2°, or at 2θ of 13.7±0.2°, or at 2θ of 14.2±0.2°, or at 2θ of 15.5±0.2°, or at 2θ of 16. 6±0.2°, or 2θ has a diffraction peak at 17.3±0.2°, or 2θ has a diffraction peak at 18.4±0.2°, or 2θ has a diffraction peak at 19.0±0.2°, or 2θ has a diffraction peak at 19.5±0.2°, or 2θ has a diffraction peak at 20.5±0.2°, or 2θ has a diffraction peak at 21.3±0.2°, or 2θ has a diffraction peak at 26.5±0.2°; or 2θ has a diffraction peak at 28.6±0.2°; preferably, comprising 2, 4, 6, 8 or 10 diffraction peaks optionally selected therefrom;

[0035] Preferably, its powder X-ray diffraction pattern contains at least one or more diffraction peaks located at 2θ of 9.2±0.2°, 10.2±0.2°, 16.6±0.2° or 18.4±0.2°; preferably contains 2-4 of them, more preferably contains 3-4, most preferably contains 4; optionally, further, it may also contain one or more diffraction peaks at 2θ of 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2° or 26.5±0.2°, preferably contains 2, 3, 4 or 5 of them; for example:

[0036] 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 18.4±0.2°;

[0037] 9.2±0.2°、10.2±0.2°、16.6±0.2°、17.3±0.2°；

[0038] 9.2±0.2°、12.8±0.2°、16.6±0.2°、18.4±0.2°；

[0039] 9.2±0.2°、10.2±0.2°、17.3±0.2°、19.0±0.2°；

[0040] 9.2±0.2°、12.8±0.2°、17.3±0.2°、19.0±0.2°；

[0041] 10.2±0.2°、16.6±0.2°、17.3±0.2°、21.3±0.2°；

[0042] 10.2±0.2°、12.8±0.2°、16.6±0.2°、17.3±0.2°；

[0043] 12.8±0.2°、17.3±0.2°、19.0±0.2°、21.3±0.2°；

[0044] 9.2±0.2°、10.2±0.2°、16.6±0.2°、18.4±0.2°；19.0±0.2°；

[0045] 9.2±0.2°、10.2±0.2°、16.6±0.2°、17.3±0.2°；19.0±0.2°；

[0046] 9.2±0.2°、12.8±0.2°、16.6±0.2°、18.4±0.2°；19.0±0.2°；

[0047] 9.2±0.2°、10.2±0.2°、17.3±0.2°、19.0±0.2°；21.3±0.2°；

[0048] 9.2±0.2°、12.8±0.2°、17.3±0.2°、19.0±0.2°；21.3±0.2°；

[0049] 10.2±0.2°、16.6±0.2°、17.3±0.2°、21.3±0.2°；26.5±0.2°；

[0050] 10.2±0.2°、12.8±0.2°、16.6±0.2°、17.3±0.2°；19.0±0.2°；

[0051] 12.8±0.2°, 17.3±0.2°, 19.0±0.2°, 21.3±0.2°; 26.5±0.2°;

[0052] 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 18.4±0.2°; 19.0±0.2°; 21.3±0.2°;

[0053] 9.2±0.2°, 10.2±0.2°, 16.6±0.2°, 17.3±0.2°; 19.0±0.2°; 21.3±0.2°;

[0054] 9.2±0.2°, 12.8±0.2°, 16.6±0.2°, 18.4±0.2°; 19.0±0.2°; 21.3±0.2°;

[0055] 9.2±0.2°, 10.2±0.2°, 17.3±0.2°, 19.0±0.2°; 21.3±0.2°; 26.5±0.2°;

[0056] 9.2±0.2°, 12.8±0.2°, 17.3±0.2°, 19.0±0.2°; 21.3±0.2°; 26.5±0.2°;

[0057] 10.2±0.2°, 16.6±0.2°, 17.3±0.2°, 18.4±0.2°; 21.3±0.2°; 26.5±0.2°;

[0058] 10.2±0.2°, 12.8±0.2°, 16.6±0.2°, 17.3±0.2°; 18.4±0.2°; 19.0±0.2°;

[0059] 12.8±0.2°, 17.3±0.2°, 18.4±0.2°; 19.0±0.2°, 21.3±0.2°; 26.5±0.2°;

[0060] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 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 at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0061] 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°;

[0062] 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 14.2±0.2°;

[0063] 8.6±0.2°, 10.8±0.2°, 14.2±0.2°, 28.6±0.2°;

[0064] 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°;

[0065] 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 28.6±0.2°;

[0066] 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°;

[0067] 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 14.2±0.2°, 28.6±0.2°;

[0068] 8.6±0.2°, 10.8±0.2°, 12.0±0.2°, 13.7±0.2°, 14.2±0.2°, 28.6±0.2°;

[0069] The X-ray powder diffraction spectrum of the crystalline form I has characteristic peaks at 2θ of 9.2±0.2° and 18.4±0.2°; preferably, it also has characteristic peaks at 2θ of 10.2±0.2°, 16.6±0.2°, 17.3±0.2° and 19.0±0.2°; more preferably, it also has characteristic peaks at 2θ of 12.8±0.2° and 21.3±0.2°; further preferably, it also has characteristic peaks at 2θ of The invention relates to a nanostructured carbon foam having characteristic peaks at 26.5±0.2° and 28.6±0.2°, and more preferably, the nanostructured carbon foam also has characteristic peaks 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°.

[0070] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0071] Table 1

[0072] The X-ray powder diffraction pattern of the crystalline form I of compound 9 described in the present invention is substantially as shown in FIG1 , the DSC pattern is substantially as shown in FIG2 , and the TGA pattern is substantially as shown in FIG3 .

[0073] The crystalline form I of compound 9 described in the present invention is an anhydrate crystalline form.

[0074] The powder X-ray diffraction pattern of the crystalline form II has a diffraction peak at 2θ of 9.9±0.2°, or a diffraction peak at 2θ of 10.8±0.2°, or a diffraction peak at 2θ of 13.2±0.2°, or a diffraction peak at 2θ of 14.9±0.2°, or a diffraction peak at 2θ of 16.4±0.2°, or a diffraction peak at 2θ of 17.1±0.2°, or a diffraction peak at 2θ of 17.9±0.2°, or a diffraction peak at 2θ of 19.3±0.2°, or a diffraction peak at 2θ of 19.9±0.2°. .8±0.2°, or has a diffraction peak at 2θ of 20.2±0.2°, or has a diffraction peak at 2θ of 20.5±0.2°, or has a diffraction peak at 2θ of 21.0±0.2°, or has a diffraction peak at 2θ of 21.9±0.2°, or has a diffraction peak at 2θ of 25.8±0.2°, or has a diffraction peak at 2θ of 26.5±0.2°, or has a diffraction peak at 2θ of 27.5±0.2°; preferably, comprises diffraction peaks at any of 2, 4, 6, 8 or 10 positions;

[0075] Preferably, its powder X-ray diffraction pattern contains at least one or more diffraction peaks located at 2θ of 16.4±0.2°, 17.1±0.2°, 17.9±0.2° or 25.8±0.2°; preferably contains 2-4 of them, more preferably contains 3-4, most preferably contains 4; optionally, further, it may also contain one or more diffraction peaks at 2θ of 10.8±0.2°, 14.9±0.2°, 19.3±0.2°, 21.9±0.2° or 26.5±0.2°, preferably contains 2, 3, 4 or 5 of them; for example:

[0076] 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 25.8±0.2°;

[0077] 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 26.5±0.2°;

[0078] 16.4±0.2°, 17.1±0.2°, 25.8±0.2°, 26.5±0.2°;

[0079] 10.8±0.2°、14.9±0.2°、17.9±0.2°、25.8±0.2°；

[0080] 10.8±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°；

[0081] 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°；

[0082] 10.8±0.2°、16.4±0.2°、17.1±0.2°、19.3±0.2°；

[0083] 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°；

[0084] 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°；

[0085] 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°、26.5±0.2°；

[0086] 16.4±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°、26.5±0.2°；

[0087] 10.8±0.2°、14.9±0.2°、17.9±0.2°、25.8±0.2°、26.5±0.2°；

[0088] 10.8±0.2°、17.1±0.2°、19.3±0.2°、25.8±0.2°；26.5±0.2°；

[0089] 16.4±0.2°、17.1±0.2°、17.9±0.2°、21.9±0.2°；25.8±0.2°；

[0090] 10.8±0.2°、16.4±0.2°、17.1±0.2°、19.3±0.2°；21.9±0.2°；

[0091] 16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°；26.5±0.2°；

[0092] 14.9±0.2°、16.4±0.2°、17.1±0.2°、17.9±0.2°、25.8±0.2°；26.5±0.2°；

[0093] 14.9±0.2°, 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 26.5±0.2°; 26.5±0.2°;

[0094] 14.9±0.2°, 16.4±0.2°, 17.1±0.2°, 19.3±0.2°, 25.8±0.2°, 26.5±0.2°;

[0095] 10.8±0.2°, 14.9±0.2°, 17.9±0.2°, 21.9±0.2°, 25.8±0.2°; 26.5±0.2°;

[0096] 10.8±0.2°, 17.1±0.2°, 19.3±0.2°, 21.9±0.2°, 25.8±0.2°; 26.5±0.2°;

[0097] 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 21.9±0.2°; 25.8±0.2°; 26.5±0.2°;

[0098] 10.8±0.2°, 14.9±0.2°, 16.4±0.2°, 17.1±0.2°, 19.3±0.2°; 21.9±0.2°;

[0099] 10.8±0.2°, 16.4±0.2°, 17.1±0.2°, 17.9±0.2°, 25.8±0.2°; 26.5±0.2°;

[0100] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 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 at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0101] 9.9±0.2°、13.2±0.2°、19.8±0.2°、20.2±0.2°、

[0102] 9.9±0.2°、13.2±0.2°、19.8±0.2°、20.5±0.2°、

[0103] 9.9±0.2°、13.2±0.2°、20.5±0.2°、21.0±0.2°、

[0104] 13.2±0.2°、19.8±0.2°、20.2±0.2°、20.5±0.2°、

[0105] 9.9±0.2°、13.2±0.2°、19.8±0.2°、20.2±0.2°、20.5±0.2°、

[0106] 13.2±0.2°, 19.8±0.2°, 20.2±0.2°, 20.5±0.2°, 21.0±0.2°;

[0107] 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°;

[0108] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form II has characteristic peaks at 2θ of 16.4±0.2° and 25.8±0.2°; preferably, it also includes characteristic peaks at 2θ of 17.1±0.2°, 17.9±0.2°, 21.9±0.2° and 26.5±0.2°; more preferably, it also includes characteristic peaks at 2θ of 10.8±0.2° and 14.9±0.2°; further preferably, it also includes characteristic peaks at 2θ of 9.9±0.2° and 19.3±0.2°, and further preferably, it also includes 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°.

[0109] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0110] Table 2

[0111] The crystal form II of compound 9 of the present invention has an X-ray powder diffraction spectrum substantially as shown in FIG. 4 , a DSC spectrum substantially as shown in FIG. 5 , and a TGA spectrum substantially as shown in FIG. 6 .

[0112] The water content of the crystalline form II (monohydrate) of the compound 9 of the present invention measured by KF was 3.1% (API:water=1:0.83, molar ratio).

[0113] The present invention also provides a method for preparing a crystalline form of the compound represented by general formula (I), which specifically comprises the following steps:

[0114] 1) Weigh an appropriate amount of free base and suspend it with a poor solvent;

[0115] 2) Shake the suspension obtained above;

[0116] 3) The above suspension is quickly centrifuged, the supernatant is removed, and the solid is dried to a constant weight to obtain the target product;

[0117] in:

[0118] The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, 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; preferably isopropyl acetate, toluene, methyl tert-butyl ether, water, heptane, and n-pentane.

[0119] In a preferred embodiment of the present invention, the suspension density in step 1) is 50-200 mg / mL.

[0120] In a preferred embodiment of the present invention, the temperature in step 2) is 0-50°C.

[0121] In a preferred embodiment of the present invention, the shaking time in step 2) is selected from 1 to 10 days.

[0122] The present invention also provides a method for preparing a crystalline form of the compound represented by general formula (I), which specifically comprises the following steps:

[0123] 1) Weigh an appropriate amount of free base and dissolve it in a good solvent;

[0124] 2) adding an anti-solvent to the above solution and stirring until a solid precipitates;

[0125] 3) The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried to a constant weight to obtain the target product;

[0126] in:

[0127] 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; preferably methanol, dichloromethane and ethyl acetate.

[0128] The anti-solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane, and isopropyl acetate.

[0129] In a preferred embodiment of the present invention, the temperature in step 2) is 0-25°C.

[0130] The present invention also provides a method for preparing a crystalline form of the compound represented by general formula (I), which specifically comprises the following steps:

[0131] 1) Weigh an appropriate amount of free base and dissolve it in a good solvent by heating;

[0132] 2) The above solution was quickly placed under low temperature and stirred until solid precipitated;

[0133] 3) The above suspension was quickly centrifuged, the supernatant was removed, and the remaining solid was placed in a drying oven and dried to constant weight to obtain the target product;

[0134] in:

[0135] 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 tetrahydrofuran; preferably acetone.

[0136] In a preferred embodiment of the present invention, the temperature in step 2) is 0-25°C.

[0137] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the above-mentioned compound and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0138] The present invention further relates to the use of the crystal form of any compound or the pharmaceutical composition of the present invention in the preparation of an orexin receptor antagonist; preferably in the preparation of an OX2R selective receptor antagonist.

[0139] The present invention further relates to the crystal form of any compound or the pharmaceutical composition of the present invention or the use of the pharmaceutical composition of the present invention in the preparation of drugs for treating nervous system diseases; the nervous system diseases are preferably insomnia, depression, anxiety, drug addiction, and more preferably major depressive disorder (MDD), primary and secondary insomnia, and depression associated with insomnia.

[0140] The present invention further relates to a method for treating a nervous system disease, wherein the present invention further relates to a crystalline form of any compound or a pharmaceutical composition of the present invention; the nervous system disease is preferably insomnia, depression, anxiety, drug addiction, and more preferably major depressive disorder (MDD), primary and secondary insomnia, and depression associated with insomnia.

[0141] FIG1 is an XRPD diagram of the free base form I of compound 9.

[0142] FIG2 is a DSC diagram of the free base form I of compound 9.

[0143] FIG3 is a TGA diagram of the free base form I of compound 9.

[0144] FIG4 is an XRPD diagram of the free base form II of compound 9.

[0145] FIG5 is a DSC diagram of the free base form II of compound 9.

[0146] FIG6 is a TGA diagram of the free base form II of compound 9.

[0147] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0148] In the present invention, alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, and most preferably an alkyl 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, 5-methylhexyl, 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, etc.

[0149] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0150] In the present invention, the cycloalkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms.

[0151] Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0152] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0153] In the present invention, a heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; and further preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridine-2 (1H)-onyl, 4,5-dihydropyridazine-3 (2H)-onyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidyl, pyrrolidinone, piperidin-2-one, 3,4-dihydropyridine-2 (1H) -one, 4,5-dihydropyridazine-3 (2H) -one, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, more preferably, dihydropyrrolyl, pyrrolidyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydropyridazin-3(2H)-onyl, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl, Pyranyl. Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0154] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0155] In the present invention, aryl refers to a 6-14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6-10 members, more preferably 6-8 members, such as phenyl and naphthyl, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0156] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0157] In the present invention, heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan, more preferably 5 to 8 yuan, most preferably 5 yuan or 6 yuan, such as pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazole, pyridine. The heteroaryl ring can be fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0158] The heteroaryl group may be optionally substituted or unsubstituted, and 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0159] In the present invention, alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, and most preferably an alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

[0160] Non-limiting examples of alkoxy also include propan-2-oxy and the like.

[0161] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0162] Non-limiting examples of haloalkyl also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0163] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above;

[0164] The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0165] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0166] In the present invention, alkenyl refers to alkenyl, also known as olefin group, preferably alkenyl containing 2 to 8 carbon atoms, more preferably alkenyl containing 2 to 6 carbon atoms, further preferably alkenyl containing 2 to 4 carbon atoms, and most preferably alkenyl containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl include: vinyl, propenyl. The alkenyl group described herein can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0167] In the present invention, alkynyl refers to chain alkynyl, also known as alkyne, which refers to an unsaturated hydrocarbon group containing -C≡C-; preferably an alkynyl containing 2 to 8 carbon atoms, more preferably an alkynyl containing 2 to 6 carbon atoms, further preferably an alkynyl containing 2 to 4 carbon atoms, and most preferably an alkynyl containing 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0168] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

[0169] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0170] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0171] "Hydroxy" refers to an -OH group.

[0172] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0173] "Amino" refers to -NH2.

[0174] "Cyano" refers to -CN.

[0175] "Nitro" refers to -NO2.

[0176] "THF" refers to tetrahydrofuran.

[0177] "DMSO" refers to dimethyl sulfoxide.

[0178] "IPA" refers to isopropyl alcohol.

[0179] "MeOH" refers to methanol.

[0180] "EtOH" refers to ethanol.

[0181] "DMF" refers to N,N-dimethylformamide.

[0182] "DIPEA" refers to N,N-diisopropylethylamine.

[0183] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0184] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0185] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not occur.

[0186] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0187] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0188] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0189] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0190] X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or the parameters derived therefrom, and the X-ray powder diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). It will be understood by those skilled in the art that the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will usually change with the conditions of the instrument, and those skilled in the art should understand that the appropriate error tolerance of XRPD can be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It should be particularly noted that the relative intensity of the X-ray diffraction pattern may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, due to the influence of experimental factors such as sample height, the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the spectrum of the present invention belongs to the scope of the present invention.

[0191] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0192] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0193] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0194] "PK" refers to pharmacokinetic (PK) studies.

[0195] "KF" refers to Karl Fischer water determination (KF) experiment

[0196] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0197] Example

[0198] Preparation of intermediates:

[0199] Intermediate 1: Preparation of 2-(2-chloro-6-methylpyrimidin-4-yl)propanol

[0200] 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 hours and then at room temperature for 12 hours. The reaction solution was slowly quenched by 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 by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain intermediate 1 (362 mg, colorless oil) with a yield of 53.7%.

[0201] MS m / z(ESI):187.1[M+1]

[0202] Intermediate 2: Preparation of 2-(5-fluoro-2-(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidin-4-yl)-propan-2-ol

[0203] first step

[0204] 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 hours, cooled, a saturated solution of potassium fluoride (aq) was added and the mixture was stirred at room temperature for 1 hour. After filtering through celite, 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 obtain intermediate 2b (1.3 g, 83.5%).

[0205] MS m / z(ESI):217.0[M+1]

[0206] Step 2

[0207] Dissolve intermediate 2b (1.3 g, 6.00 mmol) in THF (10 mL) and add 3N HCl (5 mL). Stir the mixture at room temperature for 1 hour. LCMS monitoring shows that the reaction is complete. Adjust pH to about 7-8 with saturated NaHCO3, extract with ethyl acetate, and concentrate the organic phase to obtain intermediate 2c (1.1 g, 97.2%). Use it directly in the next step.

[0208] MS m / z(ESI):189.0[M+1]

[0209] 1H NMR (400MHz, Chloroform-d) δ2.69 (s, 3H), 2.62 (d, J = 2.8Hz, 3H).

[0210] Step 3

[0211] At 0°C, intermediate 2c (1.9 g, 10.07 mmol) and MeMgBr (3 M, 4.37 mL) were added to THF (40 mL). 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 obtain intermediate 2d (1.4 g, yield 67.9%).

[0212] MS m / z(ESI):205.0[M+1]

[0213] Step 4

[0214] Rac-(3aR, 6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (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 solution was stirred at 100°C for 3 hours, water (20 mL) was added, and then extracted with dichloromethane (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and the crude product was passed through a column (PE:EA=3:1) to obtain intermediate 2e (720 mg, yield 80.3%).

[0215] MS m / z(ESI):381.2[M+1]

[0216] Step 5

[0217] Intermediate 2e (1 g, 2.63 mmol) and trifluoroacetic acid (2.69 mmol, 2 mL) were added to DCM (3 mL). The reaction solution was stirred at 25° C. for 3 hours and then dried by vortexing to obtain Intermediate 2 (700 mg, yield 95.0%).

[0218] MS m / z(ESI):281.2[M+1]

[0219] Intermediate 3: Preparation of 2-(6-(3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1h)-yl)-4-methylpyridin-2-yl)propan-2-ol

[0220] The preparation method of intermediate 3 refers to the preparation method of the third, fourth and fifth steps of intermediate 2, and 6-chloro-4-methyl-2-acetyl-pyridine is used instead of intermediate 2c to obtain intermediate 3 (1.2 g, colorless oil, 53.7%).

[0221] MS m / z(ESI):262.2[M+1]

[0222] Example 1

[0223] Compound 1: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0224] first step

[0225] HATU (809 mg, 2.13 mmol) and DIPEA (550 mg, 4.26 mmol) were slowly added to a DMF (5.0 mL) 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), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 30 mL of ethyl acetate, washed with water (30 mL*3), the organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain (3aR, 6aS)-5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 1b) (452 ​​mg, light yellow solid, 79.7%).

[0226] MS m / z(ESI):402.1[M+1]

[0227] Step 2

[0228] TFA (3.0 mL) was slowly added to a solution of 1b (450 mg, 1.12 mmol) in DCM (6.0 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution 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, light yellow oil), which was used directly in the next step.

[0229] MS m / z(ESI):302.0[M+1]

[0230] Step 3

[0231] Intermediate 1 (61.5 mg, 0.33 mmol), 1c (100 mg, 0.33 mmol), Pd2(dba)3 (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 hours under nitrogen protection. After the reaction solution was cooled, water (5 mL) was added to quench it, and dichloromethane was extracted (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-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Compound 1) (32.4 mg, white solid, 21.8%).

[0232] MS m / z(ESI):452.2[M+1]

[0233] 1 H NMR (400MHz, DMSO-d6) δ8.16 (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),5.1 0(d,J=4.0Hz,1H),3.73(dtd,J=22.4,7.2,6.5,3.6Hz,2H),3.59–3.41(m,4H),3.3 5(d,J=4.8Hz,1H),3.16–2.90(m,3H),2.28(d,J=3.5Hz,3H),1.36(d,J=3.3Hz,6H).

[0234] Example 2

[0235] Compound 2: Preparation of ((3aR, 6aS)-5-(5-fluoro-4-(2-hydroxypropane-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

[0236] The synthesis method of compound 2 can refer to the synthesis method of Example 1.

[0237] MS m / z(ESI):470.2[M+1].

[0238] Example 3

[0239] Compound 3: Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3aR,6aS)-5-(6-(2-hydroxypropane-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0240] 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). Tetramethyl chlorouronium 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 then extracted with dichloromethane (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and the crude product was purified by preparative HPLC to obtain compound 3 (64 mg, yield 60.5%).

[0241] MS m / z(ESI):462.2[M+1]

[0242] 1 H NMR (400MHz, DMSO-d6) δ8.93(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).

[0243] Example 4

[0244] Compound 4: Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3aR,6aS)-5-(6-(2-fluoropropane-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0245] 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, and then extracted with dichloromethane (30 mL*2). The organic phases were combined and dried over Na2SO4, and then spin-dried. The crude product was purified by preparative HPLC to obtain compound 4 (31 mg, yield 68.6%).

[0246] MS: m / z(ESI):464.2[M+1].

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.92(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).

[0248] Example 5

[0249] Compound 5: Preparation of ((3aR, 6aS)-5-(5-fluoro-4-(2-fluoropropane-2-yl)-6-methylpyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0250] The synthesis method of compound 5 refers to the synthesis method of Example 4, and compound 2 is used as the raw material to replace compound 3 to obtain compound 5 (30 mg, yield 66%).

[0251] MS: m / z(ESI):472.2[M+1].

[0252] 1H NMR (400MHz, DMSO-d6) δ8.16(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,1 H),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).

[0253] Example 6

[0254] Compound 6: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropane-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0255] first step

[0256] 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, and the reaction solution was stirred at 0°C for 0.5 h. Saturated ammonium chloride (5 ml) was added to the reaction solution, and dichloromethane (3*10 mL) was used for extraction. The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by column (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%).

[0257] MS m / z(ESI):186.1[M+1]

[0258] Step 2

[0259] Compound 6-2 (65.95 mg, 0.36 mmol), compound 3c (100 mg, 0.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (34.22 mg, 59.20 μmol), and palladium acetate (6.63 mg, 29.61 μmol) were dissolved in 1,4-dioxane (2 mL), and then potassium tert-butoxide (33.16 mg, 296.07 μmol) was added to the reaction solution, and the reaction solution was stirred at 100 °C under microwave conditions for 1 h. Saturated brine (10 ml) was added to the reaction solution, extracted with dichloromethane (3*10 mL), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was prepared and purified to obtain (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropane-2-yl)-4-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Compound 6) (8 mg, 6.00% yield).

[0260] MS m / z(ESI):451.1[M+1].

[0261] 1 H NMR (400MHz, DMSO) δ7.95 (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).

[0262] Example 7

[0263] 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

[0264] first step

[0265] Dissolve tributyl(1-ethoxyvinyl)stannane (11.90 g, 32.95 mmol) and compound 7a (5 g, 29.95 mmol) in DMF (5 mL), then add bistriphenylphosphine palladium (II) chloride (1.05 g, 1.50 mmol), and stir the reaction solution at 100°C for 2 h. After the reaction, add saturated potassium fluoride (10 ml) aqueous solution and stir for 1 h, filter, wash the filter cake with dichloromethane (10 mL*3), combine the organic phases, dry, and concentrate to obtain a crude product. The crude product is purified by column purification (petroleum ether / ethyl acetate system) to obtain compound 7b (5.6 g, yield 92.3%).

[0266] MS m / z(ESI):203.0[M+1]

[0267] Step 2

[0268] 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 solution. The reaction solution was stirred at 50 ° C for 2 h, saturated sodium chloride (10 mL) was added to the reaction solution, and dichloromethane (10 mL*3) was used for extraction. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column (petroleum ether / ethyl acetate system) to obtain compound 7c (4.4 g, yield 91.2%).

[0269] MS m / z(ESI):175.0[M+1]

[0270] Step 3

[0271] Compound 7c (4.4 g, 25.21 mmol) was dissolved in tetrahydrofuran (5 mL). Methylmagnesium bromide (3 M, 9.24 mL) was added to the reaction solution at -78 °C, and the reaction solution was stirred for 15 min at -78 °C. Saturated ammonium chloride (10 mL) was added to the reaction solution, and dichloromethane (10 mL*3) was used for extraction. 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%).

[0272] MS m / z(ESI):191.0[M+1]

[0273] Step 4

[0274] The synthesis method of compound 7 refers to the synthesis method of compound 6, using compound 1c and compound 7d as raw materials to obtain compound 7 (38 mg, yield 42.6%).

[0275] MS: m / z(ESI):456.2[M+1]

[0276] 1 H NMR (400MHz, DMSO) δ8.21(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=14.6,8.1H z,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).

[0277] Example 8

[0278] Compound 8: Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3R,6S)-5-(6-(2-hydroxypropane-2-yl)-5-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0279] first step

[0280] 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 H2O (1.0 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (142.49 mg, 174.62 μmol) was added to the reaction solution, and the reaction solution was stirred at 100°C for 16 hours. Saturated brine (10 ml) was added to the reaction solution, extracted with dichloromethane (3*20 mL), the organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by column (petroleum ether / ethyl acetate system) to obtain methyl 2-fluoro-6-(pyrimidin-2-yl)benzoate (Compound 8-2) (0.2 g, 49.1%).

[0281] MS m / z(ESI):233.1[M+1]

[0282] Step 2

[0283] Compound 8-2 (0.8 g, 3.45 mmol) was dissolved in water (2 mL) and methanol (2 mL), and then sodium hydroxide (413.39 mg, 10.33 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 ° C for 16 hours. 2 mol / L hydrochloric acid solution (10 ml) was added to the reaction solution to adjust the pH of the reaction solution to acidic, and ethyl acetate (3*20 mL) was used for extraction. The organic phases were combined, dried, and concentrated to obtain 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 purification.

[0284] MS m / z(ESI):219.1[M+1]

[0285] Step 3

[0286] Compound 8-3 (0.2 g, 917.43 μmol) and N,N-dimethylformamide (0.1 ml) were dissolved in dichloromethane (2 mL), and then oxalyl chloride (232.70 mg, 1.83 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 0.5 h, and the reaction solution was concentrated to obtain a 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), and then N-ethyl-N-isopropylpropan-2-amine (352.29 mg, 2.73 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 1 h. Saturated brine (10 ml) was added to the reaction solution, extracted with dichloromethane (3*10 mL), the organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by column purification (petroleum ether / ethyl acetate system) to obtain (3R, 6S)-5-(2-fluoro-6-(pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 8-4) (0.2 g, 53.4%).

[0287] MS m / z(ESI):413.2[M+1]

[0288] Step 4

[0289] Compound 8-4 (200.00 mg, 485.43 μmol) was dissolved in hydrochloric acid / 1,4-dioxane (4M, 2 mL), and then the reaction solution was stirred at room temperature for 1 h. The reaction solution was filtered, the filter cake was collected, and dried to obtain (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%).

[0290] MS m / z(ESI):313.2[M+1]

[0291] Step 5

[0292] The synthesis method of compound 8 refers to the synthesis method of compound 6, using compound 8-5 and compound 2-(6-chloro-3-methylpyridin-2-yl)-propan-2-ol as raw materials to obtain (2-fluoro-6-(pyrimidin-2-yl)phenyl)((3R, 6S)-5-(6-(2-hydroxypropane-2-yl)-5-methylpyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 8) (1.8 mg, 2.6%).

[0293] MS: m / z(ESI):462.2[M+1]

[0294] Example 9

[0295] Compound 9: 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-(pyrimidin-2-yl)phenyl)methanone

[0296] The synthesis method of compound 9 refers to the synthesis method of compound 6, using compounds 8-5 and 7d as raw materials to obtain compound 9 (22 mg, yield 28.6%).

[0297] MS: m / z(ESI):467.2[M+1]

[0298] 1 H NMR (400MHz, DMSO) δ8.86(dd,J=48.0,4.9Hz,2H),8.32(s,1H),8.02(dd,J=35.7,7.8Hz,1H),7.60(dd,J=14.0,7.9 Hz,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).

[0299] Example 10

[0300] Compound 10: Preparation of (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0301] 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 solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse preparative HPLC chromatography (acetonitrile / water system) to obtain compound 10 (16.3 mg, yield 12.2%).

[0302] MS m / z(ESI):470.2[M+1]

[0303] 1 H NMR(400MHz, DMSO-d6)δ8.03(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).

[0304] Embodiment 11

[0305] Compound 11: Preparation of (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0306] first step

[0307] 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 solution was heated to 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into 200 mL of water, and extracted with methyl tert-butyl ether (100 mL*2). The organic phases were combined, washed with water (100 mL) and saturated sodium chloride solution (100 mL) in turn, 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 obtain compound 11a (6.5 g, yield 40.0%).

[0308] MS m / z(ESI):189.0[M+1]

[0309] 1 H NMR (400MHz, CDCl3) δ8.00 (s, 2H), 7.67-7.65 (m, 1H), 7.62-7.55 (m, 2H).

[0310] Step 2

[0311] 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 for 4 hours. The reaction solution was cooled to 0°C, the pH was adjusted to about 1 with dilute hydrochloric acid, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with water (100 mL) and saturated sodium chloride solution (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11b (1.5 g, yield 90.8%).

[0312] MS m / z(ESI):208.0[M+1]

[0313] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 2H), 7.87 (d, J = 7.6Hz, 1H), 7.63-7.58 (m, 1H), 7.52-7.49 (m, 1H).

[0314] Step 3

[0315] Dissolve (cis)-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (120 mg, 0.565 mmol) in anhydrous acetonitrile (2 mL), add 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), and react at room temperature for 2 hours. Pour the reaction solution into 30 mL of water and extract with ethyl acetate (30 mL*2). Combine the organic phases, wash with water (80 mL) and saturated sodium chloride solution (80 mL) in turn, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain compound 11c (210 mg, yield 92.6%).

[0316] MS m / z(ESI):402.2[M+1]

[0317] 1 H NMR(400MHz,DMSO-d6)δ8.07(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).

[0318] Step 4

[0319] Compound 11c (80 mg, 0.199 mmol) was dissolved in anhydrous dichloromethane (2 mL), and a dioxane hydrochloride solution (4 M, 2 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 11d (60 mg, yield 99.9%).

[0320] MS m / z(ESI):302.1[M+1]

[0321] Step 5

[0322] Compound 11d (60 mg, 0.199 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), intermediate 2d (45 mg, 0.220 mmol) and cesium carbonate (130 mg, 0.399 mmol) were added, and the mixture was heated to 110°C for 2 hours. The reaction solution was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse preparative HPLC chromatography (acetonitrile / water system) to obtain compound 11 (31.3 mg, yield 33.5%).

[0323] MS m / z(ESI):470.2[M+1]

[0324] 1 H NMR(400MHz, DMSO-d6)δ8.00(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),3.64-3.5 9(m,1H),3.57-3.49(m,2H),3.43-3.34(m,2H),3.29-3.25(m,1H),3.1 3-3.09(m,1H),2.99-2.93(m,2H),2.32(d,J=2.8Hz,3H),1.46(s,6H).

[0325] Example 12

[0326] Compound 12: Preparation of ((3aR, 6aS)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyridin-2-yl)phenyl)methanone

[0327] first step

[0328] 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 DMF (60 mL) solution of compound 12a (4 g, 17.16 mmol) and 2-(tributylstannyl)pyridine (6.97 g, 18.93 mmol). The mixture was reacted at 120°C for 5 hours. After cooling to room temperature, 150 mL of water was added and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified to give compound 12b (2.8 g, yield 70.5%).

[0329] MS m / z(ESI):232.1[M+1]

[0330] Step 2

[0331] Sodium hydroxide (688.98 mg, 17.22 mmol) was added to a mixed solution of water (5.0 mL) and methanol (5.0 mL) of compound 12b (800 mg, 3.46 mmol). The mixture was reacted at 25°C for 3 hours. 2N HCl was added until pH = 2, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying to obtain compound 12c (650 mg, yield 86.5%).

[0332] MS m / z(ESI):218.0[M+1]

[0333] Step 3

[0334] Tetramethyl chlorouronium hexafluorophosphate (257 mg, 0.92 mmol) and N-methylimidazole (188 mg, 2.29 mmol) were added to a solution of 12c (100 mg, 0.46 mmol) and intermediate 2 (129 mg, 0.46 mmol) in acetonitrile (3.0 mL). Stir at 25°C for 30 minutes. 20 mL of water was added to the reaction solution and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain compound 12 (40 mg, yield 18.1%).

[0335] MS m / z(ESI):480.2[M+1]

[0336] 1H NMR (400MHz, DMSO-d6) δ8.64–8.44(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).

[0337] Embodiment 13

[0338] Compound 13: Preparation of (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0339] first step

[0340] Dissolve 5-fluoro-2-iodobenzoic acid (300 mg, 1.13 mmol) in anhydrous N,N-dimethylformamide (4 mL), add 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), and react at 120°C for 15 minutes in a microwave oven. The reaction solution 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 with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse C18 column chromatography (acetonitrile / water system) to give compound 13a (150 mg, yield 64.2%).

[0341] MS m / z(ESI):208.0[M+1].

[0342] Step 2

[0343] The preparation method of compound 13 refers to the third step of the preparation method of compound 12, and compound 13a is used to replace compound 12c to obtain compound 13 (60 mg, yield 30%).

[0344] MS m / z(ESI):470.2[M+1].

[0345] 1 H NMR(400MHz,DMSO-d6)δ7.98(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).

[0346] Embodiment 14

[0347] Compound 14: Preparation of (5-fluoro-2-(pyrimidin-2-yl)phenyl)((cis)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0348] first step

[0349] 2-Chloropyrimidine (280 mg, 2.44 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and water (1 mL), 2-boric acid-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 protection for 2 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, filtered, the filtrate was concentrated under reduced pressure, 10 mL of ethanol was added, the inorganic salt was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product compound 14a (260 mg, yield 73.1%), which was directly used in the next step.

[0350] MS m / z(ESI):219.1[M+1].

[0351] Step 2

[0352] The preparation method of compound 14b refers to the preparation method of compound 11c.

[0353] MS m / z(ESI):413.2[M+1].

[0354] Step 3

[0355] The preparation method of compound 14c refers to the preparation method of compound 11d.

[0356] MS m / z(ESI):313.1[M+1].

[0357] Step 4

[0358] The preparation method of compound 14 refers to the preparation method of compound 11.

[0359] MS m / z(ESI):481.2[M+1].

[0360] 1 H NMR(400MHz, DMSO-d6)δ8.81(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,1 H),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).

[0361] Embodiment 15

[0362] Compound 15: Preparation of ((3aR, 6aS)-5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone

[0363] first step

[0364] 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 DMF (60 mL) solution of compound 15a (4 g, 17.16 mmol) and 2-(tributylstannyl)pyrimidine (6.97 g, 18.88 mmol). The mixture was reacted at 120°C for 5 hours. After cooling to room temperature, 150 ml of water was added and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified to give compound 15b (2.8 g, yield 70.3%).

[0365] MS m / z(ESI):233.1[M+1].

[0366] Step 2

[0367] Sodium hydroxide (688.98 mg, 17.22 mmol) was added to a mixed solution of compound 15b (800 mg, 3.45 mmol) in water (5.0 mL) and methanol (5.0 mL). The mixture was reacted at 25°C for 3 hours. 2N HCl was added until pH = 2, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying to obtain compound 15c (650 mg, yield 86.5%).

[0368] MS m / z(ESI):219.0[M+1].

[0369] Step 3

[0370] Tetramethyl chlorouronium hexafluorophosphate (257 mg, 0.92 mmol) and N-methylimidazole (188 mg, 2.29 mmol) were added to a solution of 106c (100 mg, 0.46 mmol) and intermediate 2 (129 mg, 0.46 mmol) in acetonitrile (3.0 mL). Stir at 25°C for 30 minutes. 20 mL of water was added to the reaction solution and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain compound 15 (40 mg, yield 18.2%).

[0371] MS m / z(ESI):481.2[M+1].

[0372] 1 H NMR (400MHz, DMSO-d6) δ8.85(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).

[0373] Biological test evaluation

[0374] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0375] 1. Cell function experiment

[0376] Test Example 1: Determination of the Effect of the Compounds of the Invention on Calcium Flux in Cells Stably Expressing OX1 and OX2 Receptors

[0377] 1. Experimental purpose:

[0378] The inhibitory effect of the compounds on calcium flux activity in CHO-K1 / human OX1R and CHO-K1 / human OX2R cells was detected.

[0379] 2. Experimental instruments and reagents

[0380] 2.1 Instruments:

[0381] 384-well cell culture plate (Corning: 3764);

[0382] Plate reader FLIPR Tetra (Molecular Device).

[0383] 2.2 Reagents:

[0384] DMEM, high glucose (Gibco: 12100);

[0385] Fetal bovine serum (Biosera: FB-1058 / 500);

[0386] P / S (Biosera: XC-A4122);

[0387] 5X Matrigel(Corning: 354230);

[0388] HBSS (Sigma: H1387);

[0389] HEPES (Invitrogen: 15630080);

[0390] Fluo-8AM (AAT Bioquest: 21080);

[0391] Probenecid (Sigma: P8761);

[0392] Pluronic F-127 (Sigma: P2443-250G);

[0393] 1000X Fluo-8AM (2mM): Fluo-8AM was dissolved in DMSO, shaken for 1-2min, and stored at -20℃ after aliquoting;

[0394] Complete culture medium: DMEM + 10% FBS + 1X P / S;

[0395] Cell seeding medium: DMEM + 10% FBS + 1X PS;

[0396] Assay buffer: 1X HBSS + 20 mM HEPES + 1 mM Probenecid + 0.025% Pluronic F-127;

[0397] 1X Matrigel: dilute 5X Matrigel with DMEM;

[0398] Cell lines: CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines.

[0399] 3. Experimental methods:

[0400] 1) CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines were cultured separately in complete medium at 37°C, 5% CO2 until 70% to 90% confluency;

[0401] 2) Coat a 384-well cell culture plate with 1X Matrigel, 5uL per well, at room temperature for 10-30 minutes;

[0402] 3) The cells were digested and resuspended in cell inoculation medium, and 8,000 cells / well / 20 μL of CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines were inoculated into two 384-well cell culture plates, respectively, and cultured at 37°C, 5% CO2 for 24 hours;

[0403] 4) Take the cell culture plate out of the CO2 incubator and equilibrate at room temperature for 10 minutes;

[0404] 5) Take out 1000X Fluo-8AM and dilute it to 1X Fluo-8AM with assay buffer 1 equilibrated to room temperature, with a concentration of 2 μM;

[0405] 6) Remove the culture medium from the cell culture plate, add 20 μL 1X Fluo-8AM to each well, centrifuge at 300 rpm for 60 seconds at room temperature, and incubate at room temperature in the dark for 1 hour;

[0406] 7) Determine the EC80 of OX1 and OX2 receptor agonists (OX-A for OX1R assays, OX-B for OX2R assays): Prepare and dilute the working solutions of OX1 and OX2 receptor agonists respectively, add the diluted OX1 and OX2 receptor agonists to the experimental wells of the corresponding 384-well cell culture plates of CHO-K1 / human OX1R and CHO-K1 / human OX2R cell lines respectively using FLIPR Tetra, read and collect data at the same time, and obtain the EC80 of OX-A and OX-B respectively according to the experimental data processing method below;

[0407] 8) Repeat steps 1-7 to prepare positive compounds (suvorexant and seltorexant) and test compounds. Add the diluted compounds (11 concentration points) to the experimental wells of the corresponding two 384-well cell culture plates using FLIPR Tetra. After 15 minutes, add OX1 and OX2 receptor agonists to the wells of the two cell lines according to the previously obtained EC80, and read and collect data at the same time to determine the IC50 of the positive compounds and the test compounds.

[0408] 4. Experimental data processing method:

[0409] FLIPR Tetra reads and collects the fluorescence signal value (RFU), takes the maximum RFU value, and calculates the percentage inhibition (activation) data {% inhibition (activation) rate = (RFUsample-RFUlow control) / (RFUhigh control-RFUlow control) × 100} according to the reading values ​​of the Low control (DMSO control) and High control (100nM positive compound) experimental groups. Prism8 is used to fit the percentage inhibition (activation) rate and 11-point concentration data to the parameter nonlinear logic formula to calculate the IC of the compound. 50 value.

[0410] 5. Experimental results:

[0411] The compound of the present invention shows good inhibitory effect in the experiment of the influence of cells stably expressing OX2 receptor on calcium flow, and the inhibitory effect of the compound on OX2 receptor is significantly better than that on OX1 receptor, and has good selectivity.

[0412] 2. Pharmacokinetic Evaluation Test

[0413] Pharmacokinetic evaluation test in rats

[0414] 1. Research objectives:

[0415] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) at a dose of 5 mg / kg after oral administration.

[0416] 2. Experimental plan:

[0417] 2.1 Experimental drugs:

[0418] The compounds of the present invention are self-made.

[0419] 2.2 Experimental Animals:

[0420] There were 3 male SD rats in each group, from Shanghai Jiesijie Experimental Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

[0421] 2.3 Preparation prescription:

[0422] Oral drug preparation: 20% HP-β-CD in Water

[0423] Weigh 20 g of HP-β-CD powder, dissolve it in 100 mL of purified water, vortex, mix, and sonicate to obtain a clear solution.

[0424] The example compound was weighed into a 20 mL glass bottle, and the solution was added thereto, followed by ultrasonication for 10 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0425] 2.4 Administration:

[0426] Three male SD rats were fasted overnight and then given po;

[0427] The po dose is 5 mg / kg, and the administration volume is 10 mL / kg.

[0428] 2.5 Sample collection:

[0429] Blood collection: 0.2 mL of blood was collected from the jugular vein of rats before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C. The rats were fed 4 h after administration.

[0430] Brain tissue collection: After the experimental animals were euthanized by CO2, brain tissue was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration. The brain tissue was rinsed with pre-cooled PBS, wiped dry, weighed, and stored at -80℃.

[0431] 2.6 Sample processing:

[0432] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, and the mixture was centrifuged at 3500×g for 5 to 20 minutes.

[0433] 2) The supernatant solution after treatment is subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument is AB Sciex API 4000Qtrap.

[0434] 2.7 Liquid phase analysis:

[0435] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0436] ●Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase:

[0437] Liquid A is 0.1% formic acid aqueous solution, and liquid B is acetonitrile

[0438] Flow rate: 0.4 mL / min

[0439] ● Elution time: 0-4.0 minutes, eluent is as follows:

[0440] 3. Test results and analysis:

[0441] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the rat pharmacokinetic experiment are shown below:

[0442] 4. Experimental conclusion:

[0443] The data show that in the pharmacokinetic evaluation experiment in rats, the Example compounds of the present invention show higher exposure after oral administration, especially higher exposure in the brain.

[0444] 3. Evaluation of the effect of the compounds of the present invention on the sleep structure of rats by remote EEG and EMG sleep technology 1. Experimental purpose

[0445] In this experiment, the DSI telemetry electroencephalogram and electromyography system was used to detect the effects of the compounds of the present invention on the sleep structure of SD rats.

[0446] 2. Experimental instruments and reagents

[0447] 2.1. Main instruments

[0448] DSI Telemetry Pressure System: Implantable Model: TL11M2-F40-EET, Data Sciences International. HD-S02, Data Sciences International.

[0449] Data acquisition software: Ponemah Software 5.0, Data Sciences International.

[0450] Data analysis software: NeuroScore, Data Sciences International.

[0451] Precision electronic balance

[0452] Electronic balance

[0453] Ultrasound

[0454] Constant temperature magnetic stirrer

[0455] Vortex

[0456] 2.2. Main reagents

[0457] HP-β-CD

[0458] 3. Experimental Procedure

[0459] 3.1. Purchase and acclimatization of experimental animals

[0460] SD rats weighed 190-210g (5-6W) when they arrived at the facility. After the animals arrived at the facility, they were kept in an animal breeding room with strictly controlled environmental conditions for 7-9 days. During the adaptation period, the experimental animals were placed in a 12h light-dark alternation environment to adjust the rhythm time, and the health status of the animals was monitored every day.

[0461] 3.2. Grouping

[0462] All animals were weighed upon arrival at the animal facility, were adaptively raised, and had electrodes surgically implanted, with the number of animals meeting the requirement of statistical testing and pharmacodynamic guidelines of at least 6 per group.

[0463] Experimental procedures

[0464] 1) Surgical implantation of electrodes: The experimental animals were placed in a 12-hour light-dark alternation environment to adapt for 7-9 days (lights off: 07:00; lights on: 19:00). On the day of the experiment, the animals were anesthetized with Zota (ip, 20 mg / kg) and thiazine (ip, 8 mg / kg). After anesthesia, the brain was fixed with a stereotaxic instrument, the surgical area of ​​the head was prepared, the skull was drilled and the electrodes were implanted. At the same time, two electromyographic electrodes were inserted into the neck muscles in parallel, and the two ends were fixed with sutures to prevent their ends from contacting each other. The implant was then placed under the skin of the back, and the surgical wound was sutured and disinfected.

[0465] 2) Postoperative care: After surgery, the rats were carefully placed in a clean recovery cage in a lateral position to ensure that the airway was unobstructed. The light and dark were automatically alternating for 12 hours (lights off: 07:00, lights on: 19:00), the temperature was constant at 20-26°C, and the relative humidity was 40-70%. The animals were given 3 days of care after surgery, the surgical incision was treated with cefradine powder locally, gentamicin 4-8 mg / kg was given subcutaneously, and meloxicam 0.1 ml / mouse was injected subcutaneously for 3 consecutive days. The experiment was carried out after 7-10 days of recovery, and the animals were randomly divided into groups according to their weight.

[0466] 3) Dosage plan and indicator monitoring: 7-10 days after surgery, basic EEG and EMG recordings were performed, and medication was started after the basic EEG and EMG recordings were completed, and medication was continued for seven days. On the first and seventh days of medication, EEG and EMG recordings were performed 1 hour before medication at 11:00 on the same day, and medication was performed at 12:00, followed by EEG and EMG recordings 24 hours after medication.

[0467] 4) Experimental indicators: After drug administration, the changes in the latency of NREM and REM between different groups; the changes in the time of Wake, NREM and REM within 24 hours after drug administration.

[0468] 4. Data Collection and Analysis

[0469] The raw data were collected by DSI system Ponemah software and analyzed by NeuroScore software and GraphPad Prism software. The experimental data were expressed as mean ± standard error (Mean ± SEM) and statistically analyzed by ANOVA. P < 0.05 indicated a significant difference.

[0470] 5. Experimental Results

[0471] The distribution of wakefulness / sleep states of animals in the vehicle control group was consistent with the circadian rhythm, and no significant effect of the vehicle on the sleep structure of the animals was observed. Moreover, the distribution of animals in different wakefulness / sleep stages was consistent with that reported in the literature, indicating that the model was successful and stable.

[0472] The different sleep stages of each animal in the vehicle group and the drug-treated group from 1 hour before drug administration to after drug administration were analyzed, and the mean of each group was taken in units of 1 hour to analyze the changes in the time distribution of each group in different sleep stages.

[0473] For the lights-off stage, the total length of time the animals spent in different sleep stages at 1h, 3h, 5h, and 7h after drug administration was statistically analyzed to analyze the effects of drug efficacy among different drug administration groups.

[0474] During the lights-on stage, the total length of time the animals spent in different sleep stages 1h, 3h, 5h, and 7h after the lights were turned on was statistically analyzed to analyze the effects of drug efficacy among different drug groups.

[0475] 6. Experimental Conclusion

[0476] The compounds of the embodiments of the present invention can significantly reduce the NREM / REM latency and the total duration of wakefulness at a relatively low dose; significantly increase the total duration of NREM, have no effect on the total REM time, and have a low risk of drowsiness. It can be seen that the compounds of the present invention have a good sleep-promoting effect on rats and have a low risk of drowsiness.

[0477] IV. CYP enzyme single-site inhibition test

[0478] 1. Purpose of the experiment

[0479] The human liver microsome incubation system was used to quickly predict the inhibition of compounds on CYP450 enzyme subtypes using the single-point method.

[0480] 2. Experimental Procedure

[0481] 2.1 Solution preparation

[0482] Weigh NADPH (reduced nicotinamide adenine dinucleotide phosphate) and add 100mM phosphate buffer to a final concentration of 2.5mM. Add 4mL 100mM phosphate buffer to 50μL 20mg / mL microsomes and mix to obtain 0.25mg / mL microsomes.

[0483] Preparation of the reaction solution of the test compound:

[0484] The compound of the example to be tested was weighed, diluted to 10 mM with DMSO, and then diluted to 100 μM with 100 mM phosphate buffer.

[0485] 2.2 Experimental process:

[0486] 1. In a 96-well plate, add 40 μL liver microsomes, 10 μL substrate, and 10 μL test compound and pre-incubate for 3 min.

[0487] 2. Add 40 μL of NADPH.

[0488] 3. At 20 min, add 300 μL of acetonitrile stop solution containing internal standard.

[0489] 4. Centrifuge and inject.

[0490] 3. Experimental results:

[0491] Crystal form research

[0492] 1.1 Experimental Instruments

[0493] 1.1.1 Some parameters of physical and chemical testing instruments

[0494] 1.1.2 Chromatographic conditions

[0495] 1. Preparation of different crystal forms

[0496] 1.1 Preparation of Compound 9 Free Base Form I

[0497] About 20 mg of the free base was weighed into a 2 mL glass bottle, 100-200 μL of an organic solvent (the organic solvent may be MeOH, EtOH, EA, Acetone, IPA, IPAc, MEK, 2-Me-THF, MTBE, toluene, cyclohexane, heptane) was added, and the mixture was slurried at 50° C. for 7 days. The obtained solid was centrifuged, the supernatant was removed, and the mixture was vacuum dried at 40° C. to obtain the free base form I. After detection and analysis, the free base has the following XRPD diagram as shown in FIG. 1 , the DSC diagram as shown in FIG. 2 , and the TGA diagram as shown in FIG. 3 .

[0498] 1.2 Preparation of Compound 9 Free Base Form I (Process Preparation Method)

[0499] 1) Dissolve 15.3 g of the crude product in 20 mL of methanol, add 30 mL of water, stir for 20 min, and then add 6 mL of water (methanol: water = 1:1.8) and stir for 16 h.

[0500] 2) Filter, mix 4 mL methanol + 12 mL water, wash the filter cake, and dry at 40 ° C to obtain a light brown solid;

[0501] 3) Add 7.7 g of solid to 23 mL of methanol, heat to an external temperature of 65°C, dissolve, cool to 20°C and stir for 0.5 h. After solid precipitates, add 23 mL of water dropwise and stir for 4 h.

[0502] 4) Filter, mix 10 mL methanol + 30 mL water, wash the filter cake, and dry at 40 ° C to obtain a light brown solid;

[0503] 5) 7.3 g of solid was added to 22 mL (3 V) EA, heated to reflux and 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.

[0504] 6) Filter, mix 4 mL EA + 8 mL n-heptane, wash the filter cake, and dry at 40 ° C to obtain 6.5 g of light brown solid, and obtain free base crystal form I.

[0505] 1.3 Preparation of Compound 9 Free Base Form II

[0506] About 20 mg of the free base was weighed into a 2 mL glass bottle, 50-300 μL of solvent (solvents may be ACN, THF, DCM, water) was added, and slurry was performed at 50° C. for 7 days. During this process, the obtained clear solution evaporated at room temperature, the obtained solid was centrifuged, the supernatant was removed, and vacuum dried at 40° C. to obtain the free base crystal form II. After detection and analysis, it has the following XRPD diagram as shown in FIG. 4, the DSC diagram as shown in FIG. 5, and the TGA diagram as shown in FIG. 6.

[0507] 2. Solid stability test

[0508] 2.1 Experimental Purpose:

[0509] The physicochemical stabilities of the free base crystal form I and crystal form II under high temperature 60°C, high humidity 92.5% RH, and high temperature and high humidity 50°C 75% RH were investigated to provide a basis for the storage of the compounds.

[0510] 2.2 Experimental plan:

[0511] About 2 mg of free base crystal form I and crystal form II were taken respectively, and the changes of related substances in the crystal forms were investigated under high temperature 60°C, high humidity 92.5% RH, and high temperature and high humidity 50°C 75% RH conditions after 7 days and 14 days. The changes of related substances were calculated by HPLC using the chromatographic peak area normalization method.

[0512] Chromatographic conditions:

[0513] 2.3 Experimental results:

[0514] Physical and chemical stability results of free base form I:

[0515] Physical and chemical stability results of free base form II:

[0516] The above data show that compound 9 free base form I and free base II are relatively stable under all conditions after being placed for 7 days and 14 days.

[0517] 3. Hygroscopicity test

[0518] 3.1 Experimental Purpose

[0519] The hygroscopicity of compound 9 crystalline form I and crystalline form II under different relative humidity conditions was investigated to provide a basis for the storage of the compound.

[0520] 3.2 Experimental plan:

[0521] Compound 9 crystalline form I and crystalline form II were placed in saturated water vapor with different relative humidity to allow the compound and the water vapor to reach dynamic equilibrium, and the percentage of weight gain of the compound due to moisture absorption after equilibrium was calculated.

[0522] 3.3 Experimental results:

[0523] The free base crystal form I absorbs moisture and increases weight by about 0.3263% under 80% RH conditions, and is slightly hygroscopic. After two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, the XRPD spectrum of the free base crystal form I does not change, that is, the crystal form does not change.

[0524] The free base crystal form II absorbs moisture and increases in weight by about 0.2053% under 80% RH conditions, and is slightly hygroscopic.

[0525] 4. Solubility experiments in different media

[0526] 4.1 Experimental Purpose

[0527] The solubility of free base form I and form II in media such as pH 1.0-8.0 USP buffer, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and pure water was compared to provide a basis for the evaluation of drugability.

[0528] 4.2 Experimental plan:

[0529] About 1 mg of free base form I and form II were suspended in different media for 2 hours, and the thermodynamic solubility of the compound at 37° C. was determined by HPLC and external standard method.

[0530] 4.3 Experimental results: As shown in Table 3

[0531] Table 3

[0532] From the above experimental results, it can be seen that the thermodynamic solubility of the free base crystal form I in each medium system is higher than that of the crystal form II, and the solubility of the crystal form I meets the drug concentration required for local treatment.

[0533] 5. Animal PK studies

[0534] 5.1 Experimental Purpose:

[0535] SD rats were used as test animals to study the pharmacokinetic behavior of free base crystal form I and free base crystal form II in rats (plasma) after a single oral administration, and to compare the changes in exposure; the pharmacokinetics of the free base crystal form after a single intravenous administration were studied, and the bioavailability of free base crystal form I and free base crystal form II after oral administration was calculated.

[0536] 5.2 Experimental plan:

[0537] Free base crystal form I was suspended with a 0.5% CMCC-Na aqueous solution containing 0.5%, and free base crystal form I was suspended with a 0.5% HPMC aqueous solution containing 0.5%. After uniformity, it was gavaged and administered to rats. Three rats were parallel. The dosages of free base crystal form I (5 mg / kg, 30 mg / kg for suspension) and free base crystal form II (30 mg / kg for suspension) were administered. Free base crystal form I was dissolved with an aqueous solution containing 20% ​​HP-β-CD, filtered with a filter membrane, and injected. Rats were administered. Three rats were parallel. 5.3 Experimental results

[0538] Table 4 Animal PK test results of free base crystal form I and crystal form II

[0539] From the above data, it can be seen that the exposure of free base form I is higher than that of free base form II, and the exposure of form I at 30 mg / kg is significantly higher than that at 5 mg / kg.

Claims

The crystal form of the compound represented by general formula (I) has the following structure: in: X1 is CR6 or N; X2 is CR6 or absent; R1 is selected from halogen; R2, R3, R4 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxyl, sulfonic acid, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may be further substituted; R2, R3, R4 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxyl, sulfonic acid, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Hydroxyalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonate, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted with one or more substituents; more preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfonic acid, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonate, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or, any two or more of R2, R3, and R4 are connected to the connected atom to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may be further substituted; R5 is selected from hydroxyalkyl or haloalkyl, and may be further substituted, and the hydroxyalkyl group is preferably The haloalkyl group is preferably X' is halogen; R7 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfonic acid, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may be further substituted. The crystal form according to claim 1, characterized in that The general formula (I) is further shown in the general formula (II): wherein X1 is CH or N; X2 is CH or absent; R2, R3 or R4 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 Hydroxyalkoxy; R5 is selected from The crystal form according to claim 1 or 2, characterized in that When X2 is not present, the substituent R2 is preferably a halogen, the halogen is preferably located at the ortho position or meta position of the triazole, more preferably at the ortho position, and the halogen is preferably fluorine; when X2 is CR6, the substituent R2 is preferably a halogen, the halogen is preferably located at the ortho position or meta position of pyrimidine, more preferably at the meta position of pyrimidine, and / or at the ortho position of the carbonyl group, and the halogen is preferably fluorine. The crystal form according to claim 1, characterized in that The general formula (I) is selected from the following compounds: The invention relates to 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, including crystalline form I and crystalline form II, wherein: the powder X-ray diffraction spectrum of crystalline form I has a diffraction peak at 2θ of 8.6±0.2°, or at 2θ of 9.2±0.2°, or at 2θ of 10.2±0.2°, or at 2θ of 10.8±0.2°, or at 2θ of 12.0±0.2°, or at 2θ of 12.8±0.2 The invention relates to a diffraction peak at 2θ of 13.7±0.2°, a diffraction peak at 2θ of 14.2±0.2°, a diffraction peak at 2θ of 15.5±0.2°, a diffraction peak at 2θ of 16.6±0.2°, a diffraction peak at 2θ of 17.3±0.2°, a diffraction peak at 2θ of 18.4±0.2°, a diffraction peak at 2θ of 19.0±0.2°, a diffraction peak at 2θ of 19.5±0.2°, a diffraction peak at 2θ of 20.5±0.2°, a diffraction peak at 2θ of 21.3±0.2°, or a diffraction peak at 2θ of 21.3±0.2°. θ has a diffraction peak at 26.5±0.2°; or has a diffraction peak at 2θ of 28.6±0.2°; preferably, it comprises diffraction peaks at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of Form II has a diffraction peak at 2θ of 9.9±0.2°, or has a diffraction peak at 2θ of 10.8±0.2°, or has a diffraction peak at 2θ of 13.2±0.2°, or has a diffraction peak at 2θ of 14.9±0.2°, or has a diffraction peak at 2θ of 16.4±0.2°, or has a diffraction peak at 2θ of 17.1±0.2°, or has a diffraction peak at 2θ of 17.9±0.2°. Diffraction peak, or a diffraction peak at 2θ of 19.3±0.2°, or a diffraction peak at 2θ of 19.8±0.2°, or a diffraction peak at 2θ of 20.2±0.2°, or a diffraction peak at 2θ of 20.5±0.2°, or a diffraction peak at 2θ of 21.0±0.2°, or a diffraction peak at 2θ of 21.9±0.2°, or a diffraction peak at 2θ of 25.8±0.2°, or a diffraction peak at 2θ of 26.5±0.2°, or a diffraction peak at 2θ of 27.5±0.2°; preferably, comprising 2, 4, 6, 8 or 10 diffraction peaks optionally selected therefrom. The crystal form according to claim 5, characterized in that The powder X-ray diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2θ of 9.2±0.2°, 10.2±0.2°, 16.6±0.2° or 18.4±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also comprise one or more diffraction peaks at 2θ of 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 them; Form I The powder X-ray diffraction pattern of type II at least includes one or more diffraction peaks located at 2θ of 16.4±0.2°, 17.1±0.2°, 17.9±0.2° or 25.8±0.2°; preferably includes 2-4 of them, more preferably includes 3-4, and most preferably includes 4; optionally, further, it may also include one or more diffraction peaks at 2θ of 10.8±0.2°, 14.9±0.2°, 19.3±0.2°, 21.9±0.2° or 26.5±0.2°, preferably includes 2, 3, 4 or 5 of them. The crystal form according to claim 5, characterized in that The X-ray powder diffraction spectrum of Form I has characteristic peaks at 2θ of 9.2±0.2° and 18.4±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.2±0.2°, 16.6±0.2°, 17.3±0.2° and 19.0±0.2°; more preferably, it also includes characteristic peaks at 2θ of 12.8±0.2° and 21.3±0.2°; further preferably, it also includes characteristic peaks at 2θ of 26.5±0.2° and 28. 6±0.2° has a characteristic peak, and more preferably, further comprises characteristic peaks 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 The spectrum is basically as shown in Figure 2, and its TGA spectrum is basically as shown in Figure 3; the X-ray powder diffraction spectrum of Form II has characteristic peaks at 2θ of 16.4±0.2° and 25.8±0.2°; preferably, it also includes characteristic peaks at 2θ of 17.1±0.2°, 17.9±0.2°, 21.9±0.2° and 26.5±0.2°; more preferably, it also includes characteristic peaks at 2θ of 10.8±0.2° and 14.9±0.2°; further Preferably, it also includes characteristic peaks at 2θ of 9.9±0.2° and 19.3±0.2°, and further preferably, it also includes 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°; most preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 4; its DSC spectrum is substantially as shown in Figure 5, and its TGA spectrum is substantially as shown in Figure 6. A method for preparing a crystalline form of the compound according to any one of claims 1 to 7, comprising the following steps: 1) weighing an appropriate amount of free base and suspending it with a poor solvent, wherein the suspension density is preferably 50 to 200 mg / mL; 2) shaking the suspension obtained above, preferably at a temperature of 0 to 50° C., and preferably for 1 to 10 days; 3) rapidly centrifuging the suspension above, removing the supernatant, and drying the remaining solid to constant weight to obtain the target product; wherein: The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water, heptane or n-pentane; preferably isopropyl acetate, toluene, methyl tert-butyl ether, water, heptane or n-pentane; or, 1) weigh an appropriate amount of free base and dissolve it in a good solvent; 2) add the above Add an anti-solvent to the obtained solution and stir until a solid precipitates, preferably at a temperature of 0 to 25°C; 3) rapidly centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; 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, 2-butanone or 3-pentanone; preferably methanol, dichloromethane or ethyl acetate. The anti-solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane or isopropyl acetate; or, 1) weigh an appropriate amount of free base and heat it with a good solvent to dissolve it; 2) quickly place the above solution under low temperature and stir until solid precipitates, the temperature is preferably -10 to 5°C; 3) quickly centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; 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; preferably acetone. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 7, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the crystalline form according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 as an orexin receptor antagonist in the preparation of a medicament for treating a nervous system disease, preferably in the preparation of an OX2R selective receptor antagonist; more preferably, the nervous system disease is selected from insomnia, depression, anxiety or drug addiction, more preferably major depressive disorder, primary and secondary insomnia or depression associated with insomnia.

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