Salts, crystal forms of spirocyclic derivatives and methods of making and using the same

Abstract

The present application relates to a kind of salt containing spiro derivative, crystal form and its preparation method and application.Specifically, the present application relates to the salt of compound (R) 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methyl methylamine, crystal form and its preparation method and application and the pharmaceutical composition containing therapeutically effective amount of the salt of the compound, crystal form, and its use in the preparation of the drug for preventing and / or treating neuropsychiatric diseases.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a salt containing a spirocyclic derivative, its crystal form, preparation method, and application. Background Technology

[0002] Central nervous system disorders affect a wide range of people to varying degrees. Generally, these disorders are characterized by significant impairment in cognition or memory, and a marked deterioration in relatively primitive functional levels. Schizophrenia is a psychopathological disorder of unknown origin, typically first appearing in early adulthood, characterized by psychotic symptoms, progressive and developmental stages, and / or regression in social behavior and professional abilities. Symptoms of schizophrenia generally fall into three categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are those characterized by an "excessive" amount of normal experience, such as hallucinations and delusions. Negative symptoms are those characterized by a lack of normal experience, such as anhedonia and a lack of social interaction. Cognitive symptoms are associated with cognitive impairment in schizophrenia, such as a lack of sustained attention and impaired decision-making. Current antipsychotic medications are effective in treating positive symptoms, but are far from ideal for negative and cognitive symptoms.

[0003] Biogenic amines play important roles as neurotransmitters in the central and peripheral nervous systems. The synthesis and storage of biogenic amines, as well as their degradation and reabsorption after release, are tightly controlled. Imbalances in biogenic amine levels are known to be a major cause of brain function changes in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine, as classic biogenic amines, have been extensively studied. Among them, the serotonin system plays a crucial role in regulating the function of the prefrontal cortex (PFC), including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high densities. Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT1AR, both of which modulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data suggest that 5-HT1AR may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (such as olanzapine and aripiprazole) for 5-HT1AR and their low EPS side effects indicate that the serotonin system plays a crucial role in regulating PFC function, including mood control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high density. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment, improving negative symptoms and cognitive impairment.

[0004] In recent years, with the deepening research on classical biogenic amines, a second class of endogenous amine compounds, namely trace amines (TAs), has been discovered, including p-tyramine, β-phenylethylamine, tryptamine, and phenolethanolamine. Their levels in the mammalian nervous system are generally lower than those of classical biogenic amines, but they share similar characteristics with classical biogenic amines in terms of structure, metabolism, and subcellular localization. Trace amine-associated receptors (TAARs), as a new member of the G protein-coupled receptor (GPCR) family, have similar structures and pharmacological data to deep GPCR pharmacophores. Phylogenetic relationships of these receptor genes indicate that they form three distinct subfamilies, with TAAR1 being the first of four highly conserved genes (TAAR1-4) in humans and rodents. TAs activate TAAR1 through Gαs to exert their effects. Existing research shows that dysregulation of trace amine-associated receptors, particularly TAAR1, is closely linked to many psychiatric disorders such as schizophrenia and depression, as well as other conditions such as attention deficit hyperactivity disorder (ADHD), migraine, Parkinson's disease, substance abuse, and eating disorders. Therefore, TAAR ligands have high potential for treating these diseases.

[0005] Despite the availability of numerous medications for treating schizophrenia, a variety of adverse reactions persist in clinical use. Furthermore, while some antipsychotic drugs addressing negative symptoms have improved these symptoms in some patients, their overall effectiveness is limited. Many patients remain unable to fully recover and restore normal social functioning due to these negative symptoms, hindering their return to normal social work. Cognitive impairment is another key focus in schizophrenia treatment, affecting verbal memory, semantic processing, and attention in most patients. Currently available or marketed antipsychotic drugs offer limited improvement in cognitive function. Moreover, the treatment of treatment-resistant schizophrenia remains challenging. These patients have undergone treatment with three different antipsychotic drugs with varying active ingredients, receiving adequate dosage and duration, yet experiencing poor response or intolerance to the adverse effects of these drugs. Even with sufficient maintenance or preventative treatment, their condition may relapse or worsen. Therefore, developing effective treatments for treatment-resistant schizophrenia remains a significant challenge in clinical drug research and a direction that urgently needs to be addressed.

[0006] Currently, Sunovion's SEP-363856, which is in Phase III clinical trials, is a serotonin and / or trace amine-associated receptor agonist with significant activity against 5-HT1A and TAAR1 receptors, demonstrating good activity in existing clinical studies. Therefore, there is an urgent need to develop antipsychotic drugs that offer good and sustained efficacy in treating negative symptoms, improving patients' cognitive function, effectively treating treatment-resistant schizophrenia, and also have low adverse drug reactions and act on multiple targets to meet the huge market demand. Summary of the Invention

[0007] International patent application PCT / CN2022 / 083485 describes a series of structures containing spirocyclic derivatives. In subsequent research and development, in order to improve the solubility, stability, hygroscopicity, powder flow properties, pharmacokinetics and / or increase the bioavailability of the compounds, reduce storage costs, and extend the product cycle, this invention has conducted a comprehensive study on the acid salts and crystal forms of the above compounds.

[0008] All contents relating to international patent application PCT / CN2022 / 083485 are incorporated herein by reference.

[0009] The technical problem to be solved by the present invention is to provide a salt containing spirocyclic derivatives, its crystal form, preparation method and application.

[0010] The purpose of this invention is to provide an acid salt of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine.

[0011] In a preferred embodiment of the present invention, the acid salt is L-mandelate, phosphate, sulfate, fumarate, oxalate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, maleate, L-malate, or ethanedisulfonate.

[0012] In a preferred embodiment of the present invention, the acid salt is a phosphate, fumarate, methanesulfonate, benzenesulfonate, maleate, p-toluenesulfonate, or L-mandelate.

[0013] In a further preferred embodiment of the present invention, the number of acids in the acid salt is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0014] In a further preferred embodiment of the present invention, the molar ratio of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine to L-mandelate, phosphate, sulfate, fumarate, oxalate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, maleate, L-malate, or ethanedisulfonate is 0.8-1.2.

[0015] In a further preferred embodiment of the present invention, the acid salt is a non-solvent or a solvate, wherein the solvent is selected from one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

[0016] In a further preferred embodiment of the present invention, the number of solvents is 0-3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1, 2 or 3.

[0017] In a further preferred embodiment of the present invention, the above-mentioned acid salt is preferably anhydrous.

[0018] In a further preferred embodiment of the present invention, the acid salt is crystalline or amorphous.

[0019] In a further preferred embodiment of the present invention, the acid salt of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein:

[0020] L-mandelate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 7.25±0.2°, 15.67±0.2°, 17.38±0.2°, 21.95±0.2°, and 24.70±0.2°.

[0021] Preferably, the diffraction peaks include those located at 2θ of 7.25±0.2°, 15.67±0.2°, 17.38±0.2°, 19.20±0.2°, 20.21±0.2°, 21.43±0.2°, 21.95±0.2°, 23.63±0.2°, 24.14±0.2°, and 24.70±0.2°.

[0022] More preferably, the 2θ values ​​are 7.25±0.2°, 12.41±0.2°, 14.29±0.2°, 14.98±0.2°, 15.67±0.2°, 17.38±0.2°, 19.20±0.2°, 19.51±0.2°, 20.21±0.2°, 21.43±0.2°, 21.95±0.2°, 23.03±0.2°, 23.63±0.2°, 24.14±0.2°, and 24.70±0.2°. Diffraction peaks at 2°, 26.01±0.2°, 26.33±0.2°, 27.72±0.2°, 28.10±0.2°, 29.47±0.2°, 29.99±0.2°, 31.38±0.2°, 32.46±0.2°, 33.66±0.2°, 34.14±0.2°, 35.07±0.2°, 37.72±0.2°, 38.47±0.2°, 41.12±0.2°, and 43.84±0.2°;

[0023] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 1.

[0024] Table 1. XRPD diffraction data of L-mandelate crystal form I of the compound.

[0025]

[0026]

[0027] More preferably, the X-ray powder diffraction pattern of L-mandelate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 1 As shown; its DSC spectrum is basically as follows. Figure 2 As shown; its TGA spectrum is basically as follows. Figure 3 As shown.

[0028] Phosphate crystal form I has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 15.66±0.2°, 18.07±0.2°, 23.49±0.2°, 24.97±0.2°, and 27.13±0.2°.

[0029] Preferably, the diffraction peaks include those located at 2θ of 15.66±0.2°, 16.35±0.2°, 17.16±0.2°, 18.07±0.2°, 23.49±0.2°, 24.55±0.2°, 24.97±0.2°, 26.29±0.2°, 26.56±0.2°, and 27.13±0.2°.

[0030] More preferably, the 2θ values ​​are 4.71±0.2°, 11.96±0.2°, 12.34±0.2°, 13.17±0.2°, 13.58±0.2°, 15.66±0.2°, 16.35±0.2°, 17.16±0.2°, 18.07±0.2°, 19.43±0.2°, 19.98±0.2°, 20.62±0.2°, 21.44±0.2°, 22.70±0.2°, and 23.49±0.2°. Diffraction peaks at 2°, 24.10±0.2°, 24.55±0.2°, 24.97±0.2°, 25.71±0.2°, 26.29±0.2°, 26.56±0.2°, 27.13±0.2°, 28.35±0.2°, 28.84±0.2°, 29.88±0.2°, 31.37±0.2°, 33.09±0.2°, 34.27±0.2°, 36.41±0.2°, and 37.70±0.2°;

[0031] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 2.

[0032] Table 2. XRPD diffraction data of phosphate crystal form I of the compound.

[0033] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 4.71 18.744 9.2％ 16 24.10 3.690 8.0％ 2 11.96 7.397 12.8％ 17 24.55 3.623 13.9％ 3 12.34 7.166 6.5％ 18 24.97 3.564 22.9％ 4 13.17 6.715 5.8％ 19 25.71 3.463 6.3％ 5 13.58 6.518 5.0％ 20 26.29 3.388 13.7％ 6 15.66 5.653 21.4％ 21 26.56 3.354 14.0％ 7 16.35 5.417 14.4％ 22 27.13 3.284 36.4％ 8 17.16 5.163 16.7％ 23 28.35 3.145 12.5％ 9 18.07 4.904 100.0％ 24 28.84 3.093 9.3％ 10 19.43 4.565 7.2％ 25 29.88 2.988 4.7％ 11 19.98 4.441 11.7％ 26 31.37 2.849 5.5％ 12 20.62 4.303 13.7％ 27 33.09 2.705 5.9％ 13 21.44 4.140 10.1％ 28 34.27 2.614 4.9％ 14 22.70 3.915 9.8％ 29 36.41 2.466 6.8％ 15 23.49 3.785 23.2％ 30 37.70 2.384 6.4％

[0034] More preferably, the X-ray powder diffraction pattern of phosphate crystal form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is basically as follows: Figure 4 As shown; its DSC spectrum is basically as follows. Figure 5 As shown; its TGA spectrum is basically as follows. Figure 6 As shown.

[0035] Sulfate crystal form I has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 6.91±0.2°, 10.29±0.2°, 13.66±0.2°, 17.07±0.2°, and 27.36±0.2°.

[0036] Preferably, the diffraction peaks include those located at 2θ of 6.91±0.2°, 10.29±0.2°, 13.66±0.2°, 14.68±0.2°, 15.91±0.2°, 16.35±0.2°, 17.07±0.2°, 20.43±0.2°, 24.32±0.2°, and 27.36±0.2°.

[0037] More preferably, the 2θ values ​​are 6.91±0.2°, 10.29±0.2°, 10.79±0.2°, 13.66±0.2°, 14.46±0.2°, 14.68±0.2°, 15.44±0.2°, 15.91±0.2°, 16.35±0.2°, 17.07±0.2°, 17.85±0.2°, 19.57±0.2°, 19.84±0.2°, 20.43±0.2°, 20.72±0.2°, and 20.98±0.2°. Diffraction peaks at 2°, 21.52±0.2°, 22.07±0.2°, 22.56±0.2°, 22.81±0.2°, 23.45±0.2°, 23.91±0.2°, 24.32±0.2°, 24.64±0.2°, 25.56±0.2°, 25.98±0.2°, 26.36±0.2°, 27.36±0.2°, 27.62±0.2°, 29.35±0.2°, 30.72±0.2°, and 31.90±0.2°;

[0038] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 3.

[0039] Table 3. XRPD diffraction data of sulfate crystal form I of the compound.

[0040] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 6.91 12.782 100.0％ 17 21.52 4.127 7.6％ 2 10.29 8.592 45.7％ 18 22.07 4.025 6.0％ 3 10.79 8.194 6.0％ 19 22.56 3.938 7.1％ 4 13.66 6.477 42.4％ 20 22.81 3.896 14.1％ 5 14.46 6.119 7.6％ 21 23.45 3.790 14.2％ 6 14.68 6.031 16.6％ 22 23.91 3.719 10.8％ 7 15.44 5.734 11.9％ 23 24.32 3.656 19.1％ 8 15.91 5.566 16.6％ 24 24.64 3.610 6.6％ 9 16.35 5.417 34.5％ 25 25.56 3.482 7.5％ 10 17.07 5.192 83.8％ 26 25.98 3.427 13.8％ 11 17.85 4.966 11.6％ 27 26.36 3.378 11.8％ 12 19.57 4.533 9.2％ 28 27.36 3.257 34.3％ 13 19.84 4.471 7.0％ 29 27.62 3.227 8.6％ 14 20.43 4.344 26.9％ 30 29.35 3.041 8.2％ 15 20.72 4.284 8.1％ 31 30.72 2.908 7.8％ 16 20.98 4.231 7.8％ 32 31.90 2.803 5.4％

[0041] More preferably, the X-ray powder diffraction pattern of sulfate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is basically as follows: Figure 7 As shown; its DSC spectrum is basically as follows. Figure 8 As shown; its TGA spectrum is basically as follows. Figure 9 As shown.

[0042] Fumarate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.05±0.2°, 21.95±0.2°, 24.85±0.2°, 25.86±0.2°, and 26.35±0.2°.

[0043] Preferably, it includes diffraction peaks located at 2θ of 13.05±0.2°, 15.21±0.2°, 15.63±0.2°, 16.13±0.2°, 17.25±0.2°, 21.95±0.2°, 23.48±0.2°, 24.85±0.2°, 25.86±0.2°, and 26.35±0.2°;

[0044] More preferably, the 2θ values ​​are 8.14±0.2°, 10.14±0.2°, 13.05±0.2°, 13.83±0.2°, 15.21±0.2°, 15.63±0.2°, 16.13±0.2°, 17.25±0.2°, 18.86±0.2°, 19.21±0.2°, 19.70±0.2°, 20.97±0.2°, 21.95±0.2°, 23.48±0.2°, and 24. Diffraction peaks at 0.85±0.2°, 25.86±0.2°, 26.35±0.2°, 27.82±0.2°, 30.54±0.2°, 31.61±0.2°, 33.06±0.2°, 33.76±0.2°, 34.79±0.2°, 36.60±0.2°, 37.63±0.2°, 39.58±0.2°, 42.87±0.2°, 46.60±0.2°, and 48.58±0.2°;

[0045] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 4.

[0046] Table 4. XRPD diffraction data of fumarate crystal form I of the compound.

[0047] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 8.14 10.859 12.6％ 16 25.86 3.442 86.8％ 2 10.14 8.714 13.6％ 17 26.35 3.380 95.7％ 3 13.05 6.780 100.0％ 18 27.82 3.204 19.7％ 4 13.83 6.397 20.2％ 19 30.54 2.925 23.7％ 5 15.21 5.820 42.7％ 20 31.61 2.828 13.4％ 6 15.63 5.666 56.3％ 21 33.06 2.708 15.9％ 7 16.13 5.491 45.9％ 22 33.76 2.653 19.3％ 8 17.25 5.137 42.1％ 23 34.79 2.577 16.9％ 9 18.86 4.703 30.5％ 24 36.60 2.453 17.4％ 10 19.21 4.616 38.2％ 25 37.63 2.389 15.3％ 11 19.70 4.502 37.2％ 26 39.58 2.275 17.2％ 12 20.97 4.234 38.6％ 27 42.87 2.108 13.9％ 13 21.95 4.046 63.5％ 28 46.60 1.947 18.8％ 14 23.48 3.785 41.6％ 29 48.58 1.873 7.9％ 15 24.85 3.581 92.8％ - - - -

[0048] More preferably, the X-ray powder diffraction pattern of fumarate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 10 As shown; its DSC spectrum is basically as follows. Figure 11 As shown; its TGA spectrum is basically as follows. Figure 12 As shown.

[0049] Oxalate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 9.54±0.2°, 16.18±0.2°, 18.28±0.2°, 21.50±0.2°, and 27.64±0.2°.

[0050] Preferably, the diffraction peaks include those located at 2θ of 9.54±0.2°, 16.18±0.2°, 18.28±0.2°, 20.06±0.2°, 21.50±0.2°, 23.07±0.2°, 24.10±0.2°, 25.26±0.2°, 26.39±0.2°, and 27.64±0.2°.

[0051] More preferably, it includes diffraction peaks located at 2θ of 9.54±0.2°, 12.41±0.2°, 13.82±0.2°, 14.54±0.2°, 16.18±0.2°, 18.28±0.2°, 20.06±0.2°, 21.50±0.2°, 23.07±0.2°, 24.10±0.2°, 25.26±0.2°, 26.39±0.2°, 27.64±0.2°, 29.41±0.2°, 31.22±0.2°, 31.80±0.2°, 33.14±0.2°, and 36.80±0.2°;

[0052] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 5.

[0053] Table 5. XRPD diffraction data of oxalate crystal form I of the compound.

[0054] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 9.54 9.266 34.8％ 10 24.10 3.690 22.5％ 2 12.41 7.128 11.3％ 11 25.26 3.522 33.4％ 3 13.82 6.402 12.6％ 12 26.39 3.374 25.2％ 4 14.54 6.087 18.5％ 13 27.64 3.225 34.1％ 5 16.18 5.474 100.0％ 14 29.41 3.035 19.0％ 6 18.28 4.849 54.6％ 15 31.22 2.863 18.8％ 7 20.06 4.423 20.5％ 16 31.80 2.811 15.2％ 8 21.50 4.130 47.2％ 17 33.14 2.701 19.1％ 9 23.07 3.852 27.8％ 18 36.80 2.440 16.0％

[0055] More preferably, the X-ray powder diffraction pattern of oxalate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 13 As shown; its DSC spectrum is basically as follows. Figure 14 As shown; its TGA spectrum is basically as follows. Figure 15 As shown.

[0056] p-Toluenesulfonate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 6.19±0.2°, 11.89±0.2°, 16.79±0.2°, 18.73±0.2°, and 22.86±0.2°.

[0057] Preferably, the diffraction peaks include those located at 2θ of 6.19±0.2°, 11.89±0.2°, 14.28±0.2°, 16.79±0.2°, 18.06±0.2°, 18.73±0.2°, 19.05±0.2°, 19.30±0.2°, 22.86±0.2°, and 23.51±0.2°.

[0058] More preferably, the θ values ​​are located at 6.19±0.2°, 9.01±0.2°, 10.25±0.2°, 10.49±0.2°, 11.89±0.2°, 14.28±0.2°, 14.67±0.2°, 16.07±0.2°, 16.79±0.2°, 17.73±0.2°, 18.06±0.2°, 18.73±0.2°, 19.05±0.2°, 19.30±0.2°, and 19.76±0.2°. Diffraction peaks at 2°, 21.52±0.2°, 21.95±0.2°, 22.86±0.2°, 23.51±0.2°, 24.32±0.2°, 24.70±0.2°, 25.31±0.2°, 25.79±0.2°, 26.94±0.2°, 27.45±0.2°, 27.95±0.2°, 29.33±0.2°, 30.40±0.2°, 30.85±0.2°, and 33.28±0.2°;

[0059] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 6.

[0060] Table 6. XRPD diffraction data of p-toluenesulfonate crystal form I of the compound.

[0061]

[0062]

[0063] More preferably, the X-ray powder diffraction pattern of p-toluenesulfonate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is basically as follows: Figure 16 As shown; its DSC spectrum is basically as follows. Figure 17 As shown; its TGA spectrum is basically as follows. Figure 18 As shown.

[0064] The benzenesulfonate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 6.18±0.2°, 12.21±0.2°, 18.90±0.2°, 20.05±0.2°, and 24.38±0.2°.

[0065] Preferably, it includes diffraction peaks located at 2θ of 6.18±0.2°, 12.21±0.2°, 14.68±0.2°, 17.30±0.2°, 18.28±0.2°, 18.90±0.2°, 20.05±0.2°, 22.87±0.2°, 24.38±0.2°, and 25.95±0.2°;

[0066] More preferably, the 2θ values ​​are 6.18±0.2°, 8.75±0.2°, 10.23±0.2°, 12.21±0.2°, 14.68±0.2°, 16.39±0.2°, 16.70±0.2°, 17.06±0.2°, 17.30±0.2°, 18.28±0.2°, 18.90±0.2°, 20.05±0.2°, 21.68±0.2°, 22.06±0.2°, 22.87±0.2°, 23.55±0.2°, 23.72±0.2°, 24.38±0.2°, 24.64±0.2°, and 25. Diffraction peaks at 41±0.2°, 25.66±0.2°, 25.95±0.2°, 26.66±0.2°, 26.98±0.2°, 27.93±0.2°, 28.71±0.2°, 29.48±0.2°, 30.57±0.2°, 30.87±0.2°, 32.97±0.2°, 34.65±0.2°, 36.83±0.2°, 37.81±0.2°, 38.41±0.2°, 40.46±0.2°, 41.06±0.2°, 43.24±0.2°, 44.09±0.2°, and 47.17±0.2°;

[0067] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 7.

[0068] Table 7. XRPD diffraction data of benzenesulfonate crystal form I of the compound.

[0069]

[0070]

[0071] More preferably, the X-ray powder diffraction pattern of benzenesulfonate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 19 As shown; its DSC spectrum is basically as follows. Figure 20 As shown; its TGA spectrum is basically as follows. Figure 21 As shown.

[0072] Methanesulfonate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.82±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, and 22.10±0.2°.

[0073] Preferably, the diffraction peaks include those located at 2θ of 7.86±0.2°, 13.20±0.2°, 13.82±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, 18.62±0.2°, 22.10±0.2°, 23.77±0.2°, and 25.52±0.2°.

[0074] More preferably, the 2θ values ​​are 7.86±0.2°, 13.20±0.2°, 13.82±0.2°, 14.25±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, 18.62±0.2°, 19.64±0.2°, 20.10±0.2°, 21.43±0.2°, 22.10±0.2°, 23.06±0.2°, 23.77±0.2°, and 24.03±0.2°. Diffraction peaks at 2°, 24.40±0.2°, 24.99±0.2°, 25.52±0.2°, 26.50±0.2°, 27.50±0.2°, 27.93±0.2°, 28.65±0.2°, 29.41±0.2°, 29.88±0.2°, 30.28±0.2°, 31.69±0.2°, 32.36±0.2°, 32.78±0.2°, 33.86±0.2°, and 37.76±0.2°;

[0075] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 8.

[0076] Table 8. XRPD diffraction data of methanesulfonate crystal form I of the compound.

[0077] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 7.86 11.237 22.8％ 16 24.40 3.645 14.1％ 2 13.20 6.703 17.5％ 17 24.99 3.561 8.7％ 3 13.82 6.401 29.5％ 18 25.52 3.487 20.3％ 4 14.25 6.213 6.4％ 19 26.50 3.361 8.1％ 5 15.63 5.667 62.4％ 20 27.50 3.241 11.7％ 6 16.68 5.310 100.0％ 21 27.93 3.192 11.2％ 7 17.64 5.024 72.3％ 22 28.65 3.113 11.9％ 8 18.62 4.761 18.5％ 23 29.41 3.034 9.3％ 9 19.64 4.516 9.4％ 24 29.88 2.988 6.5％ 10 20.10 4.415 17.3％ 25 30.28 2.949 11.9％ 11 21.43 4.144 6.5％ 26 31.69 2.821 7.9％ 12 22.10 4.019 71.5％ 27 32.36 2.764 7.6％ 13 23.06 3.854 14.0％ 28 32.78 2.730 9.8％ 14 23.77 3.741 28.0％ 29 33.86 2.646 6.9％ 15 24.03 3.701 15.5％ 30 37.76 2.381 8.0％

[0078] More preferably, the X-ray powder diffraction pattern of the methanesulfonate crystal form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 22 As shown; its DSC spectrum is basically as follows. Figure 23 As shown; its TGA spectrum is basically as follows. Figure 24 As shown.

[0079] Maleate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 14.63±0.2°, 15.67±0.2°, 18.74±0.2°, 19.83±0.2°, and 20.11±0.2°.

[0080] Preferably, the diffraction peaks include those located at 2θ of 12.12±0.2°, 14.63±0.2°, 15.67±0.2°, 18.74±0.2°, 19.83±0.2°, 20.11±0.2°, 22.26±0.2°, 25.34±0.2°, 26.29±0.2°, and 28.23±0.2°.

[0081] More preferably, the 2θ values ​​are 9.36±0.2°, 10.38±0.2°, 11.43±0.2°, 12.12±0.2°, 14.63±0.2°, 15.67±0.2°, 17.84±0.2°, 18.21±0.2°, 18.74±0.2°, 19.83±0.2°, 20.11±0.2°, 20.58±0.2°, 20.89±0.2°, 22.07±0.2°, and 22.26±0.2°. Diffraction peaks at 2°, 22.88±0.2°, 23.71±0.2°, 24.48±0.2°, 25.06±0.2°, 25.34±0.2°, 26.29±0.2°, 27.40±0.2°, 27.63±0.2°, 28.23±0.2°, 29.35±0.2°, 31.34±0.2°, 32.09±0.2°, 33.69±0.2°, 34.55±0.2°, and 35.63±0.2°;

[0082] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 9.

[0083] Table 9. XRPD diffraction data of maleate crystal form I of the compound.

[0084] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 9.36 9.440 13.4％ 16 22.88 3.885 13.6％ 2 10.38 8.514 14.8％ 17 23.71 3.750 16.8％ 3 11.43 7.737 14.0％ 18 24.48 3.634 10.1％ 4 12.12 7.300 17.4％ 19 25.06 3.551 14.5％ 5 14.63 6.049 52.7％ 20 25.34 3.512 21.0％ 6 15.67 5.653 53.7％ 21 26.29 3.387 23.2％ 7 17.84 4.967 9.3％ 22 27.40 3.253 12.6％ 8 18.21 4.868 13.7％ 23 27.63 3.226 11.7％ 9 18.74 4.733 100.0％ 24 28.23 3.159 19.6％ 10 19.83 4.473 30.6％ 25 29.35 3.041 11.3％ 11 20.11 4.412 33.6％ 26 31.34 2.852 5.7％ 12 20.58 4.312 15.5％ 27 32.09 2.787 6.9％ 13 20.89 4.249 15.3％ 28 33.69 2.658 8.1％ 14 22.07 4.024 11.5％ 29 34.55 2.594 6.2％ 15 22.26 3.990 17.8％ 30 35.63 2.518 8.7％

[0085] More preferably, the X-ray powder diffraction pattern of maleate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 25 As shown; its DSC spectrum is basically as follows. Figure 26 As shown; its TGA spectrum is basically as follows. Figure 27 As shown.

[0086] L-malate crystal form I, with an acid number of 0.5, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.39±0.2°, 16.15±0.2°, 16.52±0.2°, 20.38±0.2°, and 21.11±0.2°.

[0087] Preferably, the diffraction peaks include those located at 2θ of 13.39±0.2°, 16.15±0.2°, 16.52±0.2°, 17.06±0.2°, 17.58±0.2°, 20.38±0.2°, 21.11±0.2°, 23.15±0.2°, 24.48±0.2°, and 25.50±0.2°.

[0088] More preferably, the θ values ​​are located at 8.54±0.2°, 12.30±0.2°, 13.39±0.2°, 15.63±0.2°, 16.15±0.2°, 16.52±0.2°, 17.06±0.2°, 17.58±0.2°, 18.99±0.2°, 19.62±0.2°, 20.38±0.2°, 21.11±0.2°, and 21. Diffraction peaks at 0.82±0.2°, 22.78±0.2°, 23.15±0.2°, 24.48±0.2°, 24.87±0.2°, 25.50±0.2°, 26.19±0.2°, 26.69±0.2°, 28.01±0.2°, 30.01±0.2°, 30.62±0.2°, 34.19±0.2°, and 41.34±0.2°;

[0089] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 10.

[0090] Table 10 XRPD diffraction data of L-malate crystal form I of the compound

[0091] Serial Number 2θ (±0.2°) d value relative strength Serial Number 2θ (±0.2°) d value relative strength 1 8.54 10.343 17.2％ 14 22.78 3.900 44.0％ 2 12.30 7.191 39.8％ 15 23.15 3.838 70.3％ 3 13.39 6.608 98.9％ 16 24.48 3.633 66.7％ 4 15.63 5.665 46.9％ 17 24.87 3.577 46.4％ 5 16.15 5.484 100.0％ 18 25.50 3.490 54.4％ 6 16.52 5.363 72.9％ 19 26.19 3.400 37.9％ 7 17.06 5.194 57.5％ 20 26.69 3.338 38.2％ 8 17.58 5.040 71.1％ 21 28.01 3.183 36.7％ 9 18.99 4.670 52.3％ 22 30.01 2.976 21.8％ 10 19.62 4.521 40.2％ 23 30.62 2.918 40.6％ 11 20.38 4.354 71.1％ 24 34.19 2.621 22.9％ 12 21.11 4.204 78.9％ 25 41.34 2.183 15.7％ 13 21.82 4.070 35.2％ - - - -

[0092] More preferably, the X-ray powder diffraction pattern of L-malate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 28 As shown; its DSC spectrum is basically as follows. Figure 29 As shown; its TGA spectrum is basically as follows. Figure 30 As shown.

[0093] Ethylene disulfonate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 18.38±0.2°, 18.62±0.2°, 22.58±0.2°, 23.65±0.2°, and 27.67±0.2°.

[0094] Preferably, the diffraction peaks include those located at 2θ of 15.63±0.2°, 16.80±0.2°, 18.38±0.2°, 18.62±0.2°, 21.17±0.2°, 21.87±0.2°, 22.58±0.2°, 23.65±0.2°, 24.51±0.2°, and 27.67±0.2°.

[0095] More preferably, the 2θ values ​​are 4.78±0.2°, 9.23±0.2°, 12.28±0.2°, 14.73±0.2°, 15.63±0.2°, 16.13±0.2°, 16.80±0.2°, 17.64±0.2°, 18.38±0.2°, 18.62±0.2°, 20.25±0.2°, 21.17±0.2°, 21.87±0.2°, 22.58±0.2°, 23.04±0.2°, and 23.65±0.2°. Diffraction peaks at 2°, 23.99±0.2°, 24.51±0.2°, 26.11±0.2°, 26.84±0.2°, 27.18±0.2°, 27.67±0.2°, 28.24±0.2°, 28.98±0.2°, 29.64±0.2°, 30.37±0.2°, 30.75±0.2°, 31.74±0.2°, 32.41±0.2°, 35.48±0.2°, 36.35±0.2°, and 44.85±0.2°;

[0096] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 11.

[0097] Table 11 XRPD diffraction data of ethylene disulfonate crystal form I of the compound

[0098]

[0099]

[0100] More preferably, the X-ray powder diffraction pattern of ethylene disulfonate form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 31 As shown; its DSC spectrum is basically as follows. Figure 32 As shown; its TGA spectrum is basically as follows. Figure 33 As shown.

[0101] On the other hand, the present invention also relates to a method for preparing the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamino acid salt, specifically comprising the following steps:

[0102] (1) Weigh an appropriate amount of the free base of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and dissolve it in solvent 1;

[0103] (2) Weigh an appropriate amount of acid and dissolve it in solvent 2; the amount of acid is preferably 0.5-2.0 equivalents;

[0104] (3) Mix the two above, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product;

[0105] or,

[0106] (1) Weigh an appropriate amount of the free base of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and dissolve it in solvent 1;

[0107] (2) Weigh an appropriate amount of acid and dissolve it in solvent 2; the amount of acid is preferably 0.5-2.0 equivalents;

[0108] (3) Mix the two above, stir and react at a certain temperature for a certain time, add solvent 3 and continue stirring and reacting for a certain time, filter and dry to obtain the target product;

[0109] in:

[0110] The reaction temperature is determined based on the solvent in the system, and is preferably room temperature.

[0111] Solvent 1, Solvent 2, and Solvent 3 are each independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; wherein Solvent 1 and Solvent 2 must be miscible when used.

[0112] The acid mentioned is L-mandelic acid, phosphoric acid, sulfuric acid, fumaric acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, maleic acid, L-malic acid, or ethanedisulfonic acid.

[0113] The present invention further relates to a pharmaceutical composition comprising an acid salt or combination thereof of any of the compounds shown in a therapeutically effective dose, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0114] The present invention further relates to the use of any of the shown compounds, acid salts, or pharmaceutical compositions thereof, in the preparation of pharmaceuticals.

[0115] In a further preferred embodiment of the present invention, the drug may be a drug for the prevention and / or treatment of neuropsychiatric diseases in mammals.

[0116] In a further preferred embodiment of the present invention, the neuropsychiatric disease is preferably a central nervous system disease related to 5-hydroxytryptamine receptors and / or trace amine-related receptors and / or dopamine receptors.

[0117] In a further preferred embodiment of the present invention, the 5-hydroxytryptamine receptor is preferably 5-HT. 1A Receptors.

[0118] In a further preferred embodiment of the present invention, the trace amine-associated receptor is preferably the TAAR1 receptor.

[0119] In a further preferred embodiment of the present invention, the neuropsychiatric diseases include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophrenia-like personality disorder, schizotypal personality disorder, paranoid personality disorder, psychosis, mental disorder, short-term mental disorder, sharing mental disorder, mental disorder caused by physical illness, drug-induced psychosis, psychotic disorders, aggressiveness, mental confusion, Parkinson's psychosis, irritative psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, affective disorders, anxiety disorders, and so on. Sensitive psychosis, depression, major depressive disorder, mood disorder, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain predisposition, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless limb syndrome, multiple sclerosis, sleep disorder, sleep apnea, hypersomnia, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, substance abuse dependence, addiction, eating disorder, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's disease, and premenstrual anxiety.

[0120] Detailed description of the invention

[0121] The different terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0122] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted cycloalkyl" means that alkyl may but does not have to be present, and the description includes cases where cycloalkyl is substituted with alkyl and cases where cycloalkyl is not substituted with alkyl.

[0123] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in this invention, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, along with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0124] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which is safe and effective when used in mammals and has the intended biological activity.

[0125] The term "polymorph" or "polymorphic compound" as used in this article refers to a crystal form with the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions constituting the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement, and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. The relative stability between the two solid phases is interchanged based on their temperature-stability relationship. This phenomenon of compounds existing in different lattice structures is called pharmaceutical polymorphism.

[0126] Crystal structures disclosed or claimed in this invention may exhibit similar but not identical analytical properties within a reasonable margin of error, depending on experimental conditions, purity, equipment, and other commonly used variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the scope and spirit of this invention without departing from its scope. Other embodiments of the invention will be apparent to those skilled in the art based on consideration of the specification and practice of the invention disclosed herein. The applicant expects this specification and examples to be considered exemplary and not limiting of its scope.

[0127] "X-ray powder diffraction pattern or XRPD" refers to the pattern obtained according to Bragg's formula 2d sinθ=nλ (where λ is the wavelength of the X-ray). The diffraction order n can be any positive integer, generally taking the first-order diffraction peak (n=1). The "2θ or 2θ angle" mentioned refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. When X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) onto an atomic plane of a crystal or a partial crystal sample with a lattice spacing of d, the Bragg equation is satisfied, thus allowing the measurement of this set of X-ray powder diffraction patterns.

[0128] As is known to those skilled in the art, XRPD may exhibit certain displacement and intensity deviations due to sample tiling thickness, detection methods, conditions, and instruments. Samples of the same crystal form typically possess the same major XRPD characteristic peaks, but operational errors may exist. When samples of the same crystal form obtained by those skilled in the art using appropriate methods are detected using the same instruments and methods, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally encounter a few characteristic peaks with errors exceeding this range. Errors within ±0.5° or ±0.3° should be considered as XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of this invention, its XRPD is shown in spectrum X. However, those skilled in the art understand that when the 2θ displacement deviation of the key characteristic peak is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be considered as the same crystal form and can be interpreted as within the scope of protection of this invention.

[0129] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the degree of crystallinity of the sample. Additionally, the peak positions may shift depending on variations in sample height. Moreover, if different wavelengths are used for measurement, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ), and these different XRPD patterns obtained by using different wavelengths are also within the scope of this invention.

[0130] "Interplanar spacing or interplanar spacing (d-value)" refers to the division of a space lattice into juxtaposed parallelepiped units by three non-parallel unit vectors a, b, and c, which connect adjacent points. The space lattice is then divided according to these defined parallelepiped unit vectors, resulting in a linear grid called a space lattice or crystal lattice. Lattice and crystal lattice represent the periodicity of crystal structure using geometric points and lines, respectively. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is 1 / d. Or E.

[0131] "Relative intensity (I%)" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern (XRPD) is 100%.

[0132] Differential scanning calorimetry (DSC) determines the transition temperatures of a crystal when it absorbs or releases heat due to changes in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point can be within about 5°C, typically within about 3°C, in consecutive analyses. When describing a compound as having a given DSC peak or melting point, this refers to ±5°C of that DSC peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0133] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. In this invention, TGA can also be used to determine the hydration state of compounds. The heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within approximately ±0.5% by mass.

[0134] "Amorphous," "amorphous form," or "amorphous structure" refers to matter formed when the particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. Its characteristic feature is a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous / amorphous is a special physical form of solid matter, and its locally ordered structural features suggest a close connection with crystalline substances.

[0135] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0136] "Basically as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in the X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0137] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error range of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0138] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C; in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C.

[0139] Beneficial effects

[0140] The salt crystal form of the compound of the present invention not only performs well in terms of product performance parameters such as melting point, solubility, hygroscopicity, solution stability and solid stability, but also shows significant advantages in terms of bioavailability. Attached Figure Description

[0141] Figure 1 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-mandelate crystal form I.

[0142] Figure 2 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-mandelate crystal form I.

[0143] Figure 3 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-mandelate crystal form I.

[0144] Figure 4 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine phosphate crystal form I.

[0145] Figure 5 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine phosphate crystal form I.

[0146] Figure 6 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine phosphate crystal form I.

[0147] Figure 7 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine sulfate crystal form I.

[0148] Figure 8 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine sulfate crystal form I.

[0149] Figure 9 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine sulfate crystal form I.

[0150] Figure 10 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine fumarate crystal form I.

[0151] Figure 11 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine fumarate crystal form I.

[0152] Figure 12 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine fumarate crystal form I.

[0153] Figure 13 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine oxalate crystal form I.

[0154] Figure 14 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine oxalate crystal form I.

[0155] Figure 15TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine oxalate crystal form I.

[0156] Figure 16 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine p-toluenesulfonate crystal form I.

[0157] Figure 17 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine p-toluenesulfonate crystal form I.

[0158] Figure 18 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine p-toluenesulfonate crystal form I.

[0159] Figure 19 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine benzenesulfonate crystal form I.

[0160] Figure 20 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine benzenesulfonate crystal form I.

[0161] Figure 21 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine benzenesulfonate crystal form I.

[0162] Figure 22 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine methanesulfonate crystal form I.

[0163] Figure 23 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine methanesulfonate crystal form I.

[0164] Figure 24TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine methanesulfonate crystal form I.

[0165] Figure 25 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine maleate crystal form I.

[0166] Figure 26 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine maleate crystal form I.

[0167] Figure 27 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine maleate crystal form I.

[0168] Figure 28 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-malate crystal form I.

[0169] Figure 29 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-malate crystal form I.

[0170] Figure 30 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine L-malate crystal form I.

[0171] Figure 31 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine ethanedisulfonate crystal form I.

[0172] Figure 32 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine ethanedisulfonate crystal form I.

[0173] Figure 33TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine ethanedisulfonate crystal form I.

[0174] Figure 34 DVS diagram for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine phosphate crystal form I.

[0175] Figure 35 DVS diagram for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine fumarate crystal form I. Detailed Implementation

[0176] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0177] The present invention, SEP-363856, is shown below and was prepared according to the method of Example 129 in patent document PCT / US2010 / 058884.

[0178]

[0179] The following Comparative Example 1 of the present invention is shown below, prepared according to the method of Example 89 in Patent Document PCT / US2010 / 058884.

[0180]

[0181] I. Preparation of Compounds

[0182] Example 1: Preparation of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine (compound 1)

[0183] Synthesis route:

[0184]

[0185] Step a: Synthesis of 1-(thien-2-yl)cyclopropane nitrile

[0186] Under nitrogen protection and in an ice bath, sodium hydride (60%, 1.6 g, 40.59 mmol) was added to a solution of 2-(thiophene-2-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred for 1 hour. Then, 1,2-dibromoethane (4.0 g, 21.3 mmol) was slowly added, and the reaction mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with water (300 mL) in an ice bath, and the mixture was extracted with ethyl acetate (300 mL x 3). The extract was washed with water (200 mL x 3) and saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.5 g, 61.9% yield).

[0187] 1 H NMR (300MHz, CDCl3) δ7.17 (dd, J = 5.1, 0.6Hz, 1H), 7.07-7.02 (m, 1H), 6.95-6.89 (m, 1H), 1.78-1.67 (m, 2H), 1.47-1.37 (m, 2H).

[0188] Step b: Synthesis of 1-(thiophen-2-yl)cyclopropanealdehyde

[0189] Under nitrogen protection and in an ice bath, diisobutylaluminum hydride (1M in hexane, 18.8mL, 18.8mmol) was slowly added dropwise to a tetrahydrofuran (100mL) solution of 1-(thiophene-2-yl)cyclopropanenitrile (1.4g, 9.38mmol), and the mixture was stirred for 3 hours at room temperature. After the reaction was complete, the reaction was quenched with water (300mL) in an ice bath, and the mixture was extracted with ethyl acetate (300mL x 3). The extract was washed with water (300mL x 3) and saturated brine (300mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (632.0mg, 44.3% yield).

[0190] 1 H NMR (300MHz, CDCl3) δ9.34(s,1H),7.27-7.20(m,1H),7.03-6.96(m,2H),1.73-1.64(m,2H),1.55-1.47(m,2H).

[0191] Step c: Synthesis of (1-(thien-2-yl)cyclopropyl)methanol

[0192] Under nitrogen protection, a tetrahydrofuran solution of lithium aluminum hydride (2.5 M in THF, 3.3 mL, 8.30 mmol) was slowly added dropwise to a tetrahydrofuran solution of 1-(thiophene-2-yl)cyclopropanealdehyde (632.0 mg, 4.15 mmol) (20 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water (200 mL) under ice bath conditions. The mixture was extracted with ethyl acetate (300 mL x 3), and the extract was washed with water (300 mL x 3) and saturated brine (300 mL x 3). After drying with anhydrous sodium sulfate, the extract was filtered and concentrated. The crude product was purified by column chromatography to obtain the target product (570.0 mg, 89.0% yield).

[0193] 1 H NMR (300MHz, CDCl3) δ7.17-7.11(m,1H),6.97-6.90(m,2H),3.68(s,2H),1.96(s,1H),1.06-0.89(m,4H).

[0194] Step d: Synthesis of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine

[0195] To a solution of (1-(thiophene-2-yl)cyclopropyl)methanol (250 mg, 1.62 mmol) in 2-methyltetrahydrofuran (5 mL), 2,2-dimethoxy-N-methylethylamine (386.0 mg, 3.24 mmol) and trifluoromethanesulfonic acid (0.8 mL) were added, and the mixture was stirred at 80 °C for 20 min. After the reaction was complete, the pH of the reaction solution was adjusted to 13 with 15% sodium hydroxide aqueous solution in an ice bath. Then, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3). The crude product obtained after concentrating the extract was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (7.3 mg, 2.2% yield).

[0196] 1 H NMR (400MHz, CD3OD) δ7.21(d,J=5.2Hz,1H),6.89(d,J=5.2Hz,1H),5.11(d,J=8.8Hz,1H),3.99(d,J=11.6Hz, 1H),3.68(d,J=11.2Hz,1H),3.60(dd,J=12.8,2.4Hz,1H),3.32-3.25(m,1H),2.77(s,3H),1.16-0.85(m,4H).

[0197] LC-MS[M+H] + :210.1.

[0198] Example 2: Preparation of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine (compound A)

[0199]

[0200] The compound from Example 1 was separated by a chiral column to obtain optical enantiomer 1 (compound A) and optical enantiomer 2 (compound B). Liquid chromatography method: Column: DAICEL CHIRALPAK IG column; Mobile phase A: supercritical CO2, Mobile phase B: methanol (containing 0.1% dimethylamine); Detection wavelength: 214 nm; Flow rate: 1.5 mL / min; Column temperature: 35 °C; Background column pressure: 1800 psi. Mobile phase gradient:

[0201]

[0202]

[0203] Optical enantiomer 1 (compound A):

[0204] RT: 3.62 min; [α]D 29 =-59.1(c 0.163,MeOH); LC-MS[M+H] + :210.1.

[0205] 1 H NMR (CDCl3, 600MHz): δ7.00 (d, J = 5.4Hz, 1H), 6.75 (d, J = 4.8Hz, 1H), 4.93 (dd, J = 9.0, 3.0Hz, 1H), 3.92 (dd, J = 11.4, 1.2H z,1H),3.56(d,J=11.4Hz,1H),3.02(dd,J=12.6,3.0Hz,1H),2.92(dd,J=12.6,9Hz,1H),2.51(s,3H),1.05-0.90(m,4H).

[0206] Optical enantiomer 2 (compound B):

[0207] RT: 3.23 min; [α]D 29 =65.1(c 0.175,MeOH); LC-MS[M+H] + :210.1.

[0208] 1H NMR (CDCl3, 600MHz): δ7.00 (d, J = 5.4Hz, 1H), 6.75 (d, J = 4.8Hz, 1H), 4.98 (dd, J = 9.0, 2.4Hz, 1H), 3.92 (d, J = 11.4Hz, 1H ), 3.57 (d, J = 11.4Hz, 1H), 3.07 (dd, J = 12.6, 2.4Hz, 1H), 2.95 (dd, J = 12.0, 9.0Hz, 1H), 2.54 (s, 3H), 1.08-0.90 (m, 4H).

[0209] II. Compound Biological Testing

[0210] Test Example 1: TAAR1 receptor cAMP agonist assay method

[0211] 1.1 Experimental Materials:

[0212] cAMP assay kit was purchased from Cisbio; the HE3K293 cell line stably expressing the TAAR1 receptor was constructed by Shanghai Shujing Biotechnology Co., Ltd.; IBMX was purchased from Sigma-Aldrich; Phenethylamine (PEA); ProxiPlate-384-well plates were purchased from PerkinElmer; HBSS was purchased from Thermo Fisher Scientific. The equipment used included a PerkinElmer Envision 2105 multi-functional microplate reader, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter.

[0213] 1.2 Experimental Methods:

[0214] (1) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5mM, mix well and set aside.

[0215] (2) Thaw the frozen cells rapidly in a 37°C water bath. Wash the cell suspension with HBSS buffer, centrifuge at 200×g to remove the cryopreservation solution, resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL and count the cells using a cell counter, then dilute to 1.5×10⁻⁶. 6 per mL.

[0216] (3) Add 5 μL of cell suspension (1.5 × 10⁶ cells per well) to each ProxiPlate-38 4-well plate. 4 (cells).

[0217] (4) The test compound was serially diluted in experimental buffer, and 5 μL was transferred to the reaction plate using Bravo. 5 μL of experimental buffer was placed in the negative control well, and 5 μL of PEA (final concentration 10) was placed in the positive control well. -2 M).

[0218] (5) Incubate at 37℃ for 1 hour.

[0219] (6) Add 10 μL of the detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0220] (7) The Envision 2105 multi-mode microplate reader was used for detection. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The ratio of 665 nm to 620 nm for each test well was calculated.

[0221] Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100%

[0222] The EC50 of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variableslope(four parameters) in GraphPad Prism. 50 value.

[0223] 1.3 Experimental Results:

[0224] The specific results of the compounds of the present invention in the TAAR1 receptor agonist activity test obtained through the above scheme are shown in Table 2-1.

[0225] Table 2-1 Results of the agonistic activity of the compounds of the present invention on the TAAR1 receptor

[0226]

[0227] 1.4 Experimental Conclusions:

[0228] In vitro experimental results show that compound A of the present invention has an agonist effect on the TAAR1 receptor.

[0229] Test Example 2, 5-HT 1A receptor cAMP agonist assay

[0230] 2.1 Experimental Materials:

[0231] cAMP assay kit purchased from CisBio; 5-HT stably expressed 1AThe HEK293 cell line for the recipient was constructed by Shanghai Shujing Biotechnology Co., Ltd.; Serotonin, Forskolin, and IBMX were purchased from Sigma-Aldrich; ProxiPlate-384-well plates were purchased from PerkinElmer; and HBSS was purchased from Thermo Fisher Scientific. The equipment used included a PerkinElmer Envision 2105 multi-mode microplate reader, a Tecan D300e skin-level microdispensing system, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter.

[0232] 2.2 Experimental Methods:

[0233] (1) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5mM, mix well and set aside.

[0234] (2) Cultured cells were digested with trypsin. After digestion was terminated, the cell suspension was washed with HBSS buffer, centrifuged at 200×g to remove the culture medium, and the pellet was resuspended with an appropriate amount of experimental buffer. 20 μL of the pellet was used for cell counting and diluted to 0.4×10⁻⁶. 6 per mL.

[0235] (3) Add 5 μL of cell suspension to each ProxiPlate-38 4-well plate (2 × 10⁶ cells per well). 3 (cells).

[0236] (4) The test compound was serially diluted in experimental buffer, and 5 μL was transferred to the reaction plate using Bravo. 5 μL of experimental buffer was placed in the negative control well, and 5 μL of Serotonin (final concentration 10) was placed in the positive control well. -6 M).

[0237] (5) Incubate at room temperature for 15 minutes.

[0238] (6) Add Forskolin (final concentration 1.5 × 10⁻⁶) to the reaction plate using the Tecan D300e pill-lift micro-volume dosing system. -7 M).

[0239] (7) Incubate at room temperature for 45 minutes.

[0240] (8) Add 10 μL of the detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0241] (9) Detection was performed using an Envision 2105 multi-mode microplate reader. Excitation light was set at 340 nm, and emission light at 620 nm and 665 nm. The ratio of 665 nm to 620 nm was calculated for each test well.

[0242] Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100%

[0243] The EC50 of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variableslope(four parameters) in GraphPad Prism. 50 value.

[0244] 2.3 Experimental Results:

[0245] The above methods demonstrate that the compound of the present invention is effective against 5-HT. 1A The specific results of the receptor agonist activity assay are shown in Table 2-2.

[0246] Table 2-2 Effects of the compounds of the present invention on 5-HT 1A Results of receptor agonistic activity

[0247]

[0248] 2.4 Experimental Conclusions:

[0249] In vitro experimental results show that compound A of the present invention has an effect on 5-HT 1A The receptors have agonistic effects, suggesting that the compounds of this invention can improve negative symptoms and cognitive impairment.

[0250] Test Example 3: Inhibition of MK-801-induced high spontaneous activity in mice by the compound of the present invention.

[0251] 3.1 Experimental Materials:

[0252] Test compound: The compound used in the embodiments of this invention was prepared in-house.

[0253] (+)-MK-801 maleate: purchased from Sigma-Aldrich, product number: M107-50MG.

[0254] Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[0255] 3.2 Experimental Methods:

[0256] 3.2.1 Animal grouping: Before the experiment, the animals were randomly grouped according to their weight.

[0257] 3.2.2 Animal Adaptation: Before the experiment, the mice were acclimatized to the experimental environment for at least 1 hour. That is, the animals were transferred from the feeding room to the laboratory and allowed to move freely in their cages.

[0258] 3.2.3 Administration:

[0259] Drug preparation: Take the test compound, add pure water and sonicate.

[0260] After being grouped by body weight, the animals were randomly divided into a control group, a model group, and a drug-treated group, with 9 animals per group. Detailed drug treatment information is shown in the table below:

[0261]

[0262] T-30min Oral Administration of Compound: The test compound or solvent (pure water) was administered orally or by gavage. Immediately after administration, the mice were placed in a test chamber (test chamber dimensions: length × width × height = 27 × 27 × 40 cm), and spontaneous activity of the mice was recorded within 30 minutes.

[0263] T0 min Intraperitoneal injection of modeling drug: 30 minutes after compound administration, mice were removed and administered MK-801 (0.3 mg / kg) via intraperitoneal injection. The blank control group was injected with physiological saline. After MK-801 administration, the animals were immediately returned to the test chamber, and the test was continued for 150 minutes.

[0264] 3.2.4 Data Recording and Analysis. The animal's activities (distance traveled within the test chamber) will be automatically recorded using a camera and analyzed using ANY MAZE software to calculate ED. 50 .

[0265] 3.3 Experimental results: as shown in Table 2-3.

[0266] Table 2-3 Experimental results of the inhibitory effect of the compounds of the present invention on MK-801-induced high spontaneous activity in mice.

[0267] Group <![CDATA[ED 50 (mg / kg)]]> MED (mg / kg) Compound A 4.48 10 SEP-363856 10.35 30

[0268] Note: ED 50 The effective dose is half the effective dose, and MED is the minimum effective dose.

[0269] 3.4 Experimental Conclusions:

[0270] The above methods demonstrate that compound A of the present invention can significantly inhibit MK-801-induced high spontaneous activity in mice, and the inhibitory effect gradually increases with increasing compound dosage, exhibiting a strong dose-dependent relationship. Furthermore, compared to SEP-363856, compound A of the present invention has a lower minimum effective dose and a stronger inhibitory effect.

[0271] Test Example 4: Inhibition of PCP-induced high spontaneous activity in mice by the compound of this invention.

[0272] 4.1 Experimental Materials:

[0273] Test compound: The compound used in the embodiments of this invention was prepared in-house.

[0274] Phenylexin hydrochloride (PCP): Purchased from Shanghai Yuansi Biotechnology Co., Ltd., specification: 5g.

[0275] Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[0276] 4.2 Experimental Methods:

[0277] 4.2.1 Animal grouping: Before the experiment, the animals were randomly grouped according to their weight.

[0278] 4.2.2 Animal Adaptation: Before the experiment, the mice were acclimatized to the experimental environment for at least 1 hour. That is, the animals were transferred from the feeding room to the laboratory and allowed to move freely in their cages.

[0279] 4.2.3 Administration:

[0280] Drug preparation: Take the test compound, add pure water and sonicate.

[0281] After being grouped by body weight, the animals were randomly divided into a control group, a model group, and a drug-treated group, with 9 animals per group. Detailed drug treatment information is shown in the table below:

[0282]

[0283] T-30min Compound Oral Administration: The compound of this invention or the solvent (pure water) was administered orally or by gavage. Immediately after administration, the mice were placed in a test chamber (test chamber dimensions: length × width × height = 27 × 27 × 40 cm), and the spontaneous activity of the mice was recorded within 30 minutes.

[0284] T0 min Intraperitoneal injection of modeling drug: 30 minutes after compound administration, mice were removed and administered PCP (5 mg / kg) via intraperitoneal injection. The blank control group was injected with ultrapure water. After PCP administration, the animals were immediately returned to the test chamber, and the test continued for 60 minutes.

[0285] 4.2.4 Data Recording and Analysis. The animal's activities (distance traveled within the test chamber) will be automatically recorded using a camera and analyzed using ANY MAZE software to calculate the ED. 50 .

[0286] 4.3 Experimental Results: As shown in Table 2-4

[0287] Table 2-4 Results of the inhibitory effects of the compounds of this invention on PCP-induced high spontaneous activity in mice.

[0288] Group <![CDATA[ED 50 (mg / kg)]]> MED (mg / kg) Compound A 0.45 0.1 SEP-363856 1.84 3

[0289] Note: ED 50 The effective dose is half the effective dose, and MED is the minimum effective dose.

[0290] 4.4 Experimental Conclusions:

[0291] The above methods demonstrate that compound A of the present invention can significantly inhibit PCP-induced hypersporadic activity in mice, and the inhibitory effect gradually increases with increasing compound dosage, exhibiting a strong dose-dependent relationship. Furthermore, compared to SEP-363856, compound A of the present invention has a lower minimum effective dose and a stronger inhibitory effect.

[0292] III. Study on the salt crystal form of the compound

[0293] The free base of compound A is an oily substance. Since the oily substance is not conducive to further drug development, we attempted to form a salt from the free state of compound A and further studied the salt crystal form of compound A.

[0294] Experimental apparatus:

[0295]

[0296]

[0297] 1. Preparation of the crystal form of compound A salt

[0298] 1.1 Preparation of Compound A L-Mandinate Crystal Form I

[0299] In a 25 mL round-bottom flask, the free basic compound A (129 mg, 0.62 mmol) prepared in Example 2 was added, and acetone (1.0 mL) was stirred at room temperature until dissolved. Then, a solution of L-mandelic acid (102 mg, 0.67 mmol) in acetone (1.0 mL) was added to the above solution, and the mixture was stirred overnight at room temperature. Isopropyl ether (4.0 mL) was added to the above solvent. An oily substance initially appeared in the solution. After stirring for a period of time, the mixture was filtered and dried overnight at 60 °C under forced air to obtain a white solid, which was identified as compound A, L-mandelic acid salt crystal form I (142 mg).

[0300] After testing and analysis, it has the following properties: Figure 1 The XRPD diagram shown is as follows: Figure 2 The DSC diagram shown and as follows Figure 3 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0301] 1.2 Preparation of phosphate crystal form I of compound A

[0302] In a 25 mL round-bottom flask, add the free base compound A (505 mg, 2.42 mmol) prepared in Example 2 and ethanol (4.0 mL), heat to 60 °C and stir until dissolved. Then add 1 M phosphoric acid-ethanol solution (2.4 mL, 2.4 mmol), keep warm and stir for 1 hour, cool naturally to room temperature overnight, filter, and dry in a forced-air dryer at 50 °C for 5 hours to obtain a white solid, which was identified as compound A phosphate crystal form I (530 mg).

[0303] After testing and analysis, it has the following properties: Figure 4 The XRPD diagram shown is as follows: Figure 5 The DSC diagram shown and as follows Figure 6 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0304] 1.3 Preparation of Compound A Sulfate Crystal Form I

[0305] In a 25 mL round-bottom flask, add the free base compound A (125 mg, 0.60 mmol) prepared in Example 2 and isopropanol (3.0 mL), and stir until dissolved at room temperature. Then add 1 M sulfuric acid-isopropanol solution (0.30 mL, 0.30 mmol), and react at room temperature for 2 hours. Then add isopropyl ether (2.0 mL), and continue stirring at room temperature. Then filter, and dry in a forced-air dryer at 50 °C for 3 hours to obtain a white solid, which was identified as compound A sulfate crystal form I (66.8 mg).

[0306] After testing and analysis, it has the following properties: Figure 7 The XRPD diagram shown is as follows: Figure 8 The DSC diagram shown and as follows Figure 9 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0307] 1.4 Preparation of Compound A Fumarate Crystal Form I

[0308] In a 25 mL round-bottom flask, the free alkali compound A (105 mg, 0.50 mmol) prepared in Example 2 and ethanol (1.0 mL) were added and stirred at room temperature until dissolved. Then, a solution of fumaric acid (64 mg, 0.55 mmol) in ethanol (1.0 mL) was added and the mixture was stirred at room temperature for 2 days. Then, isopropyl ether (8.0 mL) was added and the mixture was stirred at room temperature. The mixture was then filtered and dried at 50 °C for 4 hours to obtain a white solid, which was identified as compound A fumarate crystal form I (63 mg).

[0309] After testing and analysis, it has the following properties: Figure 10 The XRPD diagram shown is as follows: Figure 11 The DSC diagram shown and as follows Figure 12 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0310] 1.5 Preparation of Compound A Oxalate Crystal Form I

[0311] In a 25 mL round-bottom flask, the free base compound A (104.3 mg, 0.50 mmol) prepared in Example 2 and ethanol (1.0 mL) were added and stirred at room temperature until dissolved. Then, a solution of oxalic acid (49 mg, 0.54 mmol) in ethanol (1.0 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was then filtered and dried at 50 °C for 4 hours to obtain a white solid, which was identified as compound A oxalate crystal form I (113.7 mg).

[0312] After testing and analysis, it has the following properties: Figure 13 The XRPD diagram shown is as follows: Figure 14 The DSC diagram shown and as follows Figure 15 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0313] 1.6 Preparation of compound A p-toluenesulfonate crystal form I

[0314] In a 25 mL round-bottom flask, the free alkali compound A (106.7 mg, 0.51 mmol) prepared in Example 2 and ethanol (1.0 mL) were added and stirred at room temperature until dissolved. Then, a solution of p-toluenesulfonic acid monohydrate (106 mg, 0.56 mmol) in ethanol (1.0 mL) was added and the mixture was stirred at room temperature for 2 days. Then, isopropyl ether (8.0 mL) was added and the mixture was stirred at room temperature. The mixture was then filtered and dried at 50 °C for 4 hours to obtain a white solid, which was identified as compound A p-toluenesulfonate crystal form I (98.6 mg).

[0315] After testing and analysis, it has the following properties: Figure 16 The XRPD diagram shown is as follows: Figure 17 The DSC diagram shown and as follows Figure 18 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0316] 1.7 Preparation of Compound A Benzenesulfonate Crystal Form I

[0317] In a 25 mL round-bottom flask, the free alkali compound A (503 mg, 2.41 mmol) prepared in Example 2 was added and dissolved in 4.0 mL of ethanol at room temperature. Then, a solution of benzenesulfonic acid (405 mg, 2.41 mmol) in ethanol (2.0 mL) was added and the mixture was stirred at room temperature for 20 hours. The mixture was then filtered and dried in a forced-air dryer at 50 °C for 5 hours to obtain a white solid, which was identified as benzenesulfonate form I of compound A (529.9 mg).

[0318] After testing and analysis, it has the following properties: Figure 19 The XRPD diagram shown is as follows: Figure 20 The DSC diagram shown and as follows Figure 21 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0319] 1.8 Preparation of Compound A Methanesulfonate Crystal Form I

[0320] In a 25 mL round-bottom flask, the free base compound A (143.8 mg, 0.69 mmol) prepared in Example 2 and ethyl acetate (1.0 mL) were added and stirred at room temperature until dissolved. Then, 1 M methanesulfonic acid-ethyl acetate solution (0.65 mL, 0.65 mmol) was added and stirred at room temperature for 3 hours. The mixture was then filtered and dried at 50 °C for 3 hours to obtain a white solid, which was identified as compound A methanesulfonate crystal form I (132.1 mg).

[0321] After testing and analysis, it has the following properties: Figure 22 The XRPD diagram shown is as follows: Figure 23 The DSC diagram shown and as follows Figure 24 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0322] 1.9 Preparation of maleate crystal form I of compound A

[0323] In a 25 mL round-bottom flask, the free base compound A (135 mg, 0.65 mmol) prepared in Example 2 was added and dissolved in ethyl acetate (1.0 mL) by stirring at room temperature. Then, a solution of maleic acid (76 mg, 0.65 mmol) in ethyl acetate (1.0 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was then filtered and dried in a forced-air dryer at 50 °C for 5 hours to obtain a white solid, which was identified as maleate salt form I of compound A (135.2 mg).

[0324] After testing and analysis, it has the following properties: Figure 25 The XRPD diagram shown is as follows: Figure 26 The DSC diagram shown and as follows Figure 27 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0325] 1.10 Preparation of Compound A L-malate Crystal Form I

[0326] In a 25 mL round-bottom flask, the free alkali compound A (107 mg, 0.51 mmol) prepared in Example 2 was added and dissolved in ethyl acetate (1.0 mL) by stirring at room temperature. Then, a solution of L-malic acid (69 mg, 0.51 mmol) in ethyl acetate (1.0 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was then filtered and dried in a forced-air dryer at 50 °C for 5 hours to obtain a white solid, which was identified as compound AL-malate crystal form I (75 mg).

[0327] After testing and analysis, it has the following properties: Figure 28 The XRPD diagram shown is as follows: Figure 29 The DSC diagram shown and as follows Figure 30 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0328] 1.11 Preparation of Compound A, I crystalline form of ethylene disulfonate

[0329] In a 25 mL round-bottom flask, the free alkali compound A (137 mg, 0.66 mmol) prepared in Example 2 was added and dissolved in ethanol (1.0 mL) by stirring at room temperature. Then, a solution of ethanedisulfonic acid (125 mg, 0.66 mmol) in ethanol (1.0 mL) was added, and the mixture was stirred at room temperature. The mixture was then filtered and dried in a forced-air dryer at 50 °C for 5 hours to obtain a white solid, which was identified as ethanedisulfonate form I of compound A (123 mg).

[0330] After testing and analysis, it has the following properties: Figure 31 The XRPD diagram shown is as follows: Figure 32 The DSC diagram shown and as follows Figure 33 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0331] 2. Solubility Experiment

[0332] 2.1 Experimental Objective:

[0333] The equilibrium solubility of different salt crystal forms of compound A in water was investigated over 24 hours.

[0334] 2.2 Experimental Scheme:

[0335] Excess amounts of compounds A, L-mandelate crystal form I, phosphate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, and maleate crystal form I were weighed and placed in different 10 mL centrifuge tubes. 1 mL of deionized water was added, the tubes were sealed with a sealing film, and the samples were shaken at 37 °C and 150 rpm for 24 h on a constant temperature shaker. After dilution and injection through a 0.45 μm organic filter, the samples were analyzed by HPLC.

[0336] 2.2 Experimental Results: The solubility results are shown in Table 3.1 below:

[0337] Table 3.1 Equilibrium solubility of different salt crystal forms of compound A in water after 24 h

[0338] Sample Name Solubility (mg / mL) Phosphate crystal form I 121.94 Oxalate crystal form I 12.13 Fumarate crystal form I 104.16 Benzenesulfonate crystal form I 119.46 Maleate crystal form I 103.86 Methanesulfonate crystal form I 116.10 p-Toluenesulfonate crystal form I 92.75 L-Mandrine Crystal Form I 66.74

[0339] 2.4 Experimental Conclusions:

[0340] The data in the table show that the solubility of compound A in aqueous medium is significantly improved after it is formed into a salt.

[0341] 3. Hygroscopicity test

[0342] 3.1 Experimental Objective:

[0343] The hygroscopic and deliquescent properties of compound A in phosphate form I and fumarate form I were investigated.

[0344] 3.2 Experimental Procedure:

[0345] At room temperature (25°C), 40.56 mg of compound A phosphate crystal form I and 34.61 mg of compound A fumarate crystal form I were weighed and placed in a DVS sample pan for testing.

[0346] 3.3 Experimental Results:

[0347] The DVS diagram of phosphate form I of compound A is shown below. Figure 34 As shown in the figure, the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis phenomenon during desorption, the two curves do not overlap. Figure 34 The results show that when the relative humidity (RH) is between 0% and 80%, the mass change ΔW% of the sample approaches 2% as the humidity increases, indicating that the sample is hygroscopic.

[0348] The DVS diagram of compound A fumarate crystal form I is shown below. Figure 35 As shown in the figure, the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis phenomenon during desorption, the two curves do not overlap. Figure 35 The results show that when the relative humidity (RH) is between 0% and 80%, the mass change ΔW% is less than 2% as the humidity increases, indicating that the sample is slightly hygroscopic.

[0349] 3.4 Experimental Conclusions:

[0350] Compound A, phosphate crystal form I, exhibits hygroscopicity with a moisture absorption weight gain of nearly 2% at RH 80% and 25℃. Compound A, fumarate crystal form I, exhibits hygroscopicity with a moisture absorption weight gain between 0.2% and 2% at RH 80% and 25℃.

[0351] 4. Solution stability experiment

[0352] 4.1 Experimental Objective:

[0353] The solution stability of compound A with different salt crystal forms was investigated.

[0354] 4.2 Experimental Design and Results:

[0355] Solutions with pH values ​​of 1.0, 3.0, 5.0, and 7.0 were prepared using hydrochloric acid, phosphoric acid, and sodium hydroxide. Appropriate amounts of compound A (phosphate form I, fumarate form I, methanesulfonate form I, and maleate form I) were weighed and added to their respective 20 mL volumetric flasks and labeled. The solutions were dissolved and diluted to volume using different pH media, filtered through a 0.45 μm organic filter, and analyzed by HPLC. The changes in the concentration of the samples were monitored from 0 to 24 h, and the results were calculated.

[0356] 4.3 Experimental Results:

[0357] Compound A, including phosphate form I, fumarate form I, methanesulfonate form I, and maleate form I, all exhibited good stability over 24 hours under different pH conditions (1.0, 3.0, 5.0, and 7.0).

Claims

1. An acid salt of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, characterized in that, The acid salt is L-mandelate, phosphate, sulfate, fumarate, oxalate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, maleate, L-malate, or ethanedisulfonate.

2. The acid salt according to claim 1, characterized in that, The acid salt is a phosphate, fumarate, methanesulfonate, benzenesulfonate, maleate, p-toluenesulfonate, or L-mandelate.

3. The acid salt according to claim 1, characterized in that, The acid salt contains 0.2-3 acids.

4. The acid salt according to claim 1, characterized in that, The number of acids in the acid salt is 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

5. The acid salt according to claim 1, characterized in that, The acid salt contains 0.5, 1, 2, or 3 acids.

6. The acid salt according to claim 1, characterized in that, The acid salt contains one acid.

7. The acid salt according to claim 1, characterized in that, The acid salt is a nonsolvent.

8. The acid salt according to any one of claims 1-7, characterized in that, The acid salt is in crystalline form.

9. The acid salt according to claim 8, characterized in that, The acid salt is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein: The X-ray powder diffraction pattern of the L-mandelate crystal form I includes diffraction peaks located at 2θ of 7.25±0.2°, 15.67±0.2°, 17.38±0.2°, 21.95±0.2°, and 24.70±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form I includes diffraction peaks located at 2θ of 15.66±0.2°, 18.07±0.2°, 23.49±0.2°, 24.97±0.2°, and 27.13±0.2°. The X-ray powder diffraction pattern of the sulfate crystal form I includes diffraction peaks located at 2θ of 6.91±0.2°, 10.29±0.2°, 13.66±0.2°, 17.07±0.2°, and 27.36±0.2°. The X-ray powder diffraction pattern of the fumarate crystal form I includes diffraction peaks located at 2θ of 13.05±0.2°, 21.95±0.2°, 24.85±0.2°, 25.86±0.2°, and 26.35±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form I includes diffraction peaks located at 2θ of 9.54±0.2°, 16.18±0.2°, 18.28±0.2°, 21.50±0.2°, and 27.64±0.2°. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I includes diffraction peaks located at 2θ of 6.19±0.2°, 11.89±0.2°, 16.79±0.2°, 18.73±0.2°, and 22.86±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form I includes diffraction peaks located at 2θ of 6.18±0.2°, 12.21±0.2°, 18.90±0.2°, 20.05±0.2°, and 24.38±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes diffraction peaks located at 2θ of 13.82±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, and 22.10±0.2°. The X-ray powder diffraction pattern of the maleate crystal form I includes diffraction peaks located at 2θ of 14.63±0.2°, 15.67±0.2°, 18.74±0.2°, 19.83±0.2°, and 20.11±0.2°. The X-ray powder diffraction pattern of the L-malate crystal form I includes diffraction peaks located at 2θ of 13.39±0.2°, 16.15±0.2°, 16.52±0.2°, 20.38±0.2°, and 21.11±0.2°. The X-ray powder diffraction pattern of the ethylene sulfonate crystal form I includes diffraction peaks located at 2θ of 18.38±0.2°, 18.62±0.2°, 22.58±0.2°, 23.65±0.2°, and 27.67±0.2°.

10. The acid salt according to claim 9, characterized in that, The acid salt is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein: The X-ray powder diffraction pattern of the L-mandelate crystal form I includes diffraction peaks at 2θ of 7.25±0.2°, 15.67±0.2°, 17.38±0.2°, 19.20±0.2°, 20.21±0.2°, 21.43±0.2°, 21.95±0.2°, 23.63±0.2°, 24.14±0.2°, and 24.70±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form I includes diffraction peaks located at 2θ of 15.66±0.2°, 16.35±0.2°, 17.16±0.2°, 18.07±0.2°, 23.49±0.2°, 24.55±0.2°, 24.97±0.2°, 26.29±0.2°, 26.56±0.2°, and 27.13±0.2°. The X-ray powder diffraction pattern of the sulfate crystal form I includes diffraction peaks located at 2θ of 6.91±0.2°, 10.29±0.2°, 13.66±0.2°, 14.68±0.2°, 15.91±0.2°, 16.35±0.2°, 17.07±0.2°, 20.43±0.2°, 24.32±0.2°, and 27.36±0.2°. The X-ray powder diffraction pattern of the fumarate crystal form I includes diffraction peaks located at 2θ of 13.05±0.2°, 15.21±0.2°, 15.63±0.2°, 16.13±0.2°, 17.25±0.2°, 21.95±0.2°, 23.48±0.2°, 24.85±0.2°, 25.86±0.2°, and 26.35±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form I includes diffraction peaks at 2θ of 9.54±0.2°, 16.18±0.2°, 18.28±0.2°, 20.06±0.2°, 21.50±0.2°, 23.07±0.2°, 24.10±0.2°, 25.26±0.2°, 26.39±0.2°, and 27.64±0.2°. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I includes diffraction peaks at 2θ of 6.19±0.2°, 11.89±0.2°, 14.28±0.2°, 16.79±0.2°, 18.06±0.2°, 18.73±0.2°, 19.05±0.2°, 19.30±0.2°, 22.86±0.2°, and 23.51±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form I includes diffraction peaks located at 2θ of 6.18±0.2°, 12.21±0.2°, 14.68±0.2°, 17.30±0.2°, 18.28±0.2°, 18.90±0.2°, 20.05±0.2°, 22.87±0.2°, 24.38±0.2°, and 25.95±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes diffraction peaks located at 2θ of 7.86±0.2°, 13.20±0.2°, 13.82±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, 18.62±0.2°, 22.10±0.2°, 23.77±0.2°, and 25.52±0.2°. The X-ray powder diffraction pattern of maleate crystal form I includes diffraction peaks located at 2θ of 12.12±0.2°, 14.63±0.2°, 15.67±0.2°, 18.74±0.2°, 19.83±0.2°, 20.11±0.2°, 22.26±0.2°, 25.34±0.2°, 26.29±0.2°, and 28.23±0.2°. The X-ray powder diffraction pattern of the L-malate crystal form I includes diffraction peaks at 2θ of 13.39±0.2°, 16.15±0.2°, 16.52±0.2°, 17.06±0.2°, 17.58±0.2°, 20.38±0.2°, 21.11±0.2°, 23.15±0.2°, 24.48±0.2°, and 25.50±0.2°. The X-ray powder diffraction pattern of the ethylene disulfonate crystal form I includes diffraction peaks located at 2θ of 15.63±0.2°, 16.80±0.2°, 18.38±0.2°, 18.62±0.2°, 21.17±0.2°, 21.87±0.2°, 22.58±0.2°, 23.65±0.2°, 24.51±0.2°, and 27.67±0.2°.

11. The acid salt according to claim 10, characterized in that, The acid salt is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein: The X-ray powder diffraction pattern of the L-mandelate crystal form I includes values ​​at 2θ of 7.25±0.2°, 12.41±0.2°, 14.29±0.2°, 14.98±0.2°, 15.67±0.2°, 17.38±0.2°, 19.20±0.2°, 19.51±0.2°, 20.21±0.2°, 21.43±0.2°, 21.95±0.2°, 23.03±0.2°, 23.63±0.2°, and 24.14±0.2°. Diffraction peaks at 24.70±0.2°, 26.01±0.2°, 26.33±0.2°, 27.72±0.2°, 28.10±0.2°, 29.47±0.2°, 29.99±0.2°, 31.38±0.2°, 32.46±0.2°, 33.66±0.2°, 34.14±0.2°, 35.07±0.2°, 37.72±0.2°, 38.47±0.2°, 41.12±0.2°, and 43.84±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form I includes values ​​at 2θ of 4.71±0.2°, 11.96±0.2°, 12.34±0.2°, 13.17±0.2°, 13.58±0.2°, 15.66±0.2°, 16.35±0.2°, 17.16±0.2°, 18.07±0.2°, 19.43±0.2°, 19.98±0.2°, 20.62±0.2°, 21.44±0.2°, 22.70±0.2°, and 2 Diffraction peaks at 3.49±0.2°, 24.10±0.2°, 24.55±0.2°, 24.97±0.2°, 25.71±0.2°, 26.29±0.2°, 26.56±0.2°, 27.13±0.2°, 28.35±0.2°, 28.84±0.2°, 29.88±0.2°, 31.37±0.2°, 33.09±0.2°, 34.27±0.2°, 36.41±0.2°, and 37.70±0.2°; The X-ray powder diffraction pattern of the sulfate crystal form I includes values ​​at 2θ of 6.91±0.2°, 10.29±0.2°, 10.79±0.2°, 13.66±0.2°, 14.46±0.2°, 14.68±0.2°, 15.44±0.2°, 15.91±0.2°, 16.35±0.2°, 17.07±0.2°, 17.85±0.2°, 19.57±0.2°, 19.84±0.2°, 20.43±0.2°, 20.72±0.2°, 2 Diffraction peaks at 0.98±0.2°, 21.52±0.2°, 22.07±0.2°, 22.56±0.2°, 22.81±0.2°, 23.45±0.2°, 23.91±0.2°, 24.32±0.2°, 24.64±0.2°, 25.56±0.2°, 25.98±0.2°, 26.36±0.2°, 27.36±0.2°, 27.62±0.2°, 29.35±0.2°, 30.72±0.2°, and 31.90±0.2°; The X-ray powder diffraction pattern of fumarate crystal form I includes values ​​at 2θ of 8.14±0.2°, 10.14±0.2°, 13.05±0.2°, 13.83±0.2°, 15.21±0.2°, 15.63±0.2°, 16.13±0.2°, 17.25±0.2°, 18.86±0.2°, 19.21±0.2°, 19.70±0.2°, 20.97±0.2°, 21.95±0.2°, and 23.48± Diffraction peaks at 0.2°, 24.85±0.2°, 25.86±0.2°, 26.35±0.2°, 27.82±0.2°, 30.54±0.2°, 31.61±0.2°, 33.06±0.2°, 33.76±0.2°, 34.79±0.2°, 36.60±0.2°, 37.63±0.2°, 39.58±0.2°, 42.87±0.2°, 46.60±0.2°, and 48.58±0.2°; The X-ray powder diffraction pattern of the oxalate crystal form I includes diffraction peaks at 2θ of 9.54±0.2°, 12.41±0.2°, 13.82±0.2°, 14.54±0.2°, 16.18±0.2°, 18.28±0.2°, 20.06±0.2°, 21.50±0.2°, 23.07±0.2°, 24.10±0.2°, 25.26±0.2°, 26.39±0.2°, 27.64±0.2°, 29.41±0.2°, 31.22±0.2°, 31.80±0.2°, 33.14±0.2°, and 36.80±0.2°. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I includes values ​​at 2θ of 6.19±0.2°, 9.01±0.2°, 10.25±0.2°, 10.49±0.2°, 11.89±0.2°, 14.28±0.2°, 14.67±0.2°, 16.07±0.2°, 16.79±0.2°, 17.73±0.2°, 18.06±0.2°, 18.73±0.2°, 19.05±0.2°, and 19.30±0.2°. Diffraction peaks at 19.76±0.2°, 21.52±0.2°, 21.95±0.2°, 22.86±0.2°, 23.51±0.2°, 24.32±0.2°, 24.70±0.2°, 25.31±0.2°, 25.79±0.2°, 26.94±0.2°, 27.45±0.2°, 27.95±0.2°, 29.33±0.2°, 30.40±0.2°, 30.85±0.2°, and 33.28±0.2°; The X-ray powder diffraction pattern of the benzenesulfonate crystal form I includes values ​​at 2θ of 6.18±0.2°, 8.75±0.2°, 10.23±0.2°, 12.21±0.2°, 14.68±0.2°, 16.39±0.2°, 16.70±0.2°, 17.06±0.2°, 17.30±0.2°, 18.28±0.2°, 18.90±0.2°, 20.05±0.2°, 21.68±0.2°, 22.06±0.2°, 22.87±0.2°, 23.55±0.2°, 23.72±0.2°, 24.38±0.2°, and 24.64± Diffraction peaks at 0.2°, 25.41±0.2°, 25.66±0.2°, 25.95±0.2°, 26.66±0.2°, 26.98±0.2°, 27.93±0.2°, 28.71±0.2°, 29.48±0.2°, 30.57±0.2°, 30.87±0.2°, 32.97±0.2°, 34.65±0.2°, 36.83±0.2°, 37.81±0.2°, 38.41±0.2°, 40.46±0.2°, 41.06±0.2°, 43.24±0.2°, 44.09±0.2°, and 47.17±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes values ​​at 2θ of 7.86±0.2°, 13.20±0.2°, 13.82±0.2°, 14.25±0.2°, 15.63±0.2°, 16.68±0.2°, 17.64±0.2°, 18.62±0.2°, 19.64±0.2°, 20.10±0.2°, 21.43±0.2°, 22.10±0.2°, 23.06±0.2°, and 23.77±0.2°. Diffraction peaks at 24.03±0.2°, 24.40±0.2°, 24.99±0.2°, 25.52±0.2°, 26.50±0.2°, 27.50±0.2°, 27.93±0.2°, 28.65±0.2°, 29.41±0.2°, 29.88±0.2°, 30.28±0.2°, 31.69±0.2°, 32.36±0.2°, 32.78±0.2°, 33.86±0.2°, and 37.76±0.2°; The X-ray powder diffraction pattern of maleate crystal form I includes values ​​at 2θ of 9.36±0.2°, 10.38±0.2°, 11.43±0.2°, 12.12±0.2°, 14.63±0.2°, 15.67±0.2°, 17.84±0.2°, 18.21±0.2°, 18.74±0.2°, 19.83±0.2°, 20.11±0.2°, 20.58±0.2°, 20.89±0.2°, and 22.07±0.2°. Diffraction peaks at 22.26±0.2°, 22.88±0.2°, 23.71±0.2°, 24.48±0.2°, 25.06±0.2°, 25.34±0.2°, 26.29±0.2°, 27.40±0.2°, 27.63±0.2°, 28.23±0.2°, 29.35±0.2°, 31.34±0.2°, 32.09±0.2°, 33.69±0.2°, 34.55±0.2°, and 35.63±0.2°; The X-ray powder diffraction pattern of the L-malate crystal form I includes values ​​at 2θ of 8.54±0.2°, 12.30±0.2°, 13.39±0.2°, 15.63±0.2°, 16.15±0.2°, 16.52±0.2°, 17.06±0.2°, 17.58±0.2°, 18.99±0.2°, 19.62±0.2°, 20.38±0.2°, and 21.

11. Diffraction peaks at ±0.2°, 21.82±0.2°, 22.78±0.2°, 23.15±0.2°, 24.48±0.2°, 24.87±0.2°, 25.50±0.2°, 26.19±0.2°, 26.69±0.2°, 28.01±0.2°, 30.01±0.2°, 30.62±0.2°, 34.19±0.2°, and 41.34±0.2°; The X-ray powder diffraction pattern of the ethylene disulfonate crystal form I includes values ​​at 2θ of 4.78±0.2°, 9.23±0.2°, 12.28±0.2°, 14.73±0.2°, 15.63±0.2°, 16.13±0.2°, 16.80±0.2°, 17.64±0.2°, 18.38±0.2°, 18.62±0.2°, 20.25±0.2°, 21.17±0.2°, 21.87±0.2°, 22.58±0.2°, and 23.04±0.2°. Diffraction peaks at 23.65±0.2°, 23.99±0.2°, 24.51±0.2°, 26.11±0.2°, 26.84±0.2°, 27.18±0.2°, 27.67±0.2°, 28.24±0.2°, 28.98±0.2°, 29.64±0.2°, 30.37±0.2°, 30.75±0.2°, 31.74±0.2°, 32.41±0.2°, 35.48±0.2°, 36.35±0.2°, and 44.85±0.2°.

12. The acid salt according to any one of claims 9-11, characterized in that, The acid salt is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein: The X-ray powder diffraction pattern of L-mandelate crystal form I is basically shown in Figure 1; The X-ray powder diffraction pattern of the phosphate crystal form I is basically shown in Figure 4. The X-ray powder diffraction pattern of the sulfate crystal form I is basically shown in Figure 7. The X-ray powder diffraction pattern of fumarate crystal form I is basically shown in Figure 10. The X-ray powder diffraction pattern of the oxalate crystal form I is basically shown in Figure 13. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I is basically shown in Figure 16. The X-ray powder diffraction pattern of the benzenesulfonate crystal form I is basically shown in Figure 19; The X-ray powder diffraction pattern of the methanesulfonate crystal form I is basically shown in Figure 22; The X-ray powder diffraction pattern of maleate crystal form I is basically shown in Figure 25; The X-ray powder diffraction pattern of L-malate crystal form I is basically shown in Figure 28; The X-ray powder diffraction pattern of the ethylene disulfonate crystal form I is basically shown in Figure 31.

13. The acid salt according to any one of claims 9-11, characterized in that, The acid salt is L-mandelate crystal form I, phosphate crystal form I, sulfate crystal form I, fumarate crystal form I, oxalate crystal form I, p-toluenesulfonate crystal form I, benzenesulfonate crystal form I, methanesulfonate crystal form I, maleate crystal form I, L-malate crystal form I, or ethanedisulfonate crystal form I, wherein: The L-mandelate crystal form I has a DSC pattern as shown in Figure 2, or a TGA pattern as shown in Figure 3; The phosphate crystal form I has a DSC pattern as shown in Figure 5, or a TGA pattern as shown in Figure 6; The sulfate crystal form I has a DSC spectrum as shown in Figure 8, or a TGA spectrum as shown in Figure 9; The fumarate crystal form I has a DSC pattern as shown in Figure 11, or a TGA pattern as shown in Figure 12; The oxalate crystal form I has a DSC pattern as shown in Figure 14, or a TGA pattern as shown in Figure 15; The p-toluenesulfonate crystal form I has a DSC pattern as shown in Figure 17, or a TGA pattern as shown in Figure 18; The benzenesulfonate crystal form I has a DSC pattern as shown in Figure 20, or a TGA pattern as shown in Figure 21; The methanesulfonate crystal form I has a DSC pattern as shown in Figure 23, or a TGA pattern as shown in Figure 24; The maleate crystal form I has a DSC pattern as shown in Figure 26, or a TGA pattern as shown in Figure 27; The L-malate crystal form I has a DSC pattern as shown in Figure 29, or a TGA pattern as shown in Figure 30; The ethylene disulfonate crystal form I has a DSC pattern as shown in Figure 32, or a TGA pattern as shown in Figure 33.

14. A method for preparing the acid salt according to any one of claims 1-13, characterized in that, Specifically, the steps include the following: (1) Weigh an appropriate amount of the free base of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and dissolve it in solvent 1; (2) Weigh an appropriate amount of acid and dissolve it in solvent 2; the amount of acid is 0.5-2.0 equivalents; (3) Mix the two above, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product; Alternatively, the two can be mixed, stirred and reacted at a certain temperature for a certain time, solvent 3 can be added and stirred and reacted for a certain time, then filtered and dried to obtain the target product; in: Solvent 1, Solvent 2, and Solvent 3 are each independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; wherein Solvent 1 and Solvent 2 must be miscible when used. The acid mentioned is L-mandelic acid, phosphoric acid, sulfuric acid, fumaric acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, maleic acid, L-malic acid, or ethanedisulfonic acid.

15. A pharmaceutical composition comprising a therapeutically effective dose of an acid salt or combination thereof as shown in any one of claims 1-13, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the acid salt of any one of claims 1-13, or the pharmaceutical composition of claim 15, in the preparation of a medicament, wherein the medicament may be a medicament for the prevention and / or treatment of neuropsychiatric diseases in mammals.

17. The use according to claim 16, characterized in that, The neuropsychiatric diseases mentioned are central nervous system diseases related to serotonin receptors and / or trace amine-related receptors and / or dopamine receptors.

18. The use according to claim 17, characterized in that, The neuropsychiatric disorders mentioned include one or more of the following: schizophrenia spectrum disorders, psychosis, mental disorders, aggression, mental confusion, Tourette syndrome, epilepsy, agitation, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, anxiety disorders, depression, mood disorders, mania, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, pain, cognitive impairment, restless limb syndrome, multiple sclerosis, sleep disorders, sleep apnea, hypersomnia, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medications, insomnia, substance abuse and dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, and autism.

19. The use according to claim 18, characterized in that, The schizophrenia spectrum includes schizophrenia; the psychosis includes drug-induced psychosis, Parkinson's psychosis, irritative psychosis, organ or NOS psychosis, or affective psychosis; the mental disorder includes schizoid personality disorder, schizotypal personality disorder, delusional disorder, short-term mental disorder, sharing disorder, mental disorder caused by physical illness, post-traumatic stress disorder, affective disorder, or bipolar disorder; the pain includes neuropathic pain, inflammatory pain, fibromyalgia, or migraine; the depression includes severe depressive disorder; and the anxiety disorder includes premenstrual anxiety.

20. The use according to claim 19, characterized in that, The schizophrenia is acute schizophrenia, chronic schizophrenia, or NOS schizophrenia; the affective psychosis is seasonal affective disorder; the affective disorder is a psychoemotional disorder; and the neuropathic pain is a neuropathic pain susceptibility state.

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