Salt form of TAAR1 ligand agonist, crystal form, preparation method, and use

Abstract

The present invention relates to a salt of a TAAR1 ligand agonist, a crystal form, a preparation method, and a use. Specifically, provided are a salt of a compound of formula I, a crystal form, a preparation method, and a use in the preparation of a drug for TAAR1-mediated related diseases.

Description

A salt form, a crystal form, a preparation method and an application thereof of a TAAR1 ligand agonist Technical Field

[0001] The present disclosure belongs to the field of medicinal chemistry, and specifically relates to a salt of a TAAR1 ligand agonist, a crystal form of the salt, and a preparation method and application thereof. Background Art

[0002] Trace amine receptors (TAARs) are a family of G protein-coupled receptors activated by endogenous biogenic amines. Six TAARs and three pseudogenes have been identified in humans. TAAR1 is the most studied of all TAARs and is widely expressed in the mammalian brain, particularly in limbic and monoaminergic regions. TAAR1 can modulate presynaptic dopaminergic neurotransmission and induce activation of G protein-coupled inwardly rectifying potassium channels, thereby reducing neuronal firing rate. TAAR1 may be a potential therapeutic target for psychiatric disorders such as schizophrenia, depression, psychotic disorders associated with Parkinson's disease, behavioral symptoms of dementia, anxiety, migraine, and attention deficit hyperactivity disorder.

[0003] Currently, there are four drugs targeting TAAR1: amphetamine, RG-7906, RO-5263397, and SEP-363856. Amphetamine was approved by the FDA in 2016 for the treatment of attention deficit hyperactivity disorder (ADHD). However, this compound has a strong excitatory effect on the central nervous system. Short-term effects can cause increased heart rate, blood pressure, feelings of happiness, and reduced fatigue. However, long-term use can cause adverse reactions such as insomnia, irritability, delusions and hallucinations, and violent and aggressive behavior, leading to its classification as a controlled substance. RG-7906, RO-5263397, and SEP-363856 are all investigational TAAR1 selective agonists. RG-7906 is in Phase II clinical trials, RO-5263397 is on hold in Phase I trials, and SEP-363856, the most advanced drug, is in Phase III clinical trials. Therefore, the development of new TAAR1 agonists with improved safety and efficacy is needed to meet the needs of patients.

[0004] PCT / CN2023 / 101737 provides a TAAR1 ligand agonist with the structural formula shown below. Test results show that the compound has good TAAR1 agonist activity.

[0005] The pharmaceutical form (such as crystal form, salt) of a compound often affects the chemical stability of the drug. The difference between crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes also be accompanied by the crystal formation of other forms. In general, amorphous drug products do not have regular crystal structures and often have defects such as poor product stability, finer crystallization, more difficult filtration, easy agglomeration, and poor fluidity. In view of the importance of solid drug salt form, crystal form and its stability in clinical treatment, in-depth study of the salt form and crystal form of Formula I compound is of great significance to the development of drugs suitable for industrial production and good biological activity. Summary of the Invention

[0006] In one aspect, the present disclosure provides a pharmaceutically acceptable salt of a compound of Formula I, wherein the pharmaceutically acceptable salt is selected from citrate, succinate, maleate, fumarate, L-tartrate, gallate, mucate, phosphate, hydrochloride, oxalate, hydrobromide, sulfate, acetate, DL-lactate, ascorbate, hippurate, p-toluenesulfonate, and diphosphate.

[0007] In some embodiments, the pharmaceutically acceptable salts are maleate, mucate, phosphate, and oxalate.

[0008] In some embodiments, the pharmaceutically acceptable salts are maleate, phosphate, and oxalate.

[0009] In some embodiments, the molar ratio of the compound of formula I to the acid molecule in the pharmaceutically acceptable salt is about 1:2 to 2:1; preferably about 1:2, 1:1 or 2:1.

[0010] In some embodiments, the molar ratio of the compound of Formula I to maleic acid is about 1:1.

[0011] In some embodiments, the molar ratio of the compound of Formula I to phosphoric acid is about 1:1 or 1:2.

[0012] In one aspect, the present disclosure provides a method for preparing a pharmaceutically acceptable salt of a compound of formula I, comprising the step of mixing the compound of formula I with an acid and a solvent selected from one or more of isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether.

[0013] In some embodiments, in the method for preparing the maleate salt of the compound of formula I, the molar ratio of maleic acid to the compound of formula I is selected from 0.5:1 to 1.5:1, preferably 1:1.

[0014] In one aspect, the present disclosure provides Form A of a maleate salt of a compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 14.49±0.2°, 14.72±0.2°, 16.26±0.2°, 17.81±0.2°, 19.58±0.2°, 24.03±0.2°, 25.84±0.2°, and 29.72±0.2°.

[0015] In some embodiments, the crystalline form A of the maleate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.24±0.2°, 10.56±0.2°, 14.49±0.2°, 14.72±0.2°, 16.26±0.2°, 17.81±0.2°, 19.58±0.2°, 24.03±0.2°, 25.84±0.2°, and 29.72±0.2°.

[0016] In some embodiments, the crystalline form A of the maleate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 1-1.

[0017] In some embodiments, in the crystalline form A of the maleate salt of the compound of formula I, the molar ratio of maleic acid to the compound of formula I is about 1:1.

[0018] In an optional embodiment, the present disclosure provides a method for preparing a maleate salt of a compound of Formula I, Form A, comprising mixing a compound of Formula I, maleic acid, and a solvent, and a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization method includes volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0019] In one aspect, the present disclosure provides Form A of the phosphate salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 15.068±0.2°, 15.331±0.2°, 16.011±0.2°, 17.333±0.2°, 17.605±0.2°, 20.119±0.2°, 20.870±0.2°, 23.039±0.2°, 25.159±0.2°, 25.910±0.2°, 26.680±0.2°, 27.843±0.2°.

[0020] In some embodiments, the crystalline form A of the phosphate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 15.068±0.2°, 15.331±0.2°, 16.011±0.2°, 17.333±0.2°, 17.605±0.2°, 20.119±0.2°, 20.870±0.2°, 21.161±0.2°, 23.039±0.2°, 25.159±0.2°, 25.910±0.2°, 26.680±0.2°, 27.843±0.2°, 28.681±0.2°, 34.958±0.2°, 35.302±0.2°.

[0021] In some embodiments, the crystal form A of the phosphate salt of the compound of formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 2-1.

[0022] In an alternative embodiment, the present disclosure provides a method for preparing Form A of the phosphate salt of the compound of Formula I, comprising mixing the compound of Formula I, phosphoric acid, and a solvent, followed by a crystallization step. In an alternative embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze-drying.

[0023] In one aspect, the present disclosure provides Form A of the diphosphate salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 11.029±0.2°, 12.607±0.2°, 14.362±0.2°, 14.849±0.2°, 15.635±0.2°, 18.139±0.2°, 19.187±0.2°, 20.687±0.2°, 21.808±0.2°, 22.432±0.2°, 22.715±0.2°, 23.294±0.2°, 23.533±0.2°, 24.283±0.2°, 24.788±0.2°, 28.295±0.2°.

[0024] In some embodiments, the crystalline form A of the diphosphate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.839±0.2°, 11.029±0.2°, 12.607±0.2°, 14.362±0.2°, 14.849±0.2°, 15.635±0.2°, 17.454±0.2°, 18.139±0.2°, 19.187±0.2°,19.773±0.2°,20.369±0.2°,20.687±0.2°,21.049±0.2°,21.808±0.2°,22.432±0.2°,22.715±0.2°,23.294±0.2°,23.533±0.2°,24.283±0.2°,24.788±0.2°,28.295±0.2°.

[0025] In some embodiments, the crystalline form A of the diphosphate salt of the compound of formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 3-1.

[0026] In an alternative embodiment, the present disclosure provides a method for preparing Form A of the diphosphate salt of the compound of Formula I, comprising mixing the compound of Formula I, phosphoric acid, and a solvent, and performing a crystallization step. In an alternative embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0027] In one aspect, the present disclosure provides Form A of the oxalate salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 13.162±0.2°, 15.072±0.2°, 15.802±0.2°, 17.833±0.2°, 19.498±0.2°, 21.088±0.2°, 23.168±0.2°, 24.677±0.2°, 26.481±0.2°, 28.805±0.2°, 32.226±0.2°.

[0028] In some embodiments, the crystalline form A of the oxalate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 13.162±0.2°, 15.072±0.2°, 15.802±0.2°, 17.833±0.2°, 19.498±0.2°, 20.323±0.2°, 21.088±0.2°, 23.168±0.2°, 24.677±0.2°, 26.481±0.2°, 27.082±0.2°, 28.805±0.2°, 32.002±0.2°, 32.226±0.2°.

[0029] In some embodiments, the crystalline form A of the oxalate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 4-1.

[0030] In an alternative embodiment, the present disclosure provides a method for preparing Form A of the oxalate salt of a compound of Formula I, comprising mixing a compound of Formula I, oxalic acid, and a solvent, and performing a crystallization step. In an alternative embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0031] In one aspect, the present disclosure provides a crystalline form A of a mucic acid salt of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 12.975±0.2°, 13.451±0.2°, 14.739±0.2°, 15.310±0.2°, 16.171±0.2°, 17.231±0.2°, 17.743±0.2°, 18.12 3±0.2°,18.470±0.2°,19.647±0.2°,21.511±0.2°,22.794±0.2°,24.854±0.2°,26.852±0.2°,29.702±0.2°,30.758±0.2°,34.460±0.2°,34.869±0.2°,36.684±0.2°,37.671±0.2°.

[0032] In some embodiments, the crystalline form A of the mucic acid salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 5-1.

[0033] In an optional embodiment, the present disclosure provides a method for preparing a mucic acid salt crystalline form A of a compound of formula I, comprising mixing a compound of formula I, mucic acid, and a solvent, and a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization method includes volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0034] In one aspect, the present disclosure provides a crystalline form A of the hydrobromide salt of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 11.515±0.2°, 14.871±0.2°, 16.925±0.2°, 17.475±0.2°, 19.359±0.2°, 21.082±0.2°, 21.462±0.2°, 21.97 4±0.2°,23.566±0.2°,24.012±0.2°,24.881±0.2°,26.205±0.2°,27.458±0.2°,27.977±0.2°,28.452±0.2°,29.718±0.2°,31.123±0.2°,32.375±0.2°,39.085±0.2°,42.023±0.2°.

[0035] In some embodiments, the crystalline form A of the hydrobromide salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 6-1.

[0036] In some embodiments, the present disclosure provides a method for preparing a hydrobromide salt of a compound of Formula I, Form A, comprising mixing a compound of Formula I, hydrobromic acid, and a solvent, and performing a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization method includes volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0037] In one aspect, the present disclosure provides Form A of a fumarate salt of a compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 10.588±0.2°, 13.403±0.2°, 14.031±0.2°, 15.720±0.2°, 16.342±0.2°, 20.889±0.2°, 20.927±0.2°, 21.435±0.2°, 23.386±0.2°.

[0038] In some embodiments, the crystalline form A of the fumarate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 10.588±0.2°, 13.403±0.2°, 14.031±0.2°, 15.720±0.2°, 16.342±0.2°, 20.213±0.2°, 20.889±0.2°, 20.927±0.2°, 21.435±0.2°, 23.386±0.2°, 23.565±0.2°.

[0039] In some embodiments, the crystalline form A of the fumarate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 7-1.

[0040] In some embodiments, the present disclosure provides a method for preparing Form A of a fumarate salt of a compound of Formula I, comprising mixing a compound of Formula I, fumaric acid, and a solvent, and a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization method includes volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0041] In one aspect, the present disclosure provides a crystalline form B of a fumarate salt of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 12.504±0.2°, 14.689±0.2°, 15.041±0.2°, 15.688±0.2°, 16.052±0.2°, 16.612±0.2°, 17.462±0.2°, 19.74 7±0.2°,20.109±0.2°,20.911±0.2°,22.029±0.2°,22.430±0.2°,23.454±0.2°,23.800±0.2°,24.011±0.2°,24.632±0.2°,25.046±0.2°,25.453±0.2°,26.588±0.2°,27.589±0.2°.

[0042] In some embodiments, the crystalline form B of the fumarate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 12.504±0.2°, 13.233±0.2°, 14.084±0.2°, 14.689±0.2°, 15.041±0.2°, 15.688±0.2°, 16.052±0.2°, 16.612±0.2°, 17.462±0.2°, 19.106±0.2°, 19.747±0.2°, 20.109±0.2°, 20.911±0.2°, 21.720±0.2°,22.029±0.2°,22.430±0.2°,22.824±0.2°,23.454±0.2°,23.800±0.2°,24.011±0.2°,24.632±0.2°,25.046±0.2°,25.453±0.2°,26.055±0.2°,26.588±0.2°,27.589±0.2°,28.771±0.2°,29.536±0.2°,31.988±0.2°,37.956±0.2°,40.993±0.2°.

[0043] In some embodiments, the crystalline form B of the fumarate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 8-1.

[0044] The present disclosure provides a method for preparing a fumarate crystalline form B of a compound of formula I, comprising mixing a compound of formula I, fumaric acid, and a solvent, and a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization method includes volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0045] In one aspect, the present disclosure provides a crystalline form A of a hemi-L-tartrate salt of a compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 12.107±0.2°, 12.962±0.2°, 16.817±0.2°, 17.082±0.2°, 17.924±0.2°, 18.137±0.2°, 19. 137±0.2°,19.494±0.2°,20.731±0.2°,21.967±0.2°,22.675±0.2°,23.839±0.2°,24.767±0.2°,26.220±0.2°,26.901±0.2°,27.240±0.2°,28.888±0.2°,37.559±0.2°.

[0046] In some embodiments, the crystalline form A of the L-tartrate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 12.107±0.2°, 12.962±0.2°, 13.686±0.2°, 16.817±0.2°, 17.082±0.2°, 17.924±0.2°, 18.137±0.2°, 19.137±0.2°, 19.494±0.2°, 20.731±0.2°, 21.96 7±0.2°,22.675±0.2°,23.076±0.2°,23.839±0.2°,24.135±0.2°,24.767±0.2°,26.220±0.2°,26.901±0.2°,27.240±0.2°,27.650±0.2°,28.888±0.2°,35.012±0.2°,35.925±0.2°,37.559±0.2°,38.931±0.2°,39.157±0.2°.

[0047] In some embodiments, the crystalline form A of the L-tartrate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 9-1.

[0048] In some embodiments, the present disclosure provides a method for preparing L-tartrate crystalline form A of a compound of formula I, comprising mixing a compound of formula I, L-tartaric acid, and a solvent, and performing a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0049] In one aspect, the present disclosure provides Form A of a gallate salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 10.879±0.2°, 14.571±0.2°, 15.170±0.2°, 15.469±0.2°, 16.567±0.2°, 17.325±0.2°, 20.016±0.2°, 20.569±0.2°, 21.770±0.2°, 23.480±0.2°, 24.012±0.2°, 24.414±0.2°, 26.181±0.2°, 27.498±0.2°, 27.850±0.2°.

[0050] In some embodiments, the crystalline form A of the gallate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 10.879±0.2°, 11.529±0.2°, 13.689±0.2°, 14.571±0.2°, 15.170±0.2°, 15.469±0.2°, 16.567±0.2°, 17.325±0.2°, 18.178±0.2°, 18.933±0.2° ,20.016±0.2°,20.569±0.2°,21.770±0.2°,22.297±0.2°,23.480±0.2°,24.012±0.2°,24.414±0.2°,24.978±0.2°,25.609±0.2°,26.181±0.2°,27.498±0.2°,27.850±0.2°,31.485±0.2°,32.745±0.2°,34.343±0.2°.

[0051] In some embodiments, the crystalline form A of the gallic acid salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 10-1.

[0052] In some embodiments, the present disclosure provides a method for preparing Form A of a gallate salt of a compound of Formula I, comprising mixing a compound of Formula I, gallic acid, and a solvent, and performing a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0053] In one aspect, the present disclosure provides Form A of the p-toluenesulfonate salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.845±0.2°, 13.526±0.2°, 14.080±0.2°, 17.124±0.2°, 19.848±0.2°, 20.209±0.2°, 20.780±0.2°, 23.534±0.2°, 25.368±0.2°, 27.328±0.2°.

[0054] In some embodiments, the crystalline form A of the p-toluenesulfonate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.845±0.2°, 13.526±0.2°, 14.080±0.2°, 15.692±0.2°, 16.451±0.2°, 17.124±0.2°, 19.848±0.2°, 20.209±0.2°, 20.780±0.2°, 23.534±0.2°, 24.627±0.2°, 25.368±0.2°, 27.328±0.2°.

[0055] In some embodiments, the crystalline form A of the p-toluenesulfonate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 11-1.

[0056] In some embodiments, the present disclosure provides a method for preparing a p-toluenesulfonic acid salt of a compound of Formula I, Form A, comprising mixing a compound of Formula I, p-toluenesulfonic acid, and a solvent, followed by a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze-drying.

[0057] In one aspect, the present disclosure provides Form A of the hydrochloride salt of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 11.893±0.2°, 15.339±0.2°, 16.680±0.2°, 17.444±0.2°, 22.389±0.2°, 25.024±0.2°, 25.609±0.2°, 26.987±0.2°, 28.243±0.2°.

[0058] In some embodiments, the crystalline form A of the hydrochloride salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 11.893±0.2°, 15.339±0.2°, 16.680±0.2°, 17.444±0.2°, 17.676±0.2°, 21.356±0.2°, 21.821±0.2°, 22.389±0.2°, 25.024±0.2°, 25.609±0.2°, 26.987±0.2°, 28.243±0.2°, 28.931±0.2°, and 31.150±0.2°.

[0059] In some embodiments, the Form A of the hydrochloride salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 12-1.

[0060] In some embodiments, the present disclosure provides a method for preparing Form A of the hydrochloride salt of a compound of Formula I, comprising mixing a compound of Formula I, hydrochloric acid, and a solvent, and performing a crystallization step. In an optional embodiment, the solvent is selected from isopropyl alcohol, isopropyl acetate, toluene, and methyl tert-butyl ether. The crystallization methods include volatilization, suspension, solution crystallization, cooling, vapor diffusion, ball milling, and freeze drying.

[0061] In some embodiments, the preparation method of any one of the crystal forms described in the present disclosure further includes steps such as filtration and drying.

[0062] The present disclosure also provides a pharmaceutical composition comprising any of the aforementioned pharmaceutically acceptable salts of a compound of formula I or a crystalline form thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, and the general daily dose is about 1 to 200 mg.

[0063] In one aspect, the present disclosure also provides the use of any of the aforementioned pharmaceutically acceptable salts, crystal forms or pharmaceutical compositions of the compound of Formula I in the preparation of TAAR1 agonist drugs.

[0064] In one aspect, the present disclosure also provides use of any of the aforementioned pharmaceutically acceptable salts, crystalline forms, or pharmaceutical compositions of a compound of Formula I in the preparation of a medicament for preventing and / or controlling diseases or conditions related to the central nervous system (CNS). The central nervous system (CNS) diseases or conditions include: schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic disorders, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder caused by physical illness, drug-induced psychosis, psycho-affective disorder, aggressive psychosis, Parkinson's psychosis, irritant psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, seizures, agitation, post-traumatic stress disorder, behavioral disturbances, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychosis, obsessive-compulsive disorder, vertigo, pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome (RLS), multiple sclerosis, psychoactive substance abuse, stress-related disorders.

[0065] The affective psychosis includes: depression, major depressive disorder and dysthymia, bipolar disorder, bipolar depression, mania, seasonal affective psychosis, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD); the pain includes: neuropathic pain, neuropathic pain susceptibility state, inflammatory pain; the stress-related disorders include: acute stress disorder, post-traumatic stress disorder, and adjustment disorder.

[0066] In one aspect, the present disclosure further provides the use of any of the aforementioned pharmaceutically acceptable salts, crystalline forms, or pharmaceutical compositions of a compound of Formula I in the preparation of a medicament for preventing and / or controlling cardiovascular or metabolic diseases, including diabetes, diabetic complications, obesity, dyslipidemia, and hypertension.

[0067] Definition and Description

[0068] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0069] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0070] The compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present disclosure.

[0071] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0072] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0073] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figures 1-1, 1-2, 1-3, 1-4, and 1-5 are XRPD patterns, TGA / DSC patterns, and 1 H NMR pattern, DVS pattern and XRPD patterns before and after DVS test.

[0075] Figures 2-1, 2-2, and 2-3 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectrum.

[0076] Figures 3-1 and 3-2 are the XRPD pattern and TGA / DSC pattern of Form A of the diphosphate salt of the compound of Formula I, respectively.

[0077] Figures 4-1 and 4-2 are the XRPD pattern and TGA / DSC pattern of the oxalate crystal form A of the compound of formula I, respectively.

[0078] Figures 5-1 and 5-2 are XRPD and DSC images of the mucic acid salt form A of the compound of formula I, respectively.

[0079] Figures 6-1 and 6-2 are the XRPD pattern and TGA / DSC pattern of Form A of the hydrobromide salt of the compound of Formula I, respectively.

[0080] Figures 7-1 and 7-2 are the XRPD pattern and TGA / DSC pattern of the fumarate crystalline form A of the compound of formula I, respectively.

[0081] Figures 8-1 and 8-2 are the XRPD pattern and TGA / DSC pattern of the fumarate crystalline form B of the compound of formula I, respectively.

[0082] Figures 9-1 and 9-2 are the XRPD pattern and TGA / DSC pattern of Form A of the L-tartrate salt of the compound of Formula I, respectively.

[0083] Figures 10-1 and 10-2 are the XRPD pattern and TGA / DSC pattern of Form A of the gallate salt of the compound of Formula I, respectively.

[0084] Figures 11-1 and 11-2 are the XRPD pattern and TGA / DSC pattern of the p-toluenesulfonate crystalline form A of the compound of formula I, respectively.

[0085] Figures 12-1 and 12-2 are the XRPD pattern and TGA / DSC pattern of Form A of the hydrochloride salt of the compound of Formula I, respectively.

[0086] Figure 13: XRPD pattern of maleate salt form A of the compound of formula I under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated (40°C / 75% RH) conditions. DETAILED DESCRIPTION

[0087] The present disclosure is further described below with reference to specific embodiments and test examples, but they do not limit the scope of the present disclosure in any form.

[0088] Test conditions of the instruments used in the experiment:

[0089] X-ray powder diffraction (XRPD)

[0090] The samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). X-ray powder diffraction data were collected under ambient conditions. The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 s. The measurements were performed using Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0091] Thermogravimetric Analyzer (TGA)

[0092] The thermogravimetric analyzer (TA Discovery 55, TA, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0093] Differential Scanning Calorimetry (DSC)

[0094] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0095] Nuclear magnetic resonance spectroscopy (1H NMR)

[0096] The solid sample was dissolved in D2O solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, GER).

[0097] Dynamic moisture sorption / desorption analysis (DVS)

[0098] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each gradient increasing by 10% within the range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0099] Example 1 Synthesis of Compounds of Formula I

[0100] 1.1 Synthesis of Intermediate 1-2

[0101] Compound 1-1 (5.00 g, 30.6 mmol, 1.00 eq) and NaHCO₃ (5.65 g, 67.2 mmol, 2.61 mL, 2.20 eq) were dissolved in THF (100 mL) and water (10.0 mL). The temperature was lowered to 0-5°C, and chloroacetyl chloride (5.31 g, 47.05 mmol, 1.10 eq) was added dropwise. After the addition was complete, the temperature was naturally raised to 20°C and stirred for 24 hours. NaHCO₃ (2.57 g, 30.6 mmol, 1.00 eq) and chloroacetyl chloride (3.45 g, 30.6 mmol, 1.00 eq) were additionally added. After the addition, the reaction mixture was stirred at 20°C for 48 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was dissolved in EtOAc (150 mL) and water (100 mL). The organic phase was separated, and the aqueous phase was extracted once with EtOAc (100 mL). The combined organic phases were washed once with brine (50.0 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and concentrated to dryness to afford compound 1-2 (3.00 g, 13.6 mmol, 44.4% yield) as a white solid.

[0102] 1.2 Synthesis of Intermediates 1-3

[0103] Compound 1-2 (3.00 g, 14.7 mmol, 1.00 eq) and aminoacetaldehyde dimethyl acetal (3.25 g, 30.9 mmol, 3.37 mL, 2.10 eq) were dissolved in anhydrous toluene (30.0 mL) and heated to 115°C with stirring for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was cooled to 0-5°C, whereupon a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with EtOAc (30.0 mL). The filtrate was washed with brine (30.0 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to approximately 30.0 mL of solvent. The remaining organic phase was cooled to 0-5°C and adjusted to pH 2-3 with the dropwise addition of HCl / EtOAc (4 M). A large amount of solid precipitated. The mixture was filtered, the filter cake was washed with EtOAc (5.00 mL), and then drained to collect the solid. The solid was concentrated under reduced pressure to remove the solvent to obtain compound 1-3 (3.20 g, 9.78 mmol, yield 66.4%) as an off-white solid.

[0104] 1.3 Synthesis of Intermediates 1-4

[0105] Compound 1-3 (2.63 g, 8.52 mmol, 1.00 eq) was suspended in DCE (130 mL). MgSO₄ (2.05 g, 17.0 mmol, 2.00 eq) and MsOH (4.91 g, 51.1 mmol, 3.64 mL, 6.00 eq) were added. The reaction mixture was heated to 85°C and stirred for 3 hours. LCMS analysis confirmed the complete reaction of compound 3. The reaction mixture was cooled to 20°C, water (100 mL) was added, and the pH was adjusted to 9-10 with aqueous Na₂CO₃. Insoluble salts were removed by filtration, and the filter cake was washed with CH₂Cl₂ (150 mL) and water (100 mL). The filtrate was separated, and the aqueous phase was extracted twice with CH₂Cl₂ (150 mL). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to yield crude compound 1-4 (2.00 g) as a white solid.

[0106] 1.4. Synthesis of Compounds of Formula I

[0107] Compound 1-4 (1.49 g, 7.15 mmol, 1.00 eq) was dissolved in anhydrous THF (31 mL). LiAlH₄ (543 mg, 14.3 mmol, 2.00 eq) was added portionwise at 20°C. The reaction was heated to 66°C and stirred for 1 hour. LCMS analysis confirmed the desired product. Water (1.50 mL) was added dropwise to the reaction mixture under nitrogen, and the mixture was then dried. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0–96:4) to afford a yellow oil. The product was then preparatively isolated and lyophilized to afford compound 1. Chiral separation (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: (0.1% NH3H2O ​​EtOH); B%: 30%-30%, 4 min) afforded the compound of Formula I (retention time: 1.368 min, 275 mg, 1.39 mmol, 19.4% yield) as a white solid. 1 H NMR:(400MHz CDCl3)δ7.11(d,J=5.2Hz,1H),6.80(d,J=5.2Hz,1H),3.36-3.29(m,2H),3.07-2.90(m, 5H),2.83-2.80(m,1H),2.66-2.62(m,2H),2.54-2.48(m,1H).MS(ESI)m / z=195.1[M+H] + .

[0108] Example 2 Maleate Crystalline Form A of the Compound of Formula I

[0109] Approximately 1g of the compound of Formula I was weighed and added to a reaction flask. 10mL of isopropanol was added to dissolve the mixture. One equivalent of maleic acid was then added and allowed to react at room temperature, with real-time observation of crystallization. After solid precipitation, the reaction was maintained at 25°C for 30 minutes. The temperature was then raised to 50°C, stirred at this temperature for 2 hours, and then lowered to 25°C with stirring overnight. The reaction solution was filtered, and the filter cake was washed and dried to yield 1.44g of Form A, the maleate salt of the compound of Formula I, with a yield of 90.1% and a chemical purity of 99.86%. The XRPD pattern (Figure 1-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 1. TGA results (Figure 1-2) showed virtually no weight loss during heating from room temperature to 120°C. DSC results (Figure 1-2) revealed a melting endotherm around 177°C and an endothermic signal around 188°C. 1 H NMR results (Figures 1-3) indicate that the molar ratio of maleic acid to the compound of Formula I in Form A of the maleic acid compound of Formula I is 1:1, with no apparent organic solvent peak. DVS results (Figures 1-4) show that at 25°C, Form A of the maleic acid compound of Formula I exhibited an adsorption weight gain of approximately 0.18% at 95% RH, a weight gain of 0.03% at 80% RH, and a desorption weight loss of approximately 0.10% at 0% RH, indicating virtually no hygroscopicity. XRPD results before and after the DVS test (Figures 1-5) indicate that the sample exhibited no crystalline change. Based on these characterization results, Form A of the maleic acid compound of Formula I is an anhydrous crystalline form.

[0110] When the amount of maleic acid is 0.5 to 1.5 equivalents, maleate crystalline form A can be obtained, wherein the molar ratio of maleic acid to the compound of formula I is about 1:1.

[0111] Table 1 XRPD pattern analysis data of maleate salt form A of compound of formula I

[0112] Example 3 Phosphate Form A of the Compound of Formula I

[0113] Approximately 1g of the compound of Formula I was weighed and added to a reaction flask. 8mL of isopropanol was added. After dissolution, the temperature was raised to 50°C, and a mixture of 1 equivalent of phosphoric acid and 2mL of isopropanol was added dropwise. After the addition was complete, the reaction was incubated for 30 minutes, then heated to 80°C, stirred for 1 hour, and then cooled to 25°C and stirred overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 1.42g of an off-white solid product, Form A, phosphate salt of the compound of Formula I, in a yield of 94.4%. The chemical purity was 99.19%. The XRPD pattern (Figure 2-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 2. TGA results (Figure 2-2) showed little weight loss during heating from room temperature to 120°C. DSC results (Figure 2-2) revealed a melting endotherm at 228.9°C (peak temperature). 1H NMR results (Figures 2-3) show that there is no obvious organic solvent peak in the phosphate crystal form A of the compound of Formula I. Based on the above characterization results, it can be seen that the phosphate crystal form A is an anhydrous crystalline form.

[0114] Table 2 XRPD pattern analysis data of the phosphate salt of the compound of formula I, Form A

[0115] Example 4: Diphosphate Form A of the Compound of Formula I

[0116] Approximately 0.3 g of the compound of Formula I was weighed and added to a reaction flask. 1 mL of isopropanol was added. Once dissolved, the temperature was raised to 50°C, and a mixture of 6.0 equivalents of phosphoric acid and 1 mL of isopropanol was added dropwise. After the addition was complete, the reaction was incubated for 30 minutes, then heated to 80°C and stirred for 1 hour, then cooled to 25°C and stirred overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 0.6 g of the diphosphate salt of the compound of Formula I, Form A, in an off-white solid form, with a yield of 100%. The XRPD pattern (Figure 3-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 3. TGA results (Figure 3-2) showed virtually no weight loss during heating from room temperature to 120°C. DSC results (Figure 3-2) revealed a melting endotherm at 206.0°C (peak temperature).

[0117] Table 3 XRPD pattern analysis data of diphosphate salt of Formula I compound Form A

[0118] Example 5 Oxalate Form A of the Compound of Formula I

[0119] 200 mg of the compound of Formula I was weighed and placed in a 10 mL vial with 1.1 equivalents of oxalic acid. A predetermined amount of isopropanol was added and stirred at room temperature. The reaction solution gradually became viscous. The temperature was raised to 70°C and stirred for 1 hour, then cooled to room temperature and stirred overnight. The reaction solution was filtered, and the filter cake was washed and dried to yield 257 mg of the oxalate salt Form A of the compound of Formula I. The XRPD pattern (Figure 4-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 4. DSC results (Figure 4-2) revealed an endothermic signal at 220.9°C (peak temperature). TGA results (Figure 4-2) showed almost no weight loss before 120°C.

[0120] Table 4 XRPD pattern analysis data of the oxalate salt form A of the compound of formula I

[0121] Example 6 Mucic Acid Salt Form A of the Compound of Formula I

[0122] 100 mg of the compound of Formula I was weighed and placed in a 10 mL vial with 1.1 equivalents of mucic acid. Isopropyl acetate was added and stirred overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed and dried to yield 143 mg of the mucic acid salt, Form A, of the compound of Formula I with a chemical purity of 99.4%. The XRPD pattern (Figure 5-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 5. DSC results (Figure 5-2) revealed an endothermic signal at 171.5°C (peak temperature).

[0123] Table 5 XRPD pattern analysis data of the compound of formula I, mucic acid salt, form A

[0124] Example 7 Hydrobromide Form A of the Compound of Formula I

[0125] Weigh 200 mg of the compound of Formula I and 3.3 equivalents of hydrobromic acid into a 10 mL vial. Add a desired amount of isopropanol and stir overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed and dried to yield 280 mg of the hydrobromide salt of the compound of Formula I, Form A. The XRPD pattern (Figure 6-1) shows high crystallinity, with the positions of the characteristic peaks shown in Table 6. DSC results (Figure 6-2) reveal an endothermic signal at 284.1°C (peak temperature). TGA results (Figure 6-2) show no weight loss before 120°C.

[0126] Table 6 XRPD pattern analysis data of hydrobromide salt of compound of formula I Form A

[0127] Example 8 Fumarate Form A of the Compound of Formula I

[0128] 100 mg of the compound of Formula I and 1.1 equivalents of fumaric acid were weighed into a 10 mL vial. A predetermined amount of isopropyl alcohol was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 150 mg of the crystalline fumarate Form A of the compound of Formula I with a chemical purity of 100%. The XRPD pattern (Figure 7-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 7. The DSC results (Figure 7-2) revealed an endothermic signal at 191.9°C (peak temperature). The TGA results (Figure 7-2) showed almost no weight loss before 120°C.

[0129] Table 7 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form A

[0130] Example 9 Fumarate Form B of the Compound of Formula I

[0131] 100 mg of the compound of Formula I and 1.1 equivalents of fumaric acid were weighed into a 10 mL vial. A predetermined amount of isopropyl acetate was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 127 mg of Form B, a fumarate salt of the compound of Formula I, with a chemical purity of 99.5%. The XRPD pattern (Figure 8-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 8. DSC results (Figure 8-2) revealed endothermic signals at 172.1°C and 189.8°C (peak temperatures). TGA results (Figure 8-2) showed little weight loss before approximately 120°C.

[0132] Table 8 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form B

[0133] Example 10 L-tartrate salt of compound of formula I, Form A

[0134] 100 mg of the compound of Formula I and 1.1 equivalents of L-tartaric acid were weighed into a 10 mL vial. A predetermined amount of isopropyl acetate was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 127 mg of the L-tartrate salt, Form A, of the compound of Formula I with a chemical purity of 100%. The XRPD pattern (Figure 9-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 9. DSC results (Figure 9-2) revealed endothermic signals at 113.6°C, 136.8°C, and 202.8°C (peak temperatures). TGA results (Figure 9-2) showed a 1.1% weight loss at approximately 70°C.

[0135] Table 9 XRPD pattern analysis data of L-tartrate salt form A of Formula I compound

[0136] Example 11 Gallic acid salt of compound of formula I, Form A

[0137] 100 mg of the compound of Formula I and 1.1 equivalents of gallic acid were weighed into a 10 mL vial. A predetermined amount of methyl tert-butyl ether was added and stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed and dried to yield 137 mg of Form A gallate salt of the compound of Formula I with a chemical purity of 98.8%. The XRPD pattern (Figure 10-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 10. DSC results (Figure 10-2) revealed endothermic signals at 119.3°C, 183.9°C, and 233.4°C (peak temperatures). TGA results (Figure 10-2) showed a 3.7% weight loss at approximately 140°C.

[0138] Table 10 XRPD pattern analysis data of the gallate crystal form A of the compound of formula I

[0139] Example 12: p-Toluenesulfonate Crystalline Form A of the Compound of Formula I

[0140] 500 mg of the compound of Formula I and 1.1 equivalents of p-toluenesulfonic acid were weighed and placed in a 10 mL vial. A predetermined amount of isopropyl alcohol was added, and the mixture was heated to 60°C (bath temperature) and stirred for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed and dried to yield 620 mg of the p-toluenesulfonate salt of the compound of Formula I, Form A, with a chemical purity of 99.9%. The XRPD pattern (Figure 11-1) showed high crystallinity, with the positions of the characteristic peaks shown in Table 11. The DSC results (Figure 11-2) revealed an endothermic signal at 189.2°C (peak temperature). The TGA results (Figure 11-2) showed little weight loss before approximately 120°C.

[0141] Table 11 XRPD pattern analysis data of p-toluenesulfonic acid salt of Formula I Form A

[0142] Example 13: Hydrochloride Form A of the Compound of Formula I

[0143] Weigh 500 mg of the compound of Formula I and dissolve it in 4 ml of methanol. Then, add 5 equivalents of a 4 mol / L dioxane hydrochloride solution dropwise. Stir the mixture at room temperature for 1 hour, then heat to 50°C (bath temperature) and stir for 1 hour before cooling to room temperature. Filter, wash, and dry the filter cake to obtain 150 mg of the hydrochloride salt of the compound of Formula I with a chemical purity of 99.8%, which was then characterized. The XRPD pattern (Figure 12-1) shows high crystallinity, with the positions of the characteristic peaks shown in Table 12. DSC results (Figure 12-2) show no endothermic peaks before 250°C, but an exothermic signal at 278.4 (peak temperature). TGA results (Figure 12-2) show almost no weight loss before approximately 120°C.

[0144] Table 12 XRPD pattern analysis data of the hydrochloride salt form A of the compound of formula I

[0145] Experimental Example 1. Evaluation of the functional activity of synapses in vitro

[0146] 1. Test materials: Cells: cAMP Hunter TM CHO-K1 TAAR1 Gs cell line

[0147] Detection reagent: HitHunter cAMP Assay Detection Kit

[0148] Experimental instrument: PerkinElmer Envision TM Chemiluminescence signal detector

[0149] 2. Test method:

[0150] Cell treatment: cAMP Hunter cell line was cultured at 37°C, 5% CO2 until the confluence was 70-80%, and the cells were harvested and the cell density was adjusted to 1.5×10 4 Cells were plated at 20 μL in a white-walled 384-well microplate and incubated at 37°C, 5% CO2 overnight. Cell culture medium was discarded and 15 μL of 2:1 HBSS / 10mM Hepes:cAMP XS+Ab reagent was added to each well. The sample stock solution was diluted to 4X sample concentration using assay buffer according to a concentration gradient. 5 μL of 4X sample was added to each well and incubated at 37°C or room temperature for 30 or 60 minutes. 20 μL of cAMP XS+ED / CL mixed lysate was added to each well and incubated for 1 hour. 20 μL of cAMP XS+EA reagent was added to each well and incubated at room temperature for 3 hours. The assay was performed using PerkinElmer Envision TM The detector reads the chemiluminescent signal.

[0151] 3. Data Analysis:

[0152] EC was calculated using CBIS data analysis software (ChemInnovation, CA). 50 The percentage activity was calculated using the following formula: % activity = 100% x (average RLU of test sample - average RLU of solvent control) / (average RLU of maximum control - average RLU of solvent control). 50 The concentration of TAAR1 was 0.062 μM, showing good TAAR1 agonist activity.

[0153] Experimental Example 2. Pharmacokinetic Study in Rats

[0154] Rats: SD rats, weighing 200-250 g

[0155] Reagents: acetonitrile, MERCK; methanol, MERCK; formic acid, Sigma; tolbutamide, Sigma.

[0156] Instruments: water purifier, Millipore; electronic balance, METTLER TOLEDO; high-speed desktop centrifuge, Thermo; water bath constant temperature oscillator, Shanghai Yiheng Technology Co., Ltd.; vortex oscillator, Thermo; liquid chromatography-mass spectrometry, AB SCIEX.

[0157] Methods: SD rats were administered intravenously (IV) and orally (IG), with 3 SD rats in each group, and the compound of formula I was administered in DMSO and Tween 80 as the solvent. Dosage: 2 mg / kg for intravenous administration and 5 mg / kg for oral administration. Whole blood was collected at 0, 5 min (intravenous), 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, respectively. The whole blood was placed in a heparinized EP tube and centrifuged at 13500 rpm for 10 min to separate the plasma. After pretreatment, the plasma was analyzed by LC-MS / MS to determine the concentration of the analyte in the plasma. The results are shown in Table 13:

[0158] Table 13 Pharmacokinetic parameters of the compound of formula I after intravenous and oral administration in SD rats

[0159] The results showed that the compound of formula I had higher exposure and bioavailability after intravenous and oral administration in rats.

[0160] Experimental Example 3. In vivo efficacy study in mice

[0161] Mice: C57 mice, weighing 20-22 g

[0162] Reagents: Normal saline;

[0163] Instruments: Electronic balance, METTLER TOLEDO; TopScan monitoring system.

[0164] 3.1 Model Preparation: MK-801 can induce hyperactivity in mice and is commonly used in the preclinical evaluation of antipsychotic drugs. In this study, the model was established by administering a single intraperitoneal injection of MK-801 at a dose of 0.8 mg / kg to mice.

[0165] 3.2 Experimental Grouping: Mice were randomly divided into a model group and a Formula I compound group, with 10 animals in each group. See Table 14 for details.

[0166] Table 14 Animal grouping and drug administration

[0167] 3.3 Experimental method: Mice were randomly divided into groups. At the beginning of the experiment, the test sample was given by single gavage at the dose shown in Table 14 and then placed in an activity chamber. After 30 minutes, each mouse was intraperitoneally injected with 0.8 mg / kg MK-801 to establish the model and returned to the activity chamber. The TopScan monitoring system was used to record and analyze the activity distance (mm) of the mice after model establishment (i.e., within 30-60 minutes after administration).

[0168] 3.4 Observation indicators:

[0169] The TopScan monitoring system was used to record and analyze the distance (mm) of mice moving after model establishment (30-60 min after administration). The total distance of mice moving after model establishment (30-60 min after administration) was recorded.

[0170] 3.5 Statistical analysis

[0171] Graphpad 5.0 software was used for data analysis and processing. ANOVA test was used to compare the total distance of activity within 30-60 min between each drug-treated group and the model group. All tests were two-sided tests, and p < 0.05 indicated that the difference was statistically significant.

[0172] 3.6 Test results:

[0173] The test results showed that the total distance of animals in the Formula I compound group after modeling was 6493.12±6228.87 mm, which was significantly lower than the total distance of animals in the model group after modeling (63052.14±21618.80 mm) (p<0.05).

[0174] 3.7 Test Conclusion:

[0175] Under the experimental conditions, the compound of formula I (10 mg / kg) had a good inhibitory effect on the hyperactivity induced by MK801.

[0176] Test Example 4. Stability Study

[0177] The maleate salt crystalline form A of the compound of Formula I was subjected to stability studies under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated conditions (40°C / 75% RH). Samples were taken for XRPD characterization and HPLC testing at 7 and 15 days, respectively. The results are shown in Table 15 and Figure 13. The XRPD results showed that the maleate salt crystalline form A was stable under high temperature, high humidity, light, and accelerated conditions for 15 days, with no crystal transformation occurring. The HPLC results showed that the chemical purity of the maleate salt crystalline form A did not change significantly after 15 days of storage under high temperature, high humidity, light, and accelerated conditions. After 15 days of storage under light conditions, the sample was observed to turn slightly yellow.

[0178] Table 15 Stability study results of maleate crystal form A of compound of formula I

Claims

1. A pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is selected from citrate, succinate, maleate, fumarate, L-tartrate, gallate, mucate, phosphate, hydrochloride, oxalate, hydrobromide, sulfate, acetate, DL-lactate, ascorbate, hippurate, p-toluenesulfonate, diphosphate; preferably maleate, mucate, phosphate and oxalate, 2. Form A of the maleate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 14.49±0.2°, 14.72±0.2°, 16.26±0.2°, 17.81±0.2°, 19.58±0.2°, 24.03±0.2°, 25.84±0.2°, 29.72±0.2°; preferably at the following 2θ There are characteristic diffraction peaks at the following angles: 7.24±0.2°, 10.56±0.2°, 14.49±0.2°, 14.72±0.2°, 16.26±0.2°, 17.81±0.2°, 19.58±0.2°, 24.03±0.2°, 25.84±0.2°, 29.72±0.2°; the most preferred X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 1-1.

3. Form A of the phosphate of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 15.068±0.2°, 15.331±0.2°, 16.011±0.2°, 17.333±0.2°, 17.605±0.2°, 20.119±0.2°, 20.870±0.2°, 23.039±0.2°, 25.159±0.2°, 25.910±0.2°, 26.680±0.2°, 27.843±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ angles: 15.06 8±0.2°,15.331±0.2°,16.011±0.2°,17.333±0.2°,17.605±0.2°,20.119±0.2°,20.870±0.2°,21.161±0.2°,23.039±0.2°,25.159±0.2°,25.910±0.2°,26.680±0.2°,27.843±0.2°,28.681±0.2°,34.958±0.2°,35.302±0.2°; the X-ray powder diffraction pattern using Cu-Kα radiation is preferably as shown in Figure 2-1.

4. Form A of the diphosphate of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 11.029±0.2°, 12.607±0.2°, 14.362±0.2°, 14.849±0.2°, 15.635±0.2°, 18.139±0.2°, 19.187±0.2° , 20.687±0.2°, 21.808±0.2°, 22.432±0.2°, 22.715±0.2°, 23.294±0.2°, 23.533±0.2°, 24.283±0.2°, 24.788±0.2°, 28.295±0.2°; preferably having characteristic diffraction peaks at the following 2θ angles: 7.839±0.2° ,11.029±0.2°,12.607±0.2°,14.362±0.2°,14.849±0.2°,15.635±0.2°,17.454±0.2°,18.139±0.2°,19.187±0.2°,19.773±0.2°,20.369±0.2°,20.687±0.2°,21 .049±0.2°,21.808±0.2°,22.432±0.2°,22.715±0.2°,23.294±0.2°,23.533±0.2°,24.283±0.2°,24.788±0.2°,28.295±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 3-1.

5. Form A of the oxalate of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 13.162±0.2°, 15.072±0.2°, 15.802±0.2°, 17.833±0.2°, 19.498±0.2°, 21.088±0.2°, 23.168±0.2°, 24.677±0.2°, 26.481±0.2°, 28.805±0.2°, 32.226±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ angles : 13.162±0.2°, 15.072±0.2°, 15.802±0.2°, 17.833±0.2°, 19.498±0.2°, 20.323±0.2°, 21.088±0.2°, 23.168±0.2°, 24.677±0.2°, 26.481±0.2°, 27.082±0.2°, 28.805±0.2°, 32.002±0.2°, 32.226±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 4-1.

6. Form A of the mucic acid salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 12.975±0.2°, 13.451±0.2°, 14.739±0.2°, 15.310±0.2°, 16.171±0.2°, 17.231±0.2°, 17.743±0.2°, 18.123±0.2°, 18.470±0.2°, 1 9.647±0.2°, 21.511±0.2°, 22.794±0.2°, 24.854±0.2°, 26.852±0.2°, 29.702±0.2°, 30.758±0.2°, 34.460±0.2°, 34.869±0.2°, 36.684±0.2°, 37.671±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 5-1.

7. Form A of the hydrobromide salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 11.515±0.2°, 14.871±0.2°, 16.925±0.2°, 17.475±0.2°, 19.359±0.2°, 21.082±0.2°, 21.462±0.2°, 21.974±0.2°, 23.566±0.2°, 6-1; the X-ray powder diffraction pattern using Cu-Kα radiation is preferably as shown in Figure 6-1.

8. Form A of the fumarate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 10.588±0.2°, 13.403±0.2°, 14.031±0.2°, 15.720±0.2°, 16.342±0.2°, 20.889±0.2°, 20.927±0.2°, 21.435±0.2°, 23.386±0.2°; preferably at the following 2θ angles There are characteristic diffraction peaks: 10.588±0.2°, 13.403±0.2°, 14.031±0.2°, 15.720±0.2°, 16.342±0.2°, 20.213±0.2°, 20.889±0.2°, 20.927±0.2°, 21.435±0.2°, 23.386±0.2°, 23.565±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 7-1.

9. Form B of the fumarate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 12.504±0.2°, 14.689±0.2°, 15.041±0.2°, 15.688±0.2°, 16.052±0.2°, 16.612±0.2°, 17.462±0.2°, 19.747±0.2°, 20.109±0.2°, 8-1; the X-ray powder diffraction pattern using Cu-Kα radiation is preferably as shown in Figure 8-1.

10. Form A of the L-tartrate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 12.107±0.2°, 12.962±0.2°, 16.817±0.2°, 17.082±0.2°, 17.924±0.2°, 18.137±0.2°, 19.137±0.2°, 19.494±0.2° ,20.731±0.2°,21.967±0.2°,22.675±0.2°,23.839±0.2°,24.767±0.2°,26.220±0.2°,26.901±0.2°,27.240±0.2°,28.888±0.2°,37.559±0.2°; the X-ray powder diffraction pattern using Cu-Kα radiation is preferably shown in Figure 9-1.

11. Form A of the gallic acid salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 10.879±0.2°, 14.571±0.2°, 15.170±0.2°, 15.469±0.2°, 16.567±0.2°, 17.325±0.2°, 20.016±0.2°, 20.569±0.2°, 21.770±0.2°, 23.480±0.2°, 24.012±0.2°, 24.414±0.2°, 26.181±0.2°, 27.498±0.2°, 27.850±0.2°; preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 10-1.

12. The crystalline form A of the p-toluenesulfonate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.845±0.2°, 13.526±0.2°, 14.080±0.2°, 17.124±0.2°, 19.848±0.2°, 20.209±0.2°, 20.780±0.2°, 23.534±0.2°, 25.368±0.2°, 27.328±0.2°; preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 11-1.

13. Form A of the hydrochloride of the compound of formula I, in an X-ray powder diffraction pattern using Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ angles: 11.893±0.2°, 15.339±0.2°, 16.680±0.2°, 17.444±0.2°, 22.389±0.2°, 25.024±0.2°, 25.609±0.2°, 26.987±0.2°, 28.243±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 11.893±0.2° , 15.339±0.2°, 16.680±0.2°, 17.444±0.2°, 17.676±0.2°, 21.356±0.2°, 21.821±0.2°, 22.389±0.2°, 25.024±0.2°, 25.609±0.2°, 26.987±0.2°, 28.243±0.2°, 28.931±0.2°, 31.150±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 12-1.

14. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 1 or the crystalline form according to any one of claims 2 to 13, and a pharmaceutically acceptable carrier.

15. Use of the pharmaceutically acceptable salt according to claim 1, the crystal form according to any one of claims 2 to 13, or the pharmaceutical composition according to claim 14 in the preparation of a TAAR1 agonist drug.

16. Use of the pharmaceutically acceptable salt according to claim 1, the crystal form according to any one of claims 2 to 13, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating central nervous system-related diseases or symptoms, cardiovascular or metabolic diseases.

17. The use according to claim 16, wherein the central nervous system disease or disorder comprises: Schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic disorder, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, mental disorder, brief psychotic disorder, shared psychotic disorder, mental disorder due to physical illness, drug-induced psychosis, psycho-affective disorder, aggressive psychosis, Parkinson psychosis, irritant psychosis, Tourette syndrome, organic or NOS psychosis, epilepsy, seizure, agitation, post-traumatic stress disorder, behavioral disturbances, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, affective disorder, anxiety disorder, affective psychosis, obsessive-compulsive disorder, vertigo, pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, psychoactive substance abuse, stress-related disorders.

18. The use according to claim 17, wherein the affective psychosis comprises: Depression, major depressive disorder and dysthymia, bipolar disorder, bipolar depression, mania, seasonal affective disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD); the pain includes: neuropathic pain, neuropathic pain-prone state, inflammatory pain; the stress-related disorders include: acute stress disorder, post-traumatic stress disorder, adjustment disorder.

19. The use according to claim 16, wherein the cardiovascular or metabolic disease comprises: Diabetes, diabetic complications, obesity, dyslipidemia, hypertension.

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