CN113861183A - Salts of substituted pyrimidinylpiperazine compounds and uses thereof - Google Patents

Abstract

The present invention relates to salts of substituted pyrimidinylpiperazine compounds and their use. The invention also relates to a pharmaceutical composition containing the salt and application of the salt or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, in particular depression.

Description

Salts of substituted pyrimidinylpiperazine compounds and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a salt of a substituted pyrimidine piperazine compound and application thereof, in particular to a salt of 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylthiazole-5-formamide, a crystal form of the salt and application thereof, and further relates to a pharmaceutical composition containing the salt or the crystal form and application thereof.

Background

5-hydroxytryptamine, a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. Antagonism or agonism of certain types of 5-hydroxytryptamine receptors can be effective in modulating central nervous system dysfunction. 5-HT_1AThe receptor, a G protein-coupled receptor, is widely distributed in the region where 5-hydroxytryptamine derived from the nucleus of the midrift is accepted, and includes: frontal cortex, lateral septum, amygdala, hippocampus, and hypothalamus. In these cortical marginal regions, 5-HT_1ALocated in the postsynaptic membrane. At the same time, 5-HT_1AReceptors are also presynaptic membrane autoreceptors on the nucleus of the raphe, which reduce the firing rate of neurons (i.e., the amount of 5-hydroxytryptamine released per action potential), as well as the synthesis of neurotransmitters, which in turn reduce the activity of 5-hydroxytryptamine in the projection zone. 5-HT activating presynaptic Membrane_1AThe receptor can inhibit the synthesis of tyrosine hydroxylase and the activity of glutamate channel (generated in medial prefrontal cortex and pointing to the raphe nucleus), thereby indirectly reducing the transport of 5-hydroxytryptamine (Jonathan Savitz, Irwin Lucki, Wayne C.Drevets.5-HT)_1A receptor function in major depressive disorder.Prog Neurobiol.2009,88(1):17-31)。

Of all indications associated with 5-hydroxytryptamine dysfunction, depression is the most harmful to human health. According to the report of Depression and Other Common Mental Disorders issued by the World Health Organization (WHO) in 2017, more than 3 hundred million people are expected to suffer from Depression worldwide, and the global average incidence rate is about 4.4%.

The traditional selective 5-hydroxytryptamine reuptake inhibitor SSRIs treats depression by increasing the level of 5-hydroxytryptamine by inhibiting reuptake of 5-hydroxytryptamine and regulating its transport. However, after SSRIs, 5-HT of presynaptic membrane is also activated_1AThe autoreceptor causes the release amount of 5-hydroxytryptamine to be reduced, and the concentration of 5-hydroxytryptamine among synapses is reduced. However, SSRIs cause 5-HT with prolonged dosing time_1AThe autoreceptor is desensitized, and the activation effect is restrained, so that the normal regulation effect is exerted. From this it is concluded that for 5-HT_1AThe activation of autoreceptors is a major reason for The delay in The onset of action of SSRIs (Celada P, Pu M, Amargos-Bosch M, et al, The therapeutic role of 5-HT_1A and 5-HT_2Areceptors in the expression. J Psychiatry Neurosci,2004,29(4): 252-65). Thus, overcoming 5-HT_1AThe negative feedback effect of the autoreceptor antagonist has the prospect of enhancing and accelerating clinical antidepressant.

5-HT in contrast to SSRis_1AReceptor agonists or partial agonists act directly on the postsynaptic 5-hydroxytryptamine receptor to increase 5-hydroxytryptamine neurotransmission during the incubation period of SSRI. Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT_1APartial agonists (Feiger, A. Psychopharmacol. Bull.1996,32: 659-65). Addition of buspirone to standard SSRI treatment resulted in significant improvement in patients who previously failed to respond to standard treatment for depression (Dimitriou, e.j. clin. psychopharmacol.,1998,18: 465-9).

Different salts or different solid forms of the pharmaceutically active ingredient may have different properties. Different salts and/or solid forms may differ significantly in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and may also have different effects on the stability, bioavailability, therapeutic efficacy, etc. of the drug. Therefore, in drug development, the problem of salt form and/or solid form of the drug should be fully considered.

International application WO 2019062662A 1 discloses the compound 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylThiazole-5-carboxamides (compounds of formula (I)) having selective 5-hydroxytryptamine reuptake inhibiting activity and/or 5-HT_1AThe receptor has the activity of stimulating and has potential antidepressant effect. However, none of the salts of the compound or its crystalline forms are disclosed in the prior art.

Disclosure of Invention

The inventors have found through extensive experimental studies that the compounds do not necessarily form stable salts when reacted with different acids, for example, the compounds of formula (I) do not form salts when reacted with acids commonly used in the art, such as maleic acid, citric acid, benzoic acid, etc.; however, compounds of formula (I) can form salts with hydrochloric, nitric, hydrobromic, methanesulfonic, oxalic, fumaric and malic acids such as L-malic acid; in addition, the hydrochloride, the L-malate, the methanesulfonate and the crystal forms thereof obtained by combining the compound with hydrochloric acid, L-malic acid and methanesulfonic acid can be greatly improved in properties in all aspects, and particularly the crystal forms B, L-malate crystal form A and the methanesulfonate crystal form A of the hydrochloride have better properties such as pharmacokinetics, stability and the like. Therefore, the hydrochloride crystal form B, L-malate crystal form A and/or mesylate crystal form A of the compound shown in the formula (I) are better in property, have better pharmacokinetic property and have better pharmaceutical property.

In particular, the invention relates to a salt of a compound shown in formula (I), and application of the salt of the compound or a pharmaceutical composition containing the salt in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, particularly depression. The salt provided by the invention is hydrochloride, L-malate or methanesulfonate. Further, the salt provided by the invention is a hydrochloride crystal form A, a hydrochloride crystal form B, L-malate crystal form A or a mesylate crystal form A. The crystalline forms of the present invention may also be in the form of a solvate, such as a hydrate, or a DMF solvate.

In one aspect, the invention provides a salt of a compound of formula (I),

in some embodiments, the salt of the invention is a hydrochloride, malate, such as L-malate, mesylate, oxalate, fumarate, hydrobromide or nitrate.

In some embodiments, the salt of the compound of formula (I) of the present invention is the hydrochloride salt thereof.

In some embodiments, the salt of the invention is a hydrochloride salt of a compound of formula (I), wherein the hydrochloride salt is hydrochloride form a or hydrochloride form B.

In other embodiments, the hydrochloride form a of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °,26.99 ° ± 0.2 °.

In other embodiments, the hydrochloride form a of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,16.63 ° ± 0.2 °,16.95 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.26 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,22.44 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °,26.99 ° ± 0.2 °,28.30 ° ± 0.2 °,31.69 ° ± 0.2 °.

In other embodiments, the hydrochloride form a of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,16.63 ° ± 0.2 °,16.95 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.26 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,22.44 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °, 0.99 ° ± 0.2 °,28.30 ° ± 0.2 °,29.00 ° ± 0.2 °,30.09 ° ± 0.2 °,36 31.69 ° ± 0.45 ° ± 0.33 ° ± 0.2.2 °, 3645 ° ± 0.2 ° ± 0.670.82 ° ± 0.82 °.

In still other embodiments, the hydrochloride form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 1.

In other embodiments, a differential scanning calorimetry trace of form A of the hydrochloride salt of the present invention comprises endothermic peaks at 170.92 ℃ ± 3 ℃ and 306.24 ℃ ± 3 ℃.

In still other embodiments, the hydrochloride salt form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 2.

In other embodiments, the hydrochloride form B of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,19.93 ° ± 0.2 °,24.25 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °.

In other embodiments, the hydrochloride form B of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,15.88 ° ± 0.2 °,16.10 ° ± 0.2 °,19.03 ° ± 0.2 °,19.30 ° ± 0.2 °,19.93 ° ± 0.2 °,24.25 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °,36.93 ° ± 0.2 °.

In other embodiments, the hydrochloride form B of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,15.88 ° ± 0.2 °,16.10 ° ± 0.2 °,19.03 ° ± 0.2 °,19.30 ° ± 0.2 °,19.93 ° ± 0.2 °,21.20 ° ± 0.2 °,21.40 ° ± 0.2 °,24.25 ° ± 0.2 °,24.48 ° ± 0.2 °,25.65 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °,36.93 ° ± 0.2 °.

In still other embodiments, the hydrochloride form B of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 3.

In other embodiments, a differential scanning calorimetry trace of form B of the hydrochloride salt of the present invention comprises endothermic peaks at 167.25 ℃ ± 3 ℃ and 304.20 ℃ ± 3 ℃.

In still other embodiments, a differential scanning calorimetry trace of form B of the hydrochloride salt of the present invention comprises endothermic peaks at 83.55 ℃ ± 3 ℃, 167.25 ℃ ± 3 ℃ and 304.20 ℃ ± 3 ℃.

In still other embodiments, the hydrochloride salt form B of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 4.

In some embodiments, the salt of the compound of formula (I) of the present invention is the L-malate salt thereof.

In some embodiments, the salt of the compound of formula (I) according to the present invention is an L-malate salt thereof, wherein the L-malate salt is L-malate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 6.72 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,27.46 ° ± 0.2 °.

In other embodiments, the L-malate form a of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.72 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,17.18 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,26.66 ° ± 0.2 °,27.15 ° ± 0.2 °,27.46 ° ± 0.2 °.

In other embodiments, the L-malate form a of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.72 ° ± 0.2 °,10.82 ° ± 0.2 °,13.48 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,17.18 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,20.27 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,25.34 ° ± 0.2 °,25.88 ° ± 0.2 °,26.66 ° ± 0.2 °,27.15 ° ± 0.2 °,27.46 ° ± 0.2 °,28.54 ° ± 0.2 °,29.34 ° ± 0.2 °,30.50 ° ± 0.2 °,35.00 ° ± 0.2 °.

In still other embodiments, the L-malate form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 5.

In other embodiments, the differential scanning calorimetry trace of form a of the L-malate salt of the present invention comprises an endothermic peak at 207.30 ℃ ± 3 ℃.

In still other embodiments, the L-malate form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 6.

In some embodiments, the salt of the compound of formula (I) of the present invention is a mesylate salt thereof.

In some embodiments, the salt of the compound of formula (I) according to the present invention is a mesylate salt thereof, wherein the mesylate salt is mesylate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.52 degrees +/-0.2 degrees, 9.10 degrees +/-0.2 degrees, 10.43 degrees +/-0.2 degrees, 12.55 degrees +/-0.2 degrees, 14.97 degrees +/-0.2 degrees, 15.40 degrees +/-0.2 degrees, 17.02 degrees +/-0.2 degrees, 25.61 degrees +/-0.2 degrees and 26.57 degrees +/-0.2 degrees.

In other embodiments, the mesylate salt form a of the invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.52 ° ± 0.2 °,9.10 ° ± 0.2 °,10.43 ° ± 0.2 °,12.55 ° ± 0.2 °,14.97 ° ± 0.2 °,15.40 ° ± 0.2 °,17.02 ° ± 0.2 °,18.85 ° ± 0.2 °,19.27 ° ± 0.2 °,21.60 ° ± 0.2 °,22.47 ° ± 0.2 °,25.61 ° ± 0.2 °,26.57 ° ± 0.2 °,27.24 ° ± 0.2 °.

In other embodiments, the mesylate salt form a of the invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.52 ° ± 0.2 °,9.10 ° ± 0.2 °,10.43 ° ± 0.2 °,12.55 ° ± 0.2 °,14.97 ° ± 0.2 °,15.40 ° ± 0.2 °,17.02 ° ± 0.2 °,18.85 ° ± 0.2 °,19.27 ° ± 0.2 °,21.60 ° ± 0.2 °,22.47 ° ± 0.2 °,23.44 ° ± 0.2 °,24.25 ° ± 0.2 °,24.99 ° ± 0.2 °,25.61 ° ± 0.2 °,26.57 ° ± 0.2 °,27.24 ° ± 0.2 °,29.41 ° ± 0.2 °,33.32 ° ± 0.2 °,38.04 ° ± 0.2 °.

In still other embodiments, the mesylate salt form a of the invention has an X-ray powder diffraction pattern substantially as shown in figure 7.

In other embodiments, the differential scanning calorimetry trace of form A of the mesylate salt of the invention comprises an endothermic peak at 293.25 ℃ ± 3 ℃.

In still other embodiments, the mesylate salt form a of the invention has a differential scanning calorimetry pattern substantially as shown in figure 8.

In some embodiments, the salt of the compound of formula (I) of the present invention is an oxalate salt thereof.

In some embodiments, the salt of the compound represented by formula (I) according to the present invention is an oxalate salt thereof, wherein the oxalate salt is oxalate form a, and the X-ray powder diffraction pattern of the oxalate form a has diffraction peaks at the following 2 θ angles: 5.11 ° ± 0.2 °,8.25 ° ± 0.2 °,10.13 ° ± 0.2 °,12.37 ° ± 0.2 °,13.75 ° ± 0.2 °,15.34 ° ± 0.2 °,19.71 ° ± 0.2 °,21.17 ° ± 0.2 °,21.69 ° ± 0.2 °,22.20 ° ± 0.2 °,23.02 ° ± 0.2 °,23.57 ° ± 0.2 °,23.93 ° ± 0.2 °,24.62 ° ± 0.2 °.

In other embodiments, the crystalline form a of the oxalate salt of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.11 ° ± 0.2 °,8.25 ° ± 0.2 °,10.13 ° ± 0.2 °,12.37 ° ± 0.2 °,13.75 ° ± 0.2 °,15.34 ° ± 0.2 °,19.71 ° ± 0.2 °,21.17 ° ± 0.2 °,21.69 ° ± 0.2 °,22.20 ° ± 0.2 °,23.02 ° ± 0.2 °,23.57 ° ± 0.2 °,23.93 ° ± 0.2 °,24.62 ° ± 0.2 °,27.71 ° ± 0.2 °.

In other embodiments, the crystalline form a of the oxalate salt of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.11 ° ± 0.2 °,8.25 ° ± 0.2 °,10.13 ° ± 0.2 °,12.37 ° ± 0.2 °,13.75 ° ± 0.2 °,15.34 ° ± 0.2 °,16.47 ° ± 0.2 °,17.56 ° ± 0.2 °,18.08 ° ± 0.2 °,18.31 ° ± 0.2 °,19.39 ° ± 0.2 °,19.71 ° ± 0.2 °,20.13 ° ± 0.2 °,21.17 ° ± 0.2 °,21.69 ° ± 0.2 °,22.20 ° ± 0.2 °,23.02 ° ± 0.2 °,23.57 ° ± 0.2 °,24.62 ° ± 0.2 °,25.68 ° ± 0.2 °,25.95 ° ± 0.26.28 ° ± 0.26 ° ± 0.2.26 ° ± 0.2 ± 0.27 ° ± 0.2 °, 25.27 ° ± 0.2 °, 25.26 ° ± 0.27 ° ± 0.2 °, 25.27 ° ± 0.2 °, 25.2 °,25.95 ° ± 0.9 ° ± 0.27 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.27 ° ± 0.9 ° ± 0.2.9 ° ± 0.9 ° ± 0.2 °, 2.2.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2.9 ° ± 0.27 ° ± 0.2.9 ° ± 0.9 ° ± 0.2.2 °, 2.2.9 ° ± 0.2.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2.2.2.2.2.2 °, 2.2.2.2.2.2.2.2 °, 2.9 ° ± 0.9 ° ± 0.2.9 ° ± 0.9 ° ± 0.2.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2.9 ° ±.

In still other embodiments, the oxalate form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 9.

In other embodiments, a differential scanning calorimetry trace of form A of the oxalate salt of the invention comprises endothermic peaks at 174.62 ℃ ± 3 ℃ and 234.98 ℃ ± 3 ℃.

In still other embodiments, the oxalate form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 10.

In some embodiments, the salt of the compound of formula (I) of the present invention is a fumarate salt thereof.

In some embodiments, the salt of the compound of formula (I) according to the present invention is a fumarate salt thereof, wherein the fumarate salt is fumarate form a, and the X-ray powder diffraction pattern of fumarate form a has diffraction peaks at the following 2 Θ angles: 6.28 ° ± 0.2 °,12.60 ° ± 0.2 °,14.37 ° ± 0.2 °,15.07 ° ± 0.2 °,18.08 ° ± 0.2 °,20.25 ° ± 0.2 °,22.72 ° ± 0.2 °,23.80 ° ± 0.2 °,25.09 ° ± 0.2 °,26.19 ° ± 0.2 °,27.84 ° ± 0.2 °.

In other embodiments, the fumarate salt form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.28 ° ± 0.2 °,10.95 ° ± 0.2 °,12.60 ° ± 0.2 °,14.37 ° ± 0.2 °,15.07 ° ± 0.2 °,16.58 ° ± 0.2 °,16.71 ° ± 0.2 °,18.08 ° ± 0.2 °,20.25 ° ± 0.2 °,22.72 ° ± 0.2 °,23.80 ° ± 0.2 °,25.09 ° ± 0.2 °,26.19 ° ± 0.2 °,27.84 ° ± 0.2 °.

In other embodiments, the fumarate salt form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.28 ° ± 0.2 °,10.95 ° ± 0.2 °,12.60 ° ± 0.2 °,14.37 ° ± 0.2 °,15.07 ° ± 0.2 °,16.58 ° ± 0.2 °,16.71 ° ± 0.2 °,18.08 ° ± 0.2 °,19.11 ° ± 0.2 °,19.78 ° ± 0.2 °,20.25 ° ± 0.2 °,21.59 ° ± 0.2 °,22.72 ° ± 0.2 °,23.80 ° ± 0.2 °,25.09 ° ± 0.2 °,25.37 ° ± 0.2 °,26.19 ° ± 0.2 °,27.84 ° ± 0.2 °,28.94 ° ± 0.2 °,29.90 ° ± 0.2 °.

In still other embodiments, the fumarate salt form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 11.

In other embodiments, the differential scanning calorimetry trace of form a of the fumarate salt of the present invention comprises an endothermic peak at 224.95 ℃ ± 3 ℃.

In still other embodiments, the fumarate salt form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 12.

In some embodiments, the salt of the compound of formula (I) of the present invention is a hydrobromide salt thereof.

In some embodiments, the salt of the compound of formula (I) of the present invention is a hydrobromide salt, wherein the hydrobromide salt is hydrobromide form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.58 ° ± 0.2 °,9.60 ° ± 0.2 °,12.62 ° ± 0.2 °,14.26 ° ± 0.2 °,16.82 ° ± 0.2 °,17.59 ° ± 0.2 °,23.10 ° ± 0.2 °,24.65 ° ± 0.2 °,28.80 ° ± 0.2 °.

In other embodiments, the hydrobromide form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.58 ° ± 0.2 °,9.60 ° ± 0.2 °,11.30 ° ± 0.2 °,12.62 ° ± 0.2 °,14.26 ° ± 0.2 °,16.82 ° ± 0.2 °,17.59 ° ± 0.2 °,18.57 ° ± 0.2 °,19.18 ° ± 0.2 °,21.46 ° ± 0.2 °,23.10 ° ± 0.2 °,24.65 ° ± 0.2 °,28.80 ° ± 0.2 °.

In other embodiments, the hydrobromide form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.58 ° ± 0.2 °,9.60 ° ± 0.2 °,11.30 ° ± 0.2 °,12.62 ° ± 0.2 °,14.26 ° ± 0.2 °,16.82 ° ± 0.2 °,17.59 ° ± 0.2 °,18.57 ° ± 0.2 °,19.18 ° ± 0.2 °,19.76 ° ± 0.2 °,21.46 ° ± 0.2 °,23.10 ° ± 0.2 °,24.65 ° ± 0.2 °,25.13 ° ± 0.2 °,26.59 ° ± 0.2 °,28.13 ° ± 0.2 °,28.80 ° ± 0.2 °,29.93 ° ± 0.2 °,31.64 ° ± 0.2 °,33.03 ° ± 0.2 °,34.84 ° ± 0.2 °,35.23 ° ± 0.2 °,36.52 ° ± 0.2 °.

In still other embodiments, the crystalline form a of the hydrobromide salt of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 13.

In other embodiments, the differential scanning calorimetry trace of form A of the hydrobromide salt of the present invention comprises endothermic peaks at 191.81 ℃ ± 3 ℃ and 305.80 ℃ ± 3 ℃.

In still other embodiments, the hydrobromide form a of the invention has a differential scanning calorimetry trace substantially as shown in figure 14.

In some embodiments, the salt of the compound of formula (I) of the present invention is a nitrate salt thereof.

In some embodiments, the salt of the compound of formula (I) according to the present invention is a nitrate salt thereof, wherein the nitrate salt is nitrate salt form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 12.17 ° ± 0.2 °,14.30 ° ± 0.2 °,16.36 ° ± 0.2 °,18.27 ° ± 0.2 °,18.47 ° ± 0.2 °,18.78 ° ± 0.2 °,26.59 ° ± 0.2 °,32.03 ° ± 0.2 °.

In other embodiments, the nitrate form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 12.17 ° ± 0.2 °,14.30 ° ± 0.2 °,16.36 ° ± 0.2 °,18.27 ° ± 0.2 °,18.47 ° ± 0.2 °,18.78 ° ± 0.2 °,21.32 ° ± 0.2 °,21.78 ° ± 0.2 °,25.99 ° ± 0.2 °,26.59 ° ± 0.2 °,32.03 ° ± 0.2 °.

In other embodiments, the nitrate form a of the present invention has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 12.17 ° ± 0.2 °,14.30 ° ± 0.2 °,16.36 ° ± 0.2 °,18.27 ° ± 0.2 °,18.47 ° ± 0.2 °,18.78 ° ± 0.2 °,21.32 ° ± 0.2 °,21.78 ° ± 0.2 °,25.99 ° ± 0.2 °,26.59 ° ± 0.2 °,26.87 ° ± 0.2 °,28.01 ° ± 0.2 °,30.80 ° ± 0.2 °,32.03 ° ± 0.2 °.

In still other embodiments, the nitrate form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 15.

In other embodiments, the differential scanning calorimetry trace of form A nitrate according to the invention comprises endothermic peaks at 147.26 ℃ ± 3 ℃ and 262.60 ℃ ± 3 ℃.

In still other embodiments, the nitrate form a of the present invention has a differential scanning calorimetry trace substantially as shown in figure 16.

In another aspect, the invention relates to a pharmaceutical composition comprising any one of the salts or any one of the crystal forms of the salt of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

In one aspect, the invention relates to the use of said salt or a crystalline form thereof or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.

In some such embodiments, the central nervous system disorder of the present invention includes, but is not limited to, depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, or premenstrual tension syndrome.

In another aspect, the invention relates to the use of said salt or a crystalline form thereof or said pharmaceutical composition for the preparation of a medicament useful as a selective 5-hydroxytryptamine reuptake inhibitor and/or 5-HT_1AA receptor agonist.

In one aspect, the invention also relates to a preparation method of the salt and/or crystal form of the compound shown in the formula (I).

The solvent used in the method for producing the salt and/or crystal form of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.

The experiments for the preparation of the salts or crystalline forms according to the invention are described in detail in the examples section. Meanwhile, the invention provides property test experiments of the salt or the crystal form, such as pharmacokinetic experiments, solubility experiments, stability experiments, hygroscopicity experiments and the like. Experiments prove that the hydrochloride crystal form B, L-malate crystal form A and/or mesylate crystal form A have unexpected technical advantages: for example, the solubility of the hydrochloride form B, L-malate form a and/or mesylate form a of the present invention is high; as another example, the hydrochloride form B, L-malate form a and/or mesylate form a of the present invention has higher blood concentration and exposure in dogs, thereby having better pharmacokinetic properties; for another example, the hydrochloride form B, L-malate form a and/or mesylate form a of the present invention has good stability, for example, the stability of the form in water is good: stirring the crystal form structure in water.

Therefore, the hydrochloride crystal form B, L-malate crystal form A and/or the mesylate crystal form A have high solubility, better biological activity and higher stability, and are more suitable for pharmaceutical use.

Definitions and general terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.

"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, ethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on a surface and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, N-butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, N-heptane, N-hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, ethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.

Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.

Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program₂O₃) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" 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 in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.

When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.

The present invention relates to salts of the compounds of formula (I) and/or crystalline forms thereof, which exist in substantially pure crystalline form.

By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern (XRPD).

In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.

"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃,25 ℃, 27.5 ℃, and the like.

Compositions, formulations, administration and uses of the salts or crystalline forms thereof of the invention

The pharmaceutical composition of the invention is characterized by comprising a salt of the compound shown in the formula (I) and/or a crystal form thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the salt of the compound or crystalline form thereof in the pharmaceutical composition of the present invention is effective to detectably treat or reduce central nervous system dysfunction in a patient. The pharmaceutical compositions of the present invention may also optionally comprise other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Carriers of the known art and their use are within the scope of the present invention except for any commonly used carrier which is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any of the other ingredients of a pharmaceutically acceptable composition.

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In another aspect, the present invention relates to a process for the preparation of a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof; the process includes mixing the various ingredients. Pharmaceutical compositions comprising a salt of a compound of the invention, or a crystalline form thereof, may be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

The compounds of the present invention or salts thereof are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention.

In one embodiment, a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered orally. In another embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered by inhalation. In yet another embodiment, a salt of a compound of the invention or a salt comprising a compound of the invention may be administered intranasally.

In one embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention depend on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the salt of the compound of the invention or of the pharmaceutical composition comprising the salt of the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.

Salts of the compounds of the present invention may be administered concurrently with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in pharmaceutical compositions therewith.

For an individual of about 50-70kg, the pharmaceutical compositions and combinations of the present invention may be in unit dosage form containing about 1-1000mg, or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, salt of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.

In one embodiment, the amount of the compound in a therapeutically effective dose of a salt of a compound of the invention is from about 0.1mg to about 2,000mg per day, and the pharmaceutical composition thereof should provide a dose of the compound of from about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, or from about 10mg to about 1,000mg of the principal active ingredient or combination of principal ingredients per dosage unit form.

The salts and pharmaceutical compositions of the compounds provided by the invention can be used for preparing medicaments for preventing, treating or alleviating central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicaments for inhibiting 5-hydroxytryptamine reuptake and/or exciting 5-HT_1AA pharmaceutical product of a recipient.

In particular, the amount of compound in the compositions of the present invention is effective to detectably selectively inhibit the reuptake of 5-hydroxytryptamine and to 5-HT_1AThe receptor has an agonistic effect, and the salts of the compounds of the present invention are useful as agents for treating Central Nervous System (CNS) disorders such as depression, anxiety in humans.

Salts of the compounds of the present invention may be used, but are in no way limited to, in preventing, treating or alleviating central nervous system dysfunctional disorders by administering to a patient an effective amount of a salt or composition of the compounds of the present invention. The dysfunctional central nervous system diseases responsive to 5-hydroxytryptamine receptor modulation further include, but are not limited to, depression, anxiety, mania, schizophrenia, sleep disorders, bipolar disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, Parkinson's disease, Huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, premenstrual tension syndrome, and the like.

Salts and pharmaceutical compositions of the compounds of the invention are useful in veterinary therapy for pets, animals of the introductory variety and mammals in farm animals, in addition to human therapy. Examples of other animals include horses, dogs, and cats.

Drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of the hydrochloride form a of the compound of formula (I).

FIG. 2 is a Differential Scanning Calorimetry (DSC) chart of hydrochloride form A of the compound of formula (I).

Figure 3 is an X-ray powder diffraction (XRPD) pattern of crystalline form B of the hydrochloride salt of the compound of formula (I).

FIG. 4 is a Differential Scanning Calorimetry (DSC) profile of the hydrochloride form B of the compound of formula (I).

Figure 5 is an X-ray powder diffraction (XRPD) pattern of L-malate form a of compound of formula (I).

FIG. 6 is a Differential Scanning Calorimetry (DSC) profile of the L-malate salt form A of the compound of formula (I).

Figure 7 is an X-ray powder diffraction (XRPD) pattern of the mesylate salt form a of the compound of formula (I).

FIG. 8 is a Differential Scanning Calorimetry (DSC) profile of the mesylate salt form A of the compound of formula (I).

Figure 9 is an X-ray powder diffraction (XRPD) pattern of oxalate form a of the compound of formula (I).

FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of oxalate form A of the compound of formula (I).

Figure 11 is an X-ray powder diffraction (XRPD) pattern of form a fumarate salt of the compound of formula (I).

FIG. 12 is a Differential Scanning Calorimetry (DSC) profile of form A fumarate salt of a compound of formula (I).

Figure 13 is an X-ray powder diffraction (XRPD) pattern of crystalline form a of the hydrobromide salt of the compound of formula (I).

FIG. 14 is a Differential Scanning Calorimetry (DSC) chart of the hydrobromide form A of the compound of formula (I).

FIG. 15 is an X-ray powder diffraction (XRPD) pattern of the nitrate salt form A of the compound of formula (I).

FIG. 16 is a Differential Scanning Calorimetry (DSC) profile of the nitrate salt form A of the compound of formula (I).

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. Preparing a powdery sample into a thin layer on a monocrystalline silicon sample holder or a domestic silicon wafer, placing the thin layer on a rotary sample table, and analyzing in a step length of 0.0167 DEG within the range of 3-40 DEG or 3-60 deg. Data Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data. It is noted that the XRPD pattern of the test sample, when tested using a silicon wafer made in China, exhibited a diffraction peak at 32.97 deg., which is the background peak.

The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 350 ℃ using a 10 ℃/minute linear heating device. During use, the DSC cell was purged with dry nitrogen.

Detailed description of the invention

A specific synthesis of 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylthiazole-5-carboxamide, a compound of formula (I) is described in example 8 of International application WO 2019062662A 1.

Examples

Example 1 hydrochloride form a of the present invention

1. Preparation of hydrochloride form a

A250 mL round-bottom flask was charged with the free form of compound of formula (I) (6g) and DMF (120mL) and dissolved with stirring at room temperature. Insoluble solids were removed by suction filtration, and 1mmol/mL diluted hydrochloric acid (14.4mL) was added to the solution, followed by addition of acetone (12mL), and the reaction was stirred overnight. Suction filtration, rinsing with acetone (10mL), drying to obtain a light yellow solid as hydrochloride form a with a yield of about 89%.

2. Characterization of hydrochloride form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 7.06 °,8.60 °,9.65 °,11.47 °,12.68 °,14.25 °,16.63 °,16.95 °,17.71 °,18.77 °,19.26 °,19.89 °,21.40 °,22.44 °,23.05 °,24.52 °,25.08 °,25.37 °,26.99 °,28.30 °,29.00 °,30.09 °,31.69 °,33.45 °,34.57 °,35.27 °,36.61 °,37.98 °, with an error tolerance of ± 0.2 °. Specifically, the XRPD pattern of form a of the hydrochloride salt prepared according to the method of example 1 of the present invention is substantially as shown in figure 1.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 170.92 ℃ and 306.24 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of form a of the hydrochloride salt prepared according to the method of example 1 of the present invention is substantially as shown in figure 2.

Example 2 hydrochloride form B of the invention

1. Preparation of hydrochloride form B

A250 mL round-bottom flask was charged with the compound of formula (I) in free form (5.02g) and DMSO (50mL), dissolved with stirring at room temperature, and after addition of 1mmol/mL dilute hydrochloric acid (12mL), acetone (40mL) was added and stirring was continued overnight. And (4) carrying out suction filtration, and carrying out vacuum drying at 50 ℃ for 12h to obtain a white-like to light yellow solid which is the hydrochloride crystal form B, wherein the yield is about 90%.

2. Characterization of hydrochloride form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.30 °,10.57 °,12.29 °,14.68 °,15.88 °,16.10 °,19.03 °,19.30 °,19.93 °,21.20 °,21.40 °,24.25 °,24.48 °,25.65 °,26.48 °,27.14 °,34.38 °,36.93 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of form B of the hydrochloride salt prepared according to the method of example 2 of the present invention is substantially as shown in figure 3.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 83.55 ℃, 167.25 ℃ and 304.20 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of form B of the hydrochloride salt prepared according to the method of example 2 of the present invention is substantially as shown in figure 4.

Example 3 crystalline form a of L-malate salt according to the invention

Preparation of L-malate form A

A10 mL round-bottomed flask was charged with the compound of formula (I) in free form (501mg) and DMSO (5mL), dissolved at room temperature with stirring, and L-malic acid (750mg) was added to the above solution, followed by addition of acetone (35mL) and stirring for 24 h. Separating out solid, filtering and drying to obtain light yellow solid L-malate crystal form A with about 86% of yield.

Characterization of L-malate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 6.72 °,10.82 °,13.48 °,14.06 °,14.69 °,15.44 °,17.18 °,18.61 °,19.23 °,20.27 °,21.24 °,21.77 °,22.78 °,23.86 °,24.52 °,25.34 °,25.88 °,26.66 °,27.15 °,27.46 °,28.54 °,29.34 °,30.50 °,35.00 °, and an error tolerance of ± 0.2 ° exists. Specifically, the XRPD pattern of form a of L-malate salt prepared according to the method of example 3 of the present invention is substantially as shown in figure 5.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 207.30 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of L-malate form a prepared according to the method of example 3 of the present invention is substantially as shown in fig. 6.

Example 4 mesylate form a of the invention

1. First of allPreparation of sulfonate form A

A100 mL round-bottom flask was charged with the compound of formula (I) (501mg) in free form and DMF (10mL) and dissolved with stirring at room temperature. After addition of 1mmol/mL methanesulfonic acid (1.2mL), acetone (30mL) was added and stirring was continued for 24 h. And separating out solids, performing suction filtration, and leaching with acetone (2mL), wherein the obtained light yellow solid is dried in vacuum and is mesylate crystal form A, and the yield is about 86%.

2. Characterization of mesylate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 7.52 degrees, 9.10 degrees, 10.43 degrees, 12.55 degrees, 14.97 degrees, 15.40 degrees, 17.02 degrees, 18.85 degrees, 19.27 degrees, 21.60 degrees, 22.47 degrees, 23.44 degrees, 24.25 degrees, 24.99 degrees, 25.61 degrees, 26.57 degrees, 27.24 degrees, 29.41 degrees, 33.32 degrees, 38.04 degrees, and error tolerance of +/-0.2 degrees exists. Specifically, the XRPD pattern of form a of the mesylate salt prepared according to the invention as prepared in example 4 is substantially as shown in figure 7.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 293.25 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of form a of the mesylate salt prepared according to the invention, example 4, is substantially as shown in figure 8.

Example 5 crystalline form A of the oxalate salt of the invention

1. Preparation of oxalate form A

A100 mL round-bottom flask was charged with the compound of formula (I) (501mg) in free form and DMF (10mL) and dissolved with stirring at room temperature. Oxalic acid (150mg) was added to the solution, followed by addition of acetone (20mL) and stirring continued for 24 h. Suction filtration, rinsing with acetone (2mL) to obtain a pale yellow solid, and vacuum drying at 50 ℃ to obtain oxalate crystal form A with a yield of about 88%.

2. Characterization of oxalate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.11 °,8.25 °,10.13 °,12.37 °,13.75 °,15.34 °,16.47 °,17.56 °,18.08 °,18.31 °,19.39 °,19.71 °,20.13 °,21.17 °,21.69 °,22.20 °,23.02 °,23.57 °,23.93 °,24.62 °,25.68 °,25.95 °,26.28 °,26.55 °,26.90 °,27.44 °,27.71 °,28.25 °,28.74 °,29.69 °,30.73 °,31.36 °,33.52 °,34.02 °,34.80 °,35.65 °, and an error tolerance of ± 0.2 ° exists. Specifically, the XRPD pattern of form a of the oxalate salt prepared according to the method of example 5 of the invention is substantially as shown in figure 9.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 174.62 ℃ and 234.98 ℃, with a margin of error of ± 3 ℃. Specifically, a DSC diagram of form a of the oxalate salt prepared according to the method of example 5 of the present invention is substantially as shown in figure 10.

Example 6 fumarate salt form a of the invention

1. Preparation of fumarate salt form A

A10 mL round-bottom flask was charged with the compound of formula (I) in free form (501mg) and DMSO (5mL), and dissolved with stirring at room temperature. Fumaric acid (300mg) was added to the above solution, followed by addition of acetone (35mL), and stirring was continued for 24 h. A pale yellow solid precipitated as fumarate form a in about 89% yield.

2. Characterization of fumarate salt form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 6.28 °,10.95 °,12.60 °,14.37 °,15.07 °,16.58 °,16.71 °,18.08 °,19.11 °,19.78 °,20.25 °,21.59 °,22.72 °,23.80 °,25.09 °,25.37 °,26.19 °,27.84 °,28.94 °,29.90 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of form a of the fumarate salt prepared according to the method of example 6 of the present invention is substantially as shown in figure 11.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 224.95 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of form a of the fumarate salt prepared according to the method of example 6 of the present invention is substantially as shown in figure 12.

Example 7 hydrobromide form A of the invention

1. Preparation of hydrobromide form a

A50 mL round-bottom flask was charged with the compound of formula (I) (501mg) in free form and DMF (10mL) and dissolved with stirring at room temperature. After addition of 1mmol/mL aqueous hydrobromic acid (1.2mL), acetone (2.5mL) was added and stirring was continued for 24 h. Suction filtration and rinsing with acetone (2mL) gave a pale yellow solid which was vacuum dried as hydrobromide form a in about 83% yield.

2. Characterization of hydrobromide form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 8.58 °,9.60 °,11.30 °,12.62 °,14.26 °,16.82 °,17.59 °,18.57 °,19.18 °,19.76 °,21.46 °,23.10 °,24.65 °,25.13 °,26.59 °,28.13 °,28.80 °,29.93 °,31.64 °,33.03 °,34.84 °,35.23 °,36.52 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of form a of the hydrobromide salt prepared according to the invention in accordance with example 7 is substantially as shown in figure 13.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 191.81 ℃ and 305.80 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of crystalline form a of the hydrobromide salt prepared according to the invention in example 7 is substantially as shown in figure 14.

Example 8 nitrate salt form a of the invention

1. Preparation of nitrate crystal form A

A100 mL round-bottom flask was charged with the free form of compound of formula (I) (501mg) and DMF (10mL) and dissolved with stirring at room temperature. After addition of 1mmol/mL dilute nitric acid (1.2mL), acetone (32mL) was added and stirring was continued for 24 h. And (3) carrying out suction filtration, leaching with acetone (2mL), and vacuum drying to obtain a light yellow solid, namely the nitrate crystal form A, wherein the yield is about 87%.

2. Characterization of nitrate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 12.17 °,14.30 °,16.36 °,18.27 °,18.47 °,18.78 °,21.32 °,21.78 °,25.99 °,26.59 °,26.87 °,28.01 °,30.80 °,32.03 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of nitrate form a prepared according to the invention as in example 8 is substantially as shown in figure 15.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 147.26 ℃ and 262.60 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of nitrate form a prepared according to the method of example 8 of the present invention is substantially as shown in figure 16.

Example 9 pharmacokinetic experiments of the salts of the invention

The test samples were encapsulated for oral administration.

3 male Beagle dogs (8-12 kg) were orally administered to capsules containing test samples at a dose of 5mg/kg, and blood was collected at time points of 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. The results of the experiment are shown in table 1.

TABLE 1 pharmacokinetic experimental data for the salts of the invention

Test sample	Tmax(h)	Cmax(ng/ml)	AUClast(h*ng/ml)
				Example 2	6.00	45.5	680

And (4) experimental conclusion:

as can be seen from table 1, the hydrochloride form B described in example 2 of the present invention has a large exposure in beagle dogs and has good pharmacokinetic properties.

EXAMPLE 10 stability test of salts according to the invention

1. Stability test experiment A

At room temperature, weighing samples to be detected (50mg) in an EP tube respectively, adding water (1mL), suspending and stirring at room temperature for 24h, filtering, drying, and then carrying out X-ray powder diffraction (XRPD) analysis and identification respectively.

The experimental results are as follows: the hydrochloride crystal form B, L-malate crystal form A and the mesylate crystal form A are stirred in water at room temperature, and the crystal forms cannot change, namely, the hydrochloride crystal form B, L-malate crystal form A and the mesylate crystal form A have stable properties, such as stable crystal forms, and are suitable for industrial production and preparation development.

2. Stability test experiment B

(1)High temperature experiment: taking a proper amount of a sample to be tested, putting the sample into a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, placing the sample at the temperature of 40 +/-2 ℃ and 60 +/-2 ℃ for 30 days, sampling the sample at the 5 th, 10 th and 30 th days, and detecting according to the stability key examination items: and observing the color change of the sample, detecting the purity of the sample by HPLC, and detecting the crystal structure of the sample by XRPD.

(2)High humidity experiment: taking a proper amount of a test sample, placing the test sample into a flat weighing bottle, spreading the test sample into a thin layer with the thickness of less than or equal to 5mm, placing the test sample for 30 days at 25 ℃ under the condition of RH 90% +/-5%, sampling for 5 days, 10 days and 30 days, detecting according to a stability key examination item, observing the color change of the sample, detecting the purity of the sample by HPLC, and detecting the crystal structure of the sample by XRPD.

(3)Light test: taking a proper amount of a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with an ultraviolet lamp) with an opening, and irradiating at an illuminance of 4500 + -500 lx and an ultraviolet light of more than or equal to 0.7w/m²Standing for 30 days, sampling at 5, 10 and 30 days, observing color change of the sample, detecting purity of the sample by HPLC, and detecting crystal structure of the sample by XRPD.

And (4) experimental conclusion: after being placed under the conditions of high temperature (40 ℃ or 60 ℃), high humidity (25 ℃, RH 90% +/-5%) and illumination for 30 days, the appearance and the purity of the hydrochloride crystal form B, L-malate crystal form A and the mesylate crystal form A are not obviously changed. Namely, the crystal form B, L-malate crystal form A and the mesylate crystal form A of the hydrochloride have good stability under various lofting conditions, and are suitable for pharmaceutical use.

EXAMPLE 11 hygroscopicity test of the salts according to the invention

The experimental method comprises the following steps:

1) the dried glass weighing bottle with stopper was placed in a suitable thermostatic desiccator at 25 ℃. + -. 1 ℃ the day before, and precision weighed (m 1).

2) And taking a proper amount of the test sample, flatly paving the test sample in the weighing bottle, wherein the thickness of the test sample is about 1mm, and precisely weighing (m 2).

3) The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.

4) The weighing bottle cap is closed, precision weighing (m3) is performed, and the following calculation is performed: percent weight gain ═ m3-m2)/(m2-m1) × 100%.

5) And (4) judging the moisture absorption result:

the experimental results are as follows: the salts of the present invention are not susceptible to deliquescence from high humidity.

Example 12 solubility test of salts of the invention

Putting the salt into organic ultrapure water at 37 ℃ to prepare supersaturated solution, shaking for 24h, filtering by using a water-based filter membrane to obtain filtrate, measuring the solubility by adopting an HPLC method, wherein two samples in each batch are prepared in parallel, and the measurement result of the solubility is shown in Table 2.

Table 2 solubility of the salts according to the invention

And (4) experimental conclusion:

as can be seen from the data in table 2, the salts of the present invention have good solubility; the L-malate crystal form A described in the embodiment 3 and the mesylate crystal form A described in the embodiment 4 have the highest solubility which is far higher than other salts or crystal forms thereof, and are very beneficial to preparation development.

The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. A salt of a compound of formula (I),

wherein the salt is hydrochloride, L-malate, methanesulfonate, oxalate, fumarate, hydrobromide or nitrate.

2. The salt of claim 1, wherein the hydrochloride salt is hydrochloride form a or hydrochloride form B, the L-malate is L-malate form a, and the mesylate salt is mesylate form a; wherein the content of the first and second substances,

the hydrochloride form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °,26.99 ° ± 0.2 °;

the hydrochloride form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,19.93 ° ± 0.2 °,24.25 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °;

the X-ray powder diffraction pattern of the L-malate form A has diffraction peaks at the following 2 theta angles: 6.72 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,27.46 ° ± 0.2 °;

the mesylate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.52 degrees +/-0.2 degrees, 9.10 degrees +/-0.2 degrees, 10.43 degrees +/-0.2 degrees, 12.55 degrees +/-0.2 degrees, 14.97 degrees +/-0.2 degrees, 15.40 degrees +/-0.2 degrees, 17.02 degrees +/-0.2 degrees, 25.61 degrees +/-0.2 degrees and 26.57 degrees +/-0.2 degrees.

3. The salt according to claim 2, wherein,

the hydrochloride form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,16.63 ° ± 0.2 °,16.95 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.26 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,22.44 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °,26.99 ° ± 0.2 °,28.30 ° ± 0.2 °,31.69 ° ± 0.2 °;

the hydrochloride form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,15.88 ° ± 0.2 °,16.10 ° ± 0.2 °,19.03 ° ± 0.2 °,19.30 ° ± 0.2 °,19.93 ° ± 0.2 °,24.25 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °,36.93 ° ± 0.2 °;

the X-ray powder diffraction pattern of the L-malate form A has diffraction peaks at the following 2 theta angles: 6.72 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,17.18 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,26.66 ° ± 0.2 °,27.15 ° ± 0.2 °,27.46 ° ± 0.2 °;

the mesylate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.52 ° ± 0.2 °,9.10 ° ± 0.2 °,10.43 ° ± 0.2 °,12.55 ° ± 0.2 °,14.97 ° ± 0.2 °,15.40 ° ± 0.2 °,17.02 ° ± 0.2 °,18.85 ° ± 0.2 °,19.27 ° ± 0.2 °,21.60 ° ± 0.2 °,22.47 ° ± 0.2 °,25.61 ° ± 0.2 °,26.57 ° ± 0.2 °,27.24 ° ± 0.2 °.

4. The salt of claim 2 or 3, wherein,

the hydrochloride form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.06 ° ± 0.2 °,8.60 ° ± 0.2 °,9.65 ° ± 0.2 °,11.47 ° ± 0.2 °,12.68 ° ± 0.2 °,14.25 ° ± 0.2 °,16.63 ° ± 0.2 °,16.95 ° ± 0.2 °,17.71 ° ± 0.2 °,18.77 ° ± 0.2 °,19.26 ° ± 0.2 °,19.89 ° ± 0.2 °,21.40 ° ± 0.2 °,22.44 ° ± 0.2 °,23.05 ° ± 0.2 °,24.52 ° ± 0.2 °,25.08 ° ± 0.2 °,25.37 ° ± 0.2 °,26.99 ° ± 0.2 °,28.30 ° ± 0.2 °,29.00 ° ± 0.2 °,30.09 ° ± 0.2 °,36 31.69 ° ± 0.45 ° ± 0.33.2 °, 3645 ° ± 0.2 ° ± 0.2.670.82 ° ± 0.54 ° ± 0.82 ° ± 362 ° ± 0.54 ° ± 3.2 °;

the hydrochloride form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.30 ° ± 0.2 °,10.57 ° ± 0.2 °,12.29 ° ± 0.2 °,14.68 ° ± 0.2 °,15.88 ° ± 0.2 °,16.10 ° ± 0.2 °,19.03 ° ± 0.2 °,19.30 ° ± 0.2 °,19.93 ° ± 0.2 °,21.20 ° ± 0.2 °,21.40 ° ± 0.2 °,24.25 ° ± 0.2 °,24.48 ° ± 0.2 °,25.65 ° ± 0.2 °,26.48 ° ± 0.2 °,27.14 ° ± 0.2 °,34.38 ° ± 0.2 °,36.93 ° ± 0.2 °;

the X-ray powder diffraction pattern of the L-malate form A has diffraction peaks at the following 2 theta angles: 6.72 ° ± 0.2 °,10.82 ° ± 0.2 °,13.48 ° ± 0.2 °,14.06 ° ± 0.2 °,14.69 ° ± 0.2 °,15.44 ° ± 0.2 °,17.18 ° ± 0.2 °,18.61 ° ± 0.2 °,19.23 ° ± 0.2 °,20.27 ° ± 0.2 °,21.24 ° ± 0.2 °,21.77 ° ± 0.2 °,22.78 ° ± 0.2 °,23.86 ° ± 0.2 °,24.52 ° ± 0.2 °,25.34 ° ± 0.2 °,25.88 ° ± 0.2 °,26.66 ° ± 0.2 °,27.15 ° ± 0.2 °,27.46 ° ± 0.2 °,28.54 ° ± 0.2 °,29.34 ° ± 0.2 °,30.50 ° ± 0.2 °,35.00 ° ± 0.2 °;

the mesylate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.52 ° ± 0.2 °,9.10 ° ± 0.2 °,10.43 ° ± 0.2 °,12.55 ° ± 0.2 °,14.97 ° ± 0.2 °,15.40 ° ± 0.2 °,17.02 ° ± 0.2 °,18.85 ° ± 0.2 °,19.27 ° ± 0.2 °,21.60 ° ± 0.2 °,22.47 ° ± 0.2 °,23.44 ° ± 0.2 °,24.25 ° ± 0.2 °,24.99 ° ± 0.2 °,25.61 ° ± 0.2 °,26.57 ° ± 0.2 °,27.24 ° ± 0.2 °,29.41 ° ± 0.2 °,33.32 ° ± 0.2 °,38.04 ° ± 0.2 °.

5. The salt according to claim 2, wherein,

the hydrochloride form a has an X-ray powder diffraction pattern substantially as shown in figure 1;

said hydrochloride form B having an X-ray powder diffraction pattern substantially as shown in figure 3;

the L-malate form a has an X-ray powder diffraction pattern substantially as shown in figure 5;

the mesylate salt form a has an X-ray powder diffraction pattern substantially as shown in figure 7.

6. The salt of claim 2, wherein the differential scanning calorimetry trace of form a of the hydrochloride salt comprises endothermic peaks at 170.92 ℃ ± 3 ℃ and 306.24 ℃ ± 3 ℃;

a differential scanning calorimetry trace of form B of the hydrochloride salt comprising endothermic peaks at 167.25 ℃ ± 3 ℃ and 304.20 ℃ ± 3 ℃;

a differential scanning calorimetry trace of said L-malate form a comprising an endothermic peak at 207.30 ℃ ± 3 ℃;

the differential scanning calorimetry trace of the mesylate form A comprises an endothermic peak at 293.25 ℃ ± 3 ℃.

7. The salt of claim 2, wherein the hydrochloride salt form a has a differential scanning calorimetry trace substantially as shown in figure 2;

said hydrochloride salt form B having a differential scanning calorimetry pattern substantially as shown in figure 4;

said L-malate form a having a differential scanning calorimetry pattern substantially as shown in figure 6;

the mesylate form a has a differential scanning calorimetry trace substantially as shown in figure 8.

8. A pharmaceutical composition comprising a salt of any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

9. Use of a salt according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.

10. The use according to claim 9, wherein the central nervous system disorder is depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction or premenstrual tension syndrome.

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