CN114685442A

CN114685442A - Salts of pyridinylalkenylpiperidine derivatives and use thereof

Info

Publication number: CN114685442A
Application number: CN202111620717.2A
Authority: CN
Inventors: 钟文和; 金传飞; 叶辉青
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-12-29
Filing date: 2021-12-28
Publication date: 2022-07-01

Abstract

The present invention relates to a salt of a pyridinylpiperidine derivative and use thereof. The invention also relates to a pharmaceutical composition comprising said salt and the use of said salt or a pharmaceutical composition of said salt for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT_1FThe use in the manufacture of a medicament for the treatment of a disorder associated with a receptor, in particular migraine.

Description

Salts of pyridinylalkenylpiperidine derivatives and use thereof

Technical Field

The invention belongs to the technical field of medicines, relates to a salt of a pyridenylpiperidine derivative and application thereof, and particularly relates to a salt of 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidine-4-ylidene) methyl) pyridine-2-yl) benzamide, a crystal form of the salt and application thereof, and further relates to a pharmaceutical composition containing the salt or the crystal form of the salt.

Background

Migraine is a paroxysmal and often unilateral throbbing headache, often accompanied by nausea and vomiting, and is a common chronic neurovascular disease, which is mostly ill in children and adolescence, reaches the peak of onset in middle and young age, is common in women, and has the proportion of male patients to female patients of about 1: 2-3, the prevalence rate of the population is 5% -10%, and the population often has a genetic background.

Migraine, while not a fatal disease, can severely impact a patient's social life. In the United states, migraine causes a socio-economic burden of $ 10 to $ 17 million. In China, a large number of patients influence work, study and life due to migraine. With the pace of life increasing, the incidence of migraine tends to increase. Recent investigations have found that about 5.7% of men and 17.6% of women have on average more than 1 migraine attack per year. In addition, many people have a genetic predisposition to migraine.

The pathogenesis of migraine is complex and various, and the pathogenesis mainly comprises an angiogenetic theory, a neurogenic theory, a trigeminal neurovascular theory, biochemical factors and genetic factors. The current drug for the treatment of migraine is mainly 5-HT_1B/DReceptor agonist triptans, but triptans cause vasoconstriction and are therefore contraindicated in patients with cardiovascular and cerebrovascular and peripheral vascular disease. In addition, 40-70% of migraine sufferers have better curative effect on triptansPoor, 1/3 patients who are initially effective also frequently experience a recurrence of headache, and triptans have significantly reduced efficacy in patients with moderate to severe headache. To overcome these adverse effects of triptans, Calcitonin Gene Related Peptide (CGRP) receptor antagonists and selective 5-HT_1FReceptor agonists are produced by the administration of anti-migraine drugs. However, CGRP receptor antagonists still have several drawbacks, such as the fact that olcagepant can only be administered intravenously and not orally, the fact that telcagepant causes elevated liver enzymes in long-term use, and the fact that BI-44370 interacts with cytochrome P450 has led to clinical development discontinuation. Therefore, the development of new acute phase therapeutic drugs is urgently required. To develop selective 5-HT_1FThe receptor agonist type anti-migraine medicine is always considered to be a new promising approach.

Since 1938 Graham and Wolff's work (Arch. neuron. Psychiatry,39: 737-. They suggested that the cause of migraine headache is vasodilation of extracranial blood vessels. This view is supported by the following evidence: ergot alkaloid and sumatriptan as a water-absorbing 5-HT agent incapable of crossing the blood-brain barrier₁Agonists, which cause contraction of the vascular smooth muscle of the head, are effective in the treatment of migraine (Humphrey, et al., Ann. NY Acad. Sci.,600: 587-. However, work by the Moskowitz research group showed that migraine development was not associated with altered vessel diameter (Cephalalgia,12:5-7,1992).

The Moskowitz group suggested that currently unknown pain triggers irritate the trigeminal ganglion (which innervates the vasculature within the head tissue), causing axons on the vasculature to release vasoactive neuropeptides. These released neuropeptides then activate a series of events, resulting in pain. This neurogenic inflammation is blocked by ergot alkaloids and sumatriptan, whose blocking mechanism involves the 5-HT receptor and interacts with the 5-HT located on the trigeminal neurovascular fibers_1DSubtypes are closely related (Neurology,43(supp1.3): S16-S20,1993). Indeed, sumatriptan pairs 5-HT_1BAnd 5-HT_1DThe receptor has high affinity, the Ki is 10.3nM and 5.1nM respectively, and the activity showsVasoconstrictive activity.

The 5-hydroxytryptamine receptor, also known as serotonin receptor or 5-HT receptor, is a group of G protein coupled receptors found in the central part of the central nervous system and in the periphery of the peripheral nervous system and can be divided into seven subfamilies, 5-HT₁、5-HT₂、5-HT₃、5-HT₄、5-HT₅、5-HT₆And 5-HT₇Respectively, mediate different physiological activities. Wherein, 5-HT₁The receptor is the largest family of 5-HT receptors, and 5-HT is currently the most abundant receptor family_1A、5-HT_1B、5-HT_1D、5-HT_1EAnd 5-HT_1FFive subtypes. Isolation of expression of these 5-HT by the Kao group₁One of the receptor subtypes (termed 5-HT)_1F) Human gene (Proc. Natl. Acad. Sci. USA,90:408-412, 1993). The 5-HT_1FThe receptor exhibits pharmacological activity that is significantly different from any of the serotonin receptors disclosed. They found that sumatriptan was found to be other than on 5-HT_1BAnd 5-HT_IDIn addition to the strong affinity described above, the receptor also has an affinity for this receptor subtype with a Ki of approximately 23 nM. This indicates 5-HT_1FReceptors may play a role in migraine.

5-HT_1FThe receptors are mainly expressed in mesentery, uterus and brain, and also exist in cerebral vessels, trigeminal ganglia, trigeminal caudate nuclei and other trigeminal nerve vascular systems, as well as cerebellum, hippocampus and neocerebral cortex. 5-HT as other 5-HT receptors_1FReceptors are expressed not only in neurons but also in glial cells. Presynaptic 5-HT_1FThe receptor activation can inhibit the release of calcitonin gene-related peptide (CGRP) and block neuronal signaling in the tail nucleus of trigeminal nerve, thereby producing an anti-migraine effect, and the selective 5-HT_1FThe receptor agonism greatly reduces the side effect related to vasoconstriction caused by triptan medicaments.

Subsequently, the development of p-5-HT_1FVarious 5-HT receptors with relative selectivity for receptor subtypes_1FReceptor agonists, and such selectivity will generally reduce the vasoconstrictor activity characteristic of other compounds useful as potential drugs for the treatment of migraine and related conditions. Thus, selectingSelective 5-HT_1FReceptor agonists are the hot spot in current anti-migraine drug research.

As a result of continuous and diligent research, the inventors have found an unexpected new selective 5-HT_1FReceptor agonists with different chemical and receptor binding properties, capable of inhibiting peptide extravasation while avoiding significant vasoconstrictive activity, and thus useful in the treatment of migraine and other conditions associated with 5-HT_1FA receptor-associated disease.

Among these, the international application WO 2020038435A 1 discloses the compound 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide (compound of formula (I)), which can be used for activating 5-HT_1FReceptor, inhibition of neuronal protein extravasation. However, no research on the salt of the compound or its crystal form has been made in the prior art.

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

The inventor researches the compound to find that the compound has poor water solubility and poor druggability, so that a solid form with better druggability needs to be searched.

Disclosure of Invention

International application WO 2020038435 a1 discloses compounds of formula (I) as white solids, but does not specifically disclose the specific solid form or salt thereof. Through a large number of experimental researches, the inventors find that the salt formed by the compound shown in the formula (I) and different acids has large property difference, for example, the solubility of individual salt is reduced, the solubility of individual salt is equivalent to that of the compound, and the solubility of individual salt is improved. The salt has good stability, good water solubility, good pharmacokinetic property in organisms and high preparation purity of products, namely, various properties of the salt are more beneficial to the development of preparations, thereby having better pharmacy.

In particular, the invention relates to a salt of a compound shown as a formula (I), and a crystal form of the salt or a pharmaceutical composition containing the salt or the crystal form of the salt for preparing a medicine for preventing, treating or relieving 5-HT_1FThe use in the manufacture of a medicament for the treatment of a condition associated with a receptor, in particular migraine. The salts of the present invention may have a stable crystalline structure, and the crystalline form of the present invention may also be in the form of a solvate, e.g., a hydrate.

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

in some embodiments, the salts described herein are salts of organic or inorganic acids.

In other embodiments, the inorganic acid salts described herein include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate, or sulfate salts, and the like; the organic acid salt includes, but is not limited to, acetate, succinate, oxalate, fumarate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, salicylate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate, etc.

In some embodiments, the sulfate salt of the present invention is sulfate form a, sulfate form B, or sulfate form C, the p-toluenesulfonate salt is p-toluenesulfonate form a or p-toluenesulfonate form B, the oxalate salt is oxalate form a, the maleate salt is maleate form a, and the hydrobromide salt is hydrobromide form a.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form a, and wherein the sulfate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.37 degrees +/-0.2 degrees, 15.15 degrees +/-0.2 degrees, 18.26 degrees +/-0.2 degrees, 19.08 degrees +/-0.2 degrees, 19.26 degrees +/-0.2 degrees, 21.19 degrees +/-0.2 degrees, 21.44 degrees +/-0.2 degrees, 23.00 degrees +/-0.2 degrees and 25.79 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B of sulfate salt, and wherein the form B of sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.62 degrees +/-0.2 degrees, 9.58 degrees +/-0.2 degrees, 13.01 degrees +/-0.2 degrees, 14.70 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.58 degrees +/-0.2 degrees and 22.79 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form C, and wherein the sulfate salt form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.87 degrees +/-0.2 degrees, 9.31 degrees +/-0.2 degrees, 11.46 degrees +/-0.2 degrees, 12.65 degrees +/-0.2 degrees, 15.90 degrees +/-0.2 degrees, 17.07 degrees +/-0.2 degrees, 22.05 degrees +/-0.2 degrees, 22.44 degrees +/-0.2 degrees, 23.41 degrees +/-0.2 degrees and 26.78 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tosylate salt, characterized in that the tosylate salt is form a tosylate salt, and the crystalline form a tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.27 degrees +/-0.2 degree, 12.79 degrees +/-0.2 degree, 13.72 degrees +/-0.2 degree, 15.46 degrees +/-0.2 degree, 16.80 degrees +/-0.2 degree, 17.05 degrees +/-0.2 degree, 17.38 degrees +/-0.2 degree, 18.05 degrees +/-0.2 degree, 18.53 degrees +/-0.2 degree, 19.40 degrees +/-0.2 degree, 20.84 degrees +/-0.2 degree, 21.51 degrees +/-0.2 degree, 22.48 degrees +/-0.2 degree, 22.79 degrees +/-0.2 degree and 23.44 degrees +/-0.2 degree.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is crystalline form B p-toluenesulfonate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.00 degrees +/-0.2 degrees, 11.98 degrees +/-0.2 degrees, 15.85 degrees +/-0.2 degrees, 16.64 degrees +/-0.2 degrees, 18.92 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 19.65 degrees +/-0.2 degrees, 20.98 degrees +/-0.2 degrees, 21.38 degrees +/-0.2 degrees, 23.91 degrees +/-0.2 degrees and 24.11 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having a diffraction peak at the following 2 Θ angles in an X-ray powder diffraction pattern: 7.71 degrees +/-0.2 degrees, 15.50 degrees +/-0.2 degrees, 23.37 degrees +/-0.2 degrees, 24.90 degrees +/-0.2 degrees, 25.84 degrees +/-0.2 degrees, 29.50 degrees +/-0.2 degrees and 31.35 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a maleate salt, wherein the maleate salt is form a maleate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.37 degrees +/-0.2 degree, 9.66 degrees +/-0.2 degree, 12.63 degrees +/-0.2 degree, 14.65 degrees +/-0.2 degree, 16.82 degrees +/-0.2 degree, 18.62 degrees +/-0.2 degree, 19.07 degrees +/-0.2 degree, 19.88 degrees +/-0.2 degree, 24.20 degrees +/-0.2 degree, 24.53 degrees +/-0.2 degree, 25.64 degrees +/-0.2 degree and 26.24 degrees +/-0.2 degree.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.25 degrees +/-0.2 degrees, 12.47 degrees +/-0.2 degrees, 13.99 degrees +/-0.2 degrees, 18.28 degrees +/-0.2 degrees, 18.75 degrees +/-0.2 degrees, 19.24 degrees +/-0.2 degrees, 22.42 degrees +/-0.2 degrees, 24.16 degrees +/-0.2 degrees and 28.25 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.37 +/-0.2 degrees, 7.91 +/-0.2 degrees, 9.25 +/-0.2 degrees, 10.65 +/-0.2 degrees, 12.13 +/-0.2 degrees, 12.75 +/-0.2 degrees, 13.61 +/-0.2 degrees, 15.15 +/-0.2 degrees, 15.93 +/-0.2 degrees, 16.57 +/-0.2 degrees, 18.26 +/-0.2 degrees, 19.08 +/-0.2 degrees, 19.26 +/-0.2 degrees, 21.19 +/-0.2 degrees, 21.44 +/-0.2 degrees, 21.98 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.00 +/-0.2 degrees, 23.96 +/-0.2 degrees, 24.60 +/-0.2 degrees, 25.79 +/-0.2 degrees, 26.23 +/-0.2 degrees, 28.2 degrees, 28 +/-0.2.2.2 degrees, 28 +/-0.2.27.85 +/-0.2 degrees, 28 +/-2.2 degrees, 2 degrees, 13 +/-0.2 degrees, 2 degrees, 2.2 degrees, 30.2 degrees, 13 +/-2 degrees, 2.2 degrees, 13 +/-0.2 degrees, 2 degrees, 13 +/-0.2 degrees, 3 degrees, 2 degrees, 2.2.2.2 degrees, 3 degrees, 34 degrees, 3 +/-0.2 degrees, 3 +/-0.2 degrees, 3 degrees, 2 degrees, 3 degrees, 9 +/-0.2.2 degrees, 9 degrees, 2 degrees, 9 degrees, 2.2 degrees, 9 +/-0.2 degrees, 3 degrees, 13 degrees, 2 degrees, 9 +/-0.2.2.2 degrees, 9 degrees, 13 degrees, 2 degrees, 9 +/-0.2.2.2 degrees, 9 degrees, 13 degrees, 9 +/-0.2 degrees, 9 degrees, 2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2 degrees, 9 +/-0.2.2.2.2.2.2.2 degrees, 9 degrees, +/-0.2.2.2 degrees, 9 +/-0.2.2.2.2.2.2.2 degrees, 9 degrees (degrees, 9 degrees +/-0.2 degrees, 9 degrees (degrees +/-0.2.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B of sulfate salt, and wherein the form B of sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.62 degrees +/-0.2 degrees, 9.58 degrees +/-0.2 degrees, 10.02 degrees +/-0.2 degrees, 12.17 degrees +/-0.2 degrees, 13.01 degrees +/-0.2 degrees, 14.70 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.58 degrees +/-0.2 degrees, 18.48 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 20.13 degrees +/-0.2 degrees, 21.51 degrees +/-0.2 degrees, 22.79 degrees +/-0.2 degrees, 24.32 degrees +/-0.2 degrees and 26.61 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form C, and wherein the sulfate salt form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.87 ° ± 0.2 °, 9.31 ° ± 0.2 °, 9.52 ° ± 0.2 °, 11.46 ° ± 0.2 °, 12.65 ° ± 0.2 °, 14.57 ° ± 0.2 °, 15.36 ° ± 0.2 °, 15.90 ° ± 0.2 °, 17.07 ° ± 0.2 °, 17.71 ° ± 0.2 °, 18.63 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.55 ° ± 0.2 °, 20.80 ° ± 0.2 °, 21.56 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.44 ° ± 0.2 °, 23.41 ° ± 0.2 °, 24.20 ° ± 0.2 °, 2.2 °, 24.66 ° ± 0.2 °, 25.00 ° ± 0.2 °, 25.55 ° ± 0.2.82 ° ± 0.26 ° ± 0.2 °, 2.9 ° ± 0.9 °,2 °, 2.9 ° ± 0.2 °, 2.2.9 ° ± 0.9 ° ± 0.2 °, 2.2 °,2 °, 2.9 ° ± 0.9.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2.2.2 °, 2.9 ° ± 0.9 ° ± 0.2.2.2 °,2 °, 2.9 ° ± 0.2.2 °,2 °, 2.2 °, 2.9.9 ° ± 0.9.9 ° ± 0.2 °, 2.9 ° ± 0.2.9 ° ± 0.9.9 ° ± 0.2 °, 2.2.9 ° ± 0.9 ° ± 0.2.2 °, 2.2.2 °,2 °, 2.9.9 ° ± 0.9 ° ± 0.2.2.2.2.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2 °,2 °, 2.2.2 °,2 ° ± 2 °, 2.9 ° ± 0.2.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.9.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °, 2.2.9 ° ± 0.2.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.2 ° ± 0.9 ° ± 0.2 °, 2.2.2 °, 2.2.2.2 °, 2.9 ° ± 0.2.2.2 °, 2.2.2 ° ± 0.2.2.2.2.2.9 ° ± 0.9 ° ± 0.2 ° ± 0.2.2 °, 2.2.9.9 ° ± 0.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2.9 ° ±.

In some embodiments, the salt of the invention is a tosylate salt, characterized in that the tosylate salt is form a tosylate salt, and the crystalline form a tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.80 +/-0.2 °, 8.93 +/-0.2 °, 11.27 +/-0.2 °, 12.79 +/-0.2 °, 13.72 +/-0.2 °, 15.46 +/-0.2 °, 16.11 +/-0.2 °, 16.36 +/-0.2 °, 16.80 +/-0.2 °, 17.05 +/-0.2 °, 17.38 +/-0.2 °, 18.05 +/-0.2 °, 18.53 +/-0.2 °, 19.40 +/-0.2 °, 19.99 +/-0.2 °, 20.49 +/-0.2 °, 20.84 +/-0.2 °, 21.51 +/-0.2 °, 22.48 +/-0.2 °, 22.79 +/-0.2 °, 23.44 +/-0.2 °, 23.68 +/-0.2 °, 24.94 +/-0.2 ± 0.26 +/-0.2 °, 36 ° +/-0.9 °,2 °, 2.9 +/-0.9 ° +/-0.2 °,2 ° +/-0.2 °,3 ° +/-0.9 ° +/-0.2 °,2 °,3 ° +/-0.2 °,2 ° +/-0.2 °,3 ° +/-0.9 ° +/-0.2 °,2 ° +/-0.2 °,2 °,3 ° +/-0.2 °,3 ° +/-0.2 °,2 °,3 ° +/-0.2 °,3 ° +/-0.2 °,2 °,3 ° +/-0.2 °,2 °, 2.2.2 °,2 ° +/-0.2 °,3 ° +/-0.2 °,2 °, 0.2 ° +/-0.2 °,3 ° +/-0.2 °, 0.2 ° +/-0.2 °,3 ° +/-0.9 ° +/-0.2 °,3 ° +/-0.2 °, 0.9 ° +/-0.2 °,3 ° +/-0.2 °, 0.2 ° +/-0.2 °,3 ° +/-0.2 °, 0.2 ° +/-0.2 °, 0.9 ° +/-0.2 °, 0.

In some embodiments, the salt of the invention is a tosylate salt, characterized in that the tosylate salt is form B of tosylate salt, and the crystalline form B of tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.26 +/-0.2 DEG, 8.00 +/-0.2 DEG, 9.50 +/-0.2 DEG, 11.98 +/-0.2 DEG, 12.48 +/-0.2 DEG, 13.55 +/-0.2 DEG, 14.11 +/-0.2 DEG, 14.55 +/-0.2 DEG, 15.37 +/-0.2 DEG, 15.85 +/-0.2 DEG, 16.64 +/-0.2 DEG, 17.41 +/-0.2 DEG, 17.87 +/-0.2 DEG, 18.92 +/-0.2 DEG, 19.28 +/-0.2 DEG, 19.65 +/-0.2 DEG, 20.53 +/-0.2 DEG, 20.98 +/-0.2 DEG, 21.38 +/-0.2 DEG, 22.82 +/-0 DEG, 2 DEG, 23 +/-0.23 +/-0.2 DEG, 23.35 +/-0.2 DEG, 23.91 +/-0.2.11 +/-0.24 +/-0.2 DEG, 2.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27.27 +/-0.27 DEG, 2 DEG, 2.27 DEG, 2 DEG, 2.27 +/-0.9 DEG, 2 DEG, 2.9.9 DEG, 2 DEG, 2.9 +/-0.9 DEG, 30 DEG, 2.27 DEG, 0.27 +/-0.27 DEG, 2.9 DEG, 2 DEG, 0.27 DEG, 0.9 DEG, 0.27 DEG, 0.9 +/-0.9 DEG, 0.9 +/-0.27 DEG, 0 +/-0.9 DEG, 0 +/-0.27 DEG, 0.9 DEG, 0.27 DEG, 0 +/-0 DEG, 0 +/-0.27 DEG, 0.9 DEG, 0.27 DEG, 0.9 DEG, 0.27 DEG, 0 +/-0.27 DEG, 0.27 +/-0.27 DEG, 0 +/-0.27 DEG, 0 +/-0.27 DEG, 0.9 +/-0.27 DEG, 0 +/-0.27 DEG, 0.27 +/-0 +/-0.9 DEG, 0.9 +/-0 +/-0.9 DEG, 0 +/-0.27 DEG, 35.37 DEG +/-0.2 DEG and 37.63 DEG +/-0.2 deg.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having a diffraction peak at the following 2 Θ angles in an X-ray powder diffraction pattern: 7.71 degrees +/-0.2 degree, 11.43 degrees +/-0.2 degree, 13.50 degrees +/-0.2 degree, 14.36 degrees +/-0.2 degree, 15.50 degrees +/-0.2 degree, 16.91 degrees +/-0.2 degree, 17.67 degrees +/-0.2 degree, 19.01 degrees +/-0.2 degree, 21.20 degrees +/-0.2 degree, 22.31 degrees +/-0.2 degree, 23.37 degrees +/-0.2 degree, 24.90 degrees +/-0.2 degree, 25.84 degrees +/-0.2 degree, 26.17 degrees +/-0.2 degree, 26.49 degrees +/-0.2 degree, 27.33 degrees +/-0.2 degree, 28.66 degrees +/-0.2 degree, 29.50 degrees +/-0.2 degree, 31.35 degrees +/-0.2 degree and 32.10 degrees +/-0.2 degree.

In some embodiments, the salt of the invention is a maleate salt, wherein the maleate salt is form a maleate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 0.2, 14.65, 0.2, 0.75, 0.2, 15.27, 0.2, 16.41, 0.2, 16.82, 0.2, 18.62, 0.2, 19.07, 0.2, 19.42, 0.2, 19.88, 0.2, 20.54, 0.2, 21.27, 0.2, 22.47, 0.2, 23.56, 0.2, 24.20, 0.2, 24.53, 0.2, 25.12, 0.2, 0.24, 0.2, 0.9, 0.27, 0.2, 2, 0.9, 0.12, 0.2, 0.9, 0.2, 0, 0.2, 0, 0.2, 0.9, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.9, 0, 0.2.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.25 +/-0.2 °, 6.85 +/-0.2 °, 9.15 +/-0.2 °, 10.05 +/-0.2 °, 12.47 +/-0.2 °, 13.99 +/-0.2 °, 14.45 +/-0.2 °, 14.85 +/-0.2 °, 15.83 +/-0.2 °, 16.73 +/-0.2 °, 17.58 +/-0.2 °, 18.28 +/-0.2 °, 18.75 +/-0.2 °, 19.24 +/-0.2 °, 19.58 +/-0.2 °, 20.15 +/-0.2 °, 20.46 +/-0.2 °, 21.01 +/-0.2 °, 21.90 +/-0.2 °, 22.42 +/-0.2 °,2 °, 22.98 +/-0.2 °, 23.61 +/-0.2 °, 24.16 +/-0.2.01 +/-0.2 °, 2.0.2 °,2 ° +/-0.28 °, 2.28 +/-0.2 °,2 °, 2.2.2 °, 2.2 ° +/-2.2 °,2 ° +/-2 °, 2.2 ° +/-2.2 °,2 °, 2.2.2 ° +/-0.2 °,2 °, 2.2 ° +/-0.2 °, 2.2 °,2 °, 2.2.2 ° +/-0.2 °,2 °, 2.2.2.2 °,2 ° +/-0.2 °,2 ° +/-0.2.2 °, 2.2 °,2 °, 2.0.2 °, 2.2.2 ° +/-0.2 °, 2.2 °,2 ° +/-0.2 °,2 °, 2.2.0.2 °, 2.0.2 ° +/-of the angle of.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.37 +/-0.2 degree, 7.91 +/-0.2 degree, 9.25 +/-0.2 degree, 10.65 +/-0.2 degree, 12.13 +/-0.2 degree, 12.75 +/-0.2 degree, 13.61 +/-0.2 degree, 14.17 +/-0.2 degree, 15.15 +/-0.2 degree, 15.93 +/-0.2 degree, 16.57 +/-0.2 degree, 17.62 +/-0.2 degree, 18.26 +/-0.2 degree, 19.08 +/-0.2 degree, 19.26 +/-0.2 degree, 21.19 +/-0.2 degree, 21.44 +/-0.2 degree, 21.98 +/-0.2 degree, 22.58 +/-0.2 degree, 23.00 +/-0.2 degree, 23.96 +/-0.2 degree, 24.60 +/-0.2 degree, 25.79 +/-0.2 degree, 23 +/-0.2 degree, 0.27 +/-0.27 degree, 27.27 +/-0.2 degree, 27 +/-0.27 degree, 27.2 degree, 27 +/-0.2 degree, 27.2 degree, 23.28 degree, 27 +/-0.2 degree, 28 degree, 27.27 +/-0.27 DEG, 27 +/-0.2 degree, 27 DEG, 27.2 degree, 27 DEG 12 DEG, 28 DEG 12 DEG, 28 DEG, 27.2 DEG, 27 +/-0.2 DEG, 27 DEG, 27.2 DEG, 28 DEG, 27.2 DEG, 27 DEG, 28 DEG, 27 DEG +/-0.2 DEG, 28 DEG, 27.2 DEG, 27 DEG +/-0.2 DEG, 28 DEG, 27 DEG +/-0.2 DEG, 28 DEG, 27.2 DEG, 28 DEG, 27 DEG, 28 DEG +/-0.2 DEG, 27.2 DEG, 27 DEG, 28 DEG, 27.2 DEG, 28 DEG +/-0.2 DEG, 28 DEG, 27.2.2 DEG, 28 DEG +/-0.2 DEG, 28 DEG, 27 DEG, 27.2 DEG +/-0.2.2 DEG +/-0.2 DEG, 28 DEG, 27 DEG, 28 DEG +/-0.2 DEG, 27 DEG +/-0.2 DEG, 28 DEG, 27.2.2.2 DEG +/-0.2 DEG, 28 DEG +/-0.2.2.2.2 DEG +/-0.2 DEG, 9 DEG +/-0.2 DEG, 28 DEG +/-0.2.2.2.2 DEG, 28 DEG +/-0.2 DEG +/-0.2.2.2.2.2 DEG +/-0.2.2 DEG +/-0.2.2.2.2 DEG +/-0.2.2.2.2.2.2.2 DEG, 9 DEG +/-0.2 DEG +/-0.2.2 DEG +/-0.2 DEG, 9 DEG +/-0.2..

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is form B of a sulfate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.62 degrees +/-0.2 degrees, 9.58 degrees +/-0.2 degrees, 10.02 degrees +/-0.2 degrees, 12.17 degrees +/-0.2 degrees, 13.01 degrees +/-0.2 degrees, 14.70 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.58 degrees +/-0.2 degrees, 18.48 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 20.13 degrees +/-0.2 degrees, 21.51 degrees +/-0.2 degrees, 22.79 degrees +/-0.2 degrees, 24.32 degrees +/-0.2 degrees, 26.61 degrees +/-0.2 degrees and 30.01 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is sulfate form C, which has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.87 ° ± 0.2 °, 9.31 ° ± 0.2 °, 9.52 ° ± 0.2 °, 11.46 ° ± 0.2 °, 12.65 ° ± 0.2 °, 14.07 ° ± 0.2 °, 14.57 ° ± 0.2 °, 15.36 ° ± 0.2 °, 15.90 ° ± 0.2 °, 17.07 ° ± 0.2 °, 17.71 ° ± 0.2 °, 18.63 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.55 ° ± 0.2 °, 20.80 ° ± 0.2 °, 21.56 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.44 ° ± 0.2 °, 23.41 ° ± 0.2 °, 23.70 ° ± 0.2 °, 24.20 ° ± 0.2 °, 24.66 ° ± 0.2, 24.2 °, and/3.2 ° ±, 25.00 degrees +/-0.2 degree, 25.55 degrees +/-0.2 degree, 25.82 degrees +/-0.2 degree, 26.29 degrees +/-0.2 degree, 26.78 degrees +/-0.2 degree, 26.99 degrees +/-0.2 degree, 27.37 degrees +/-0.2 degree, 27.79 degrees +/-0.2 degree, 28.57 degrees +/-0.2 degree, 29.37 degrees +/-0.2 degree, 29.80 degrees +/-0.2 degree, 30.10 degrees +/-0.2 degree, 30.67 degrees +/-0.2 degree, 32.04 degrees +/-0.2 degree, 32.86 degrees +/-0.2 degree, 33.69 degrees +/-0.2 degree, 34.32 degrees +/-0.2 degree, 34.93 degrees +/-0.2 degree, 35.76 degrees +/-0.2 degree, 36.51 degrees +/-0.2 degree and 37.48 degrees +/-0.2 degree.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is p-toluenesulfonate salt form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 0.2, 15.46, 0.2, 16.11, 0.2, 16.36, 0.2, 17.05, 0.2, 18.53, 0.2, 19.40, 0.2, 19.99, 0.2, 20.49, 0.2, 20.84, 0.2, 21.51, 0.2, 22.19, 0.2, 23.44, 0.2, 23.68, 0.2, 24.94, 0.2, 0.26, 0.2, 2, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is crystalline form B p-toluenesulfonate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.26 +/-0.2 DEG, 8.00 +/-0.2 DEG, 9.50 +/-0.2 DEG, 11.98 +/-0.2 DEG, 12.48 +/-0.2 DEG, 13.55 +/-0.2 DEG, 14.11 +/-0.2 DEG, 14.55 +/-0.2 DEG, 15.37 +/-0.2 DEG, 15.85 +/-0.2 DEG, 16.64 +/-0.2 DEG, 17.41 +/-0.2 DEG, 17.87 +/-0.2 DEG, 18.92 +/-0.2 DEG, 19.28 +/-0.2 DEG, 19.65 +/-0.2 DEG, 20.53 +/-0.2 DEG, 20.98 +/-0.2 DEG, 21.38 +/-0.2 DEG, 22.82 +/-0.2 DEG, 2 DEG, 23 +/-0.23 DEG, 23.35 +/-0.2 DEG, 23.91 +/-0.2.11 +/-0.24.24 DEG, 2.24 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27 +/-0.27.9 DEG, 2 DEG, 2.27 +/-0.9 DEG, 2.9 DEG, 2 DEG, 27 +/-0.9 DEG, 2 DEG, 0.9 DEG, 27 +/-0.9 DEG, 0.9 +/-0.2 DEG, 0.9 DEG, 0.2 DEG, 0.9 +/-0.2 DEG, 0.2.2 DEG, 0.2 DEG, 0.2.2 DEG, 30 DEG, 0.2 DEG, 0.9 +/-0.2 DEG, 30 DEG, 0.9 +/-0.2 DEG, 0.9 DEG, 0.2 DEG, 0.9 +/-0.2 DEG, 30 +/-0.27 +/-0.2 DEG, 30 +/-0.9 +/-0.2 DEG, 30 DEG, 0.9 +/-0.2 DEG, 0.9 +/-0.27 +/-0.2 DEG, 30 +/-0.9 +/-0.2 DEG, 30 DEG, 0.2 DEG, 0 +/-0.9 +/-0.2 DEG, 0.2 +/-0.2 DEG, 30 +/-0.9 +/-0.2 DEG, 30 +/-0.9 +/-0.2 DEG, 30 +/-0.2 DEG, 0.9 +/-0 +/-0.2 DEG, 34.67 degrees +/-0.2 degrees, 35.37 degrees +/-0.2 degrees, 36.92 degrees +/-0.2 degrees, 37.63 degrees +/-0.2 degrees, 38.92 degrees +/-0.2 degrees and 39.50 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having a diffraction peak at the following 2 Θ angles in an X-ray powder diffraction pattern: 7.71 degrees +/-0.2 degrees, 11.43 degrees +/-0.2 degrees, 13.50 degrees +/-0.2 degrees, 14.36 degrees +/-0.2 degrees, 15.50 degrees +/-0.2 degrees, 16.91 degrees +/-0.2 degrees, 17.67 degrees +/-0.2 degrees, 19.01 degrees +/-0.2 degrees, 21.20 degrees +/-0.2 degrees, 22.31 degrees +/-0.2 degrees, 23.37 degrees +/-0.2 degrees, 24.90 degrees +/-0.2 degrees, 25.84 degrees +/-0.2 degrees, 26.17 degrees +/-0.2 degrees, 26.49 degrees +/-0.2 degrees, 27.33 degrees +/-0.2 degrees, 28.66 degrees +/-0.2 degrees, 29.50 degrees +/-0.2 degrees, 31.35 degrees +/-0.2 degrees, 32.10 degrees +/-0.2 degrees, 35.84 degrees +/-0.2 degrees, 37.10 degrees 0.2 degrees and 39.05 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a maleate salt, wherein the maleate salt is form a maleate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 0.2, 9.66 +/-0.2, 11.97 +/-0.2, 12.63 +/-0.2, 12.73 +/-0.2, 14.65 +/-0.2, 14.75 +/-0.2, 15.27 +/-0.2, 16.41 +/-0.2, 16.82 +/-0.2, 17.51 +/-0.2, 18.62 +/-0.2, 19.07 +/-0.2, 19.42 +/-0.2, 19.88 +/-0.2, 20.54 +/-0.2, 21.27 +/-0.2, 22.47 +/-0.2, 22.61 +/-0.2, 23.56 +/-0.2, 24.20 +/-0.2, 24.53 +/-0.2, 25.12 +/-0.2 +/-0.9 +/-0.27 +/-0.2, 36 +/-0.27 +/-0, 0.27 +/-0.27, 14, 0.27 +/-0.27, 2, 14 +/-0.2, 2, 24.27 +/-0.27, 2, 14, 2, 24, 36, 2, 24.53, 36, 2, 24.53, 3 +/-0.3, 3, 2, 3, 2, 3.12, 3, 2, 3, 2, 3.12 +/-0.9, 3, 2, 3, 2, 3, 2, 3 +/-0.9, 2, 3, 2, 3 +/-0.9, 2, 3, 2, 3 +/-0.9, 3 +/-0.9.9.9.9, 3, 2, 3, 2, 3 +/-0.9, 2, 3 +/-0.9, 2, 3 +/-0.9.9.9, 3 +/-0.9.9, 3 DEG +/-0.9, 3 +/-0.9, 3 DEG, 3 DEG +/-0.9, 0.9.9, 3 DEG +/-0.9, 2.9.9.9, 3 DEG +/-0.9, 3 +/-0.9, 2, 0.9 DEG +/-0.9, 2, 0.9.9, 3 DEG +/-0.9 DEG +/-0.9., 37.82 degrees +/-0.2 degrees, 38.42 degrees +/-0.2 degrees, 38.82 degrees +/-0.2 degrees and 39.38 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.25 +/-0.2 DEG, 6.85 +/-0.2 DEG, 9.15 +/-0.2 DEG, 10.05 +/-0.2 DEG, 12.47 +/-0.2 DEG, 13.99 +/-0.2 DEG, 14.45 +/-0.2 DEG, 14.85 +/-0.2 DEG, 15.83 +/-0.2 DEG, 16.73 +/-0.2 DEG, 17.58 +/-0.2 DEG, 18.28 +/-0.2 DEG, 18.75 +/-0.2 DEG, 19.24 +/-0.2 DEG, 19.58 +/-0.2 DEG, 20.15 +/-0.2 DEG, 20.46 +/-0.2 DEG, 21.01 +/-0.2 DEG, 21.90 +/-0.2 DEG, 22.42 +/-0.2 DEG, 22.98 +/-0.2 DEG, 23.61 +/-0.2 DEG, 24.16 +/-0.2.01 +/-0.2 DEG, 0.0 +/-0.2 DEG, 0.27 +/-0.27 DEG, 2 DEG, 27 +/-0.27 DEG, 2 DEG, 2.2 DEG, 2 DEG, 2.2 DEG, 2 DEG, 30.30 +/-0.2 DEG, 30 DEG, 30.27.2 DEG, 30 +/-0.2 DEG, 30 DEG +/-0.2 DEG, 30 DEG, 2.2.2.2 DEG, 0.2 DEG, 30 DEG, 0.2 DEG, 30 DEG +/-0.2 DEG, 2 DEG, 2.2 DEG, 2 DEG, 30 DEG, 0.2.2.2 DEG, 30 DEG, 0.2 DEG, 2 DEG, 0.2.2.2.2 DEG, 2 DEG, 2.2 DEG, 30 DEG, 2.2 DEG, 2 DEG, 30 DEG, 2.2 DEG, 30 DEG, 0.2 DEG, 30 DEG, 2 DEG, 30 DEG, 0.2.2.2.2 DEG, 2.2.2 DEG, 30 DEG, 2 DEG, 2.2 DEG, 2 DEG, 30 DEG, 0.2 DEG, 30 +/-0.2 DEG, 30 DEG, 0.2 DEG, 0.27 DEG, 0.2 DEG, 0.2.2.2.2 DEG, 30 DEG +/-0.2 DEG, 0.2 DEG +/-0.2 DEG, 30 DEG +/-0.2.30 DEG, 30 DEG, 0.2 DEG +/-0.2.2.2 DEG +/-0.2 DEG +/-0.2.2.2.2.2 DEG, 0.2.2 DEG, 0.2 DEG +/-0.2 DEG, 0.2 DEG +/-0.2 DEG, 0.2.2.2 DEG +/-0.2 DEG +/-0.2.2 DEG, 0.2.2 DEG +/-0.2.30 DEG +/-0.2 DEG, 0.2.2.2 DEG +/-0.2 DEG, 39.04 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is sulfate form a having an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B of the sulfate salt, wherein the form B of the sulfate salt has an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is sulfate form C, which has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is form a p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in fig. 4.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is in form B p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in fig. 5.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having an X-ray powder diffraction pattern substantially as shown in figure 6.

In some embodiments, the salt of the invention is a maleate salt characterized in that the maleate salt is form a maleate salt having an X-ray powder diffraction pattern substantially as shown in figure 7.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having an X-ray powder diffraction pattern substantially as shown in figure 8.

In some embodiments, the salt of the invention is a phosphate salt, wherein the phosphate salt is amorphous, wherein the amorphous phosphate salt has an X-ray powder diffraction pattern substantially as shown in figure 9.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is form B of the sulfate salt, the differential scanning calorimetry trace of which comprises endothermic peaks at 136.19 ℃ ± 3 ℃ and 185.76 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is form C of the sulfate salt, and the differential scanning calorimetry trace of form C of the sulfate salt comprises endothermic peaks at 69.42 ℃ ± 3 ℃, 103.78 ℃ ± 3 ℃ and 190.00 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tosylate salt, characterized in that the tosylate salt is form a tosylate salt, and the differential scanning calorimetry trace of form a of the tosylate salt comprises an endothermic peak at 190.50 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, characterized in that the p-toluenesulfonate salt is form B p-toluenesulfonate salt, having a differential scanning calorimetry trace comprising an endothermic peak at 228.21 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is form a oxalate salt, and wherein a differential scanning calorimetry trace of form a of the oxalate salt comprises an endothermic peak at 205.92 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a maleate salt characterized in that the maleate salt is maleate form a having a differential scanning calorimetry trace comprising an endothermic peak at 183.15 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having a differential scanning calorimetry trace comprising an endothermic peak at 243.26 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B of the sulfate salt, wherein the form B of the sulfate salt has a differential scanning calorimetry trace substantially as shown in figure 10.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form C having a differential scanning calorimetry pattern substantially as shown in fig. 11.

In some embodiments, the salt of the present invention is a tosylate salt, characterized in that the tosylate salt is tosylate form a, and the tosylate form a has a differential scanning calorimetry pattern substantially as shown in figure 12.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is in form B, and wherein the p-toluenesulfonate salt form B has a differential scanning calorimetry trace substantially as shown in fig. 13.

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having a differential scanning calorimetry pattern substantially as shown in figure 14.

In some embodiments, the salt of the invention is a maleate salt characterized in that the maleate salt is maleate form a having a differential scanning calorimetry pattern substantially as shown in figure 15.

In some embodiments, the salt of the invention is a hydrobromide salt, characterized in that the hydrobromide salt is hydrobromide form a having 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 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 said pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating the interaction of a patient with 5-HT_1FA receptor associated disease.

In some such embodiments, the invention relates to 5-HT_1FThe receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

In another aspect, the invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for activating 5-HT_1FA receptor.

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

The solvent used in the method for preparing the salt or the crystalline form thereof according to 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. In addition, many equivalent modifications, substitutions, or equivalents in the various solvent, solvent combinations, and ratios of solvent combinations described herein are contemplated as falling within the scope of 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 of the invention are described in detail in the examples section. Meanwhile, the invention provides pharmacological property test experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, hygroscopicity experiments and the like of the salt or the crystal form thereof. Experiments prove that the salt disclosed by the embodiment of the invention has good stability and good water solubility, so that the salt disclosed by the embodiment of the invention has better bioactivity and higher stability, and is more suitable for pharmaceutical application.

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.

"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, 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, dimethyl carbonate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"solvate" refers to a compound having a solvent on the surface, in the crystal lattice, or on and in the crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, dimethyl carbonate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene 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 spectrum may have experimental errors, and the peak positions and peak values of the DSC spectrum may be slightly different between different instruments and different samples, so that the DSC spectrum has the advantages of simple process, low cost and high safetyThe peak position of the endothermic peak or the value of the peak value 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 estimated that the crystal contains crystal water or a crystallization 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 said 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide 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.

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.

Pharmaceutical 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 salts and/or crystal forms of the compounds shown in the formula (I) and pharmaceutically acceptable carriers, auxiliary agents or excipients. The amount of the salt of the compound or crystalline form thereof in the pharmaceutical composition of the invention is effective to detectably treat or alleviate the symptoms of 5-HT in a patient_1FReceptor-related diseases, in particular migraine. 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, Philadelphia; 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 The formulation of 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. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

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 invention relates to a process for preparing a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the 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 salts of the compounds of the present invention or crystalline forms 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. 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 crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof. 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 crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof.

In one embodiment, the salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof 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 crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof may be administered orally. In another embodiment, a salt of a compound of the invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof may be administered by inhalation. In yet another embodiment, a salt of a compound of the invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof can be administered intranasally.

In one embodiment, the salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof may be administered once or several times at different time intervals within a specified time period 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 crystalline form thereof, or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof, 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, suitable dosing regimens of the salts of the compounds of the invention or crystalline forms thereof, or pharmaceutical compositions comprising the salts of the compounds of the invention or crystalline forms thereof, including the duration of the regimen, will depend upon 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 like factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The salts of the compounds of the present invention or crystalline forms thereof may be administered concurrently with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention or their crystalline forms may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate symptoms of the disease is administered or allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics,8th ed., Pergamon Press, 1990; remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1990.

Preferably, the compounds of formula (I) are formulated in unit dosage forms containing from about 0.001 to about 100mg of the active ingredient per dose, more often from about 1.0 to about 30mg of the active ingredient per dose. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as hereinbefore described.

The active compounds are generally effective over a wide dosage range. For example, the daily dose is generally about 0.0001-30mg/kg body weight. For adult human treatment, a particularly preferred dose (single or divided dose) is about 0.1-15 mg/kg/day. It will be understood, however, that the amount of compound actually administered will be determined by the attending physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds to be administered, the age, weight, and response of the particular patient, and the severity of the patient's symptoms, and, therefore, that the above dosage ranges should not be taken as limiting the scope of the invention in any way. In some instances, dosage levels below the lower limit of the aforesaid dosage range may be more suitable, while in other cases higher doses may be employed without causing any side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

The optimal therapeutically effective amount to be administered can be readily determined by one skilled in the art and will vary substantially depending on the strength of the formulation, the mode of administration and the advancement of the disease or disorder being treated. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, result in the need to adjust the dosage to an appropriate therapeutically effective level.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, the dosage will necessarily vary depending upon the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology and the selected vaccination regimen. The weight of the compound per unit dose, excluding the weight of the carrier (vehicle included in the drug), refers to the weight of the compound per administration.

The salt of the compound provided by the invention or the crystal form and the pharmaceutical composition thereof can be used for preparing a medicine for preventing, treating or relieving the 5-HT of a patient_1FPharmaceutical products for the treatment of receptor-related diseases, in particular for the prevention, treatment or alleviation of migraine, and for the activation of 5-HT_1FA pharmaceutical product of a recipient.

In particular, the amount of compound in the pharmaceutical compositions of the present invention is effective to detectably selectively activate 5-HT_1FThe receptor, the salt of the compound of the invention or the crystal forms thereof can be used for treating 5-HT_1FA receptor related disease such as migraine.

The salts of the compounds of the present invention or crystalline forms thereof may be used in, but are in no way limited to, the prevention, treatment, or amelioration of 5-HT associated with administration to a patient of an effective amount of a salt of the compound of the present invention or a crystalline form or pharmaceutical composition thereof_1FA receptor associated disease. The and 5-HT_1FReceptor-related disorders further including, but not limited to, migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, and dementia.

An "effective amount" or "effective dose" of a salt of a compound of the invention or a crystalline form or pharmaceutically acceptable composition thereof refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The salt of the compound of the invention or a crystalline form or pharmaceutically acceptable composition thereof may be administered in any amount and by any route effective to treat or reduce the severity of the disease in accordance with the methods of the present invention. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The salts of the compounds of the present invention or crystalline forms or pharmaceutically acceptable compositions thereof may be administered in combination with one or more other therapeutic agents, as discussed herein.

The salts of the compounds of the present invention or their crystalline forms and pharmaceutical compositions are useful in veterinary therapy for pets, animals of the introduced breed 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 sulfate salt form a of the compound of formula (I).

Figure 2 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form B of the compound of formula (I).

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

FIG. 4 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the p-toluenesulfonate salt of the compound of formula (I).

FIG. 5 is an X-ray powder diffraction (XRPD) pattern of crystalline form B p-toluenesulfonate of the compound of formula (I).

Figure 6 is an X-ray powder diffraction (XRPD) pattern of oxalate form a of the compound of formula (I).

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

Figure 8 is an X-ray powder diffraction (XRPD) pattern of crystalline form a of the hydrobromide salt of the compound of formula (I).

FIG. 9 is an X-ray powder diffraction (XRPD) pattern of the amorphous phosphate salt of the compound of formula (I).

FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of the crystalline form B of the sulfate salt of the compound of formula (I).

FIG. 11 is a Differential Scanning Calorimetry (DSC) profile of the sulfate salt form C of the compound of formula (I).

FIG. 12 is a Differential Scanning Calorimetry (DSC) profile of crystalline form A of p-toluenesulfonate of the compound of formula (I).

FIG. 13 is a Differential Scanning Calorimetry (DSC) profile of crystalline form B of p-toluenesulfonate of the compound of formula (I).

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

FIG. 15 is a Differential Scanning Calorimetry (DSC) profile of maleate form A of the compound of formula (I).

FIG. 16 is a Differential Scanning Calorimetry (DSC) chart of the hydrobromide 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. The powdered sample was prepared as a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage and analyzed in 0.0167 ° steps over a range of 3 ° -40 °. Data Collector software was used to collect Data, HighScore Plus software processed Data, and Data Viewer software read Data.

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 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.

The solubility of the invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the type of a chromatographic column is Agilent XDB-C18(4.6 multiplied by 50mm, 5 mu m). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the ratio of mobile phase A: acetonitrile/0.01M ammonium acetate 10/90(V/V) analytical method: acetonitrile/mobile phase a ═ 70/30(V/V), run time: for 10 minutes.

Detailed description of the invention

A compound of formula (I): 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide, the specific synthesis method being referred to example 12 of international application WO 2020038435 a 1.

Examples

Example 1: sulfate form A of the present invention

1. Preparation of sulfate form A

The compound represented by the formula (I) (388mg) was weighed, isopropanol (4mL) and concentrated sulfuric acid (208mg,98 mass%) were added, and the mixture was stirred at room temperature to obtain an initial clear solution, followed by stirring to increase turbidity and to cause remarkable crystallization, and further stirred overnight. The solid obtained by filtration is leached with n-heptane (2mL) and dried by vacuum pumping at 50 ℃ to obtain white solid powder which is the sulfate crystal form A and has the yield of about 81 percent.

2. Identification of sulfate form a

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.37 °, 7.91 °, 9.25 °, 10.65 °, 12.13 °, 12.75 °, 13.61 °, 14.17 °, 15.15 °, 15.93 °, 16.57 °, 17.62 °, 18.26 °, 19.08 °, 19.26 °, 21.19 °, 21.44 °, 21.98 °, 22.58 °, 23.00 °, 23.96 °, 24.60 °, 25.79 °, 26.23 °, 27.49 °, 27.85 °, 28.27 °, 28.63 °, 29.06 °, 29.53 °, 30.62 °, 31.71 °, 32.11 °, 34.91 °, 36.39 °, 37.77 °, with an error tolerance of ± 0.2 °.

Example 2: sulfate form B of the invention

1. Preparation of sulfate form B

The compound of formula (I) (1.13g) was weighed out and dissolved in ethyl acetate (11mL) at 60 ℃, concentrated sulfuric acid (0.34g, 98 mass%) was diluted with ethyl acetate (2mL) and slowly added dropwise to the ethyl acetate solution, and a large amount of white powder was formed by stirring, and ethyl acetate (5mL) was added to improve the fluidity. Cooling to room temperature, stirring for 12h, filtering the solid, leaching with n-heptane (6mL), and vacuum-drying at 50 ℃ to obtain white solid powder which is sulfate crystal form B with the yield of about 93%.

2. Identification of sulfate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.62 °, 9.58 °, 10.02 °, 12.17 °, 13.01 °, 14.70 °, 15.57 °, 16.88 °, 17.58 °, 18.48 °, 19.28 °, 20.13 °, 21.51 °, 22.79 °, 24.32 °, 26.61 °, 30.01 °, with a tolerance of ± 0.2 °.

(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 136.19 ℃ and 185.76 ℃, with a margin of error of ± 3 ℃.

Example 3: sulfate form C of the invention

1. Preparation of sulfate form C

Weighing a proper amount of sulfate crystal form B solid of the compound shown in the formula (I), flatly paving the sulfate crystal form B solid in a weighing bottle, and placing the weighed sulfate crystal form B solid in a high-humidity condition of 25 ℃ and 90 +/-2% RH for 10 days to obtain white solid powder which is sulfate crystal form C.

2. Identification of sulfate form C

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.87 °, 9.31 °, 9.52 °, 11.46 °, 12.65 °, 14.07 °, 14.57 °, 15.36 °, 15.90 °, 17.07 °, 17.71 °, 18.63 °, 19.22 °, 19.55 °, 20.80 °, 21.56 °, 22.05 °, 22.44 °, 23.41 °, 23.70 °, 24.20 °, 24.66 °, 25.00 °, 25.55 °, 25.82 °, 26.29 °, 26.78 °, 26.99 °, 27.37 °, 27.79 °, 28.57 °, 29.37 °, 29.80 °, 30.10 °, 30.67 °, 32.04 °, 32.86 °, 33.69 °, 34.32 °, 34.93 °, 35.76 °, 36.51 °, 37.48 °, and an error tolerance of ± 0.2 ° exists.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 69.42 ℃, 103.78 ℃ and 190.00 ℃, with a margin of error of ± 3 ℃.

Example 4: crystalline form A of p-toluenesulfonate of the present invention

1. Preparation of p-toluenesulfonate form A

The compound represented by the formula (I) (388mg) was weighed out, isopropanol (4mL) and p-toluenesulfonic acid monohydrate (395mg) were added, and the mixture was stirred at room temperature, increased in turbidity and remarkable in crystallization, and further stirred overnight. Filtering to obtain a solid, leaching with n-heptane (2mL), and vacuumizing at 50 ℃ to obtain white solid powder which is p-toluenesulfonate crystal form A with the yield of about 86%.

2. Identification of p-toluenesulfonate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.80 °, 8.93 °, 11.27 °, 12.79 °, 13.72 °, 15.46 °, 16.11 °, 16.36 °, 16.80 °, 17.05 °, 17.38 °, 18.05 °, 18.53 °, 19.40 °, 19.99 °, 20.49 °, 20.84 °, 21.51 °, 22.48 °, 22.79 °, 23.44 °, 23.68 °, 24.94 °, 25.66 °, 26.19 °, 26.72 °, 27.05 °, 27.92 °, 28.54 °, 29.10 °, 30.36 °, 30.81 °, 31.71 °, 32.77 °, 33.88 °, 34.46 °, 35.08 °, 35.82 °, 36.16 °, 36.63 °, 37.26 °, 38.55 °, with an error tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 190.50 ℃, with a margin of error of ± 3 ℃.

Example 5: crystalline form B of p-toluenesulfonate of the present invention

1. Preparation of p-toluenesulfonate form B

Compound (1.14g) of formula (I) was weighed, isopropanol (10mL) was added, and the mixture was stirred at room temperature; p-toluenesulfonic acid monohydrate (0.70g) was added to isopropanol (2mL) to dissolve and clear, and then added dropwise to the isopropanol solution, and the mixture was stirred at room temperature, and then stirred overnight. Filtering to obtain a solid, leaching with n-heptane (10mL), and vacuumizing at 50 ℃ to obtain white solid powder which is p-toluenesulfonate crystal form B with the yield of about 96%.

2. Identification of p-toluenesulfonate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.26 °, 8.00 °, 9.50 °, 11.98 °, 12.48 °, 13.55 °, 14.11 °, 14.55 °, 15.37 °, 15.85 °, 16.64 °, 17.41 °, 17.87 °, 18.92 °, 19.28 °, 19.65 °, 20.53 °, 20.98 °, 21.38 °, 22.82 °, 23.23 °, 23.35 °, 23.91 °, 24.11 °, 24.46 °, 24.63 °, 25.25 °, 25.65 °, 26.59 °, 27.34 °, 27.61 °, 27.79 °, 28.56 °, 28.93 °, 29.44 °, 29.85 °, 30.37 °, 30.92 °, 31.19 °, 31.64 °, 32.05 °, 33.54 °, 34.09 °, 34.67 °, 35.37 °, 36.92 °, 37.63 °, 38.92 °, 39.50 °, and an error tolerance of ± 0.2 ° exists.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 228.21 ℃, with a margin of error of ± 3 ℃.

Example 6: oxalate form A of the invention

1. Preparation of oxalate form A

The compound represented by the formula (I) (380mg) was weighed out at room temperature, dissolved in ethyl acetate (8mL), and oxalic acid (108mg) was added thereto to give a large amount of white powder. Stirring at room temperature for overnight, filtering, and vacuum drying at 50 deg.C to obtain white solid powder as oxalate crystal form A with yield of about 86%.

2. Identification of oxalate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.71 °, 11.43 °, 13.50 °, 14.36 °, 15.50 °, 16.91 °, 17.67 °, 19.01 °, 21.20 °, 22.31 °, 23.37 °, 24.90 °, 25.84 °, 26.17 °, 26.49 °, 27.33 °, 28.66 °, 29.50 °, 31.35 °, 32.10 °, 35.84 °, 37.10 °, 39.05 °, with an error tolerance of ± 0.2 °.

(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 205.92 ℃, with a margin of error of ± 3 ℃.

Example 7: maleate salt form A of the present invention

1. Preparation of maleate form a

Weighing a compound (388mg) shown in the formula (I) at room temperature, adding isopropanol (4mL) and maleic acid (242mg), stirring for dissolving clearly, continuing stirring at room temperature, increasing turbidity, obviously crystallizing, continuing stirring overnight, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain white solid powder which is a maleate crystal form A with the yield of about 88%.

2. Identification of maleate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 8.37 °, 9.66 °, 11.97 °, 12.63 °, 12.73 °, 14.65 °, 14.75 °, 15.27 °, 16.41 °, 16.82 °, 17.51 °, 18.62 °, 19.07 °, 19.42 °, 19.88 °, 20.54 °, 21.27 °, 22.47 °, 22.61 °, 23.56 °, 24.20 °, 24.53 °, 25.12 °, 25.64 °, 26.24 °, 26.70 °, 27.36 °, 27.77 °, 28.05 °, 28.36 °, 29.25 °, 29.69 °, 30.45 °, 30.82 °, 31.30 °, 31.68 °, 32.01 °, 33.04 °, 33.86 °, 34.95 °, 35.46 °, 36.77 °, 37.25 °, 37.82 °, 38.42 °, 38.82 °, 39.38 °, there is an error tolerance of ± 0.2 °.

2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 183.15 ℃, with a margin of error of ± 3 ℃.

Example 8: the crystal form A of the hydrobromide of the invention

1. Preparation of hydrobromide form a

Weighing the compound shown in the formula (I) (1.14g), adding the compound into ethyl acetate (12mL), heating to 60 ℃ under stirring for dissolving, adding hydrobromic acid (0.65g) into ethyl acetate (2mL), uniformly mixing, slowly dropwise adding the mixture into the ethyl acetate solution, separating out a large amount of white solid powder, cooling to room temperature, continuing stirring overnight, carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain white powder solid which is hydrobromide crystal form A with the yield of about 93%.

2. Identification of hydrobromide crystal form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.25 °, 6.85 °, 9.15 °, 10.05 °, 12.47 °, 13.99 °, 14.45 °, 14.85 °, 15.83 °, 16.73 °, 17.58 °, 18.28 °, 18.75 °, 19.24 °, 19.58 °, 20.15 °, 20.46 °, 21.01 °, 21.90 °, 22.42 °, 22.98 °, 23.61 °, 24.16 °, 25.01 °, 25.32 °, 25.61 °, 26.37 °, 26.85 °, 27.55 °, 28.25 °, 28.77 °, 29.13 °, 29.51 °, 29.96 °, 30.93 °, 31.48 °, 32.66 °, 33.41 °, 34.25 °, 35.48 °, 36.81 °, 37.33 °, 38.00 °, 39.04 °, and an error tolerance of ± 0.2 ° exists.

(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 243.26 ℃, with a margin of error of ± 3 ℃.

Example 9: the phosphate salt of the invention is amorphous

1. Preparation of amorphous phosphate

Weighing the compound (1.14g) shown in the formula (I), dissolving in ethyl acetate (11mL), heating to 60 ℃ to dissolve the compound under stirring, adding 0.35g of phosphoric acid into ethyl acetate (2mL) for dilution, then slowly dropwise adding the solution into the ethyl acetate solution, decompressing and rotary-steaming to dryness, adding 5mL of ethanol, stirring at room temperature to generate a large amount of white powder, continuing stirring overnight, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain white solid powder which is phosphate amorphous and has the yield of about 92%.

2. Identification of phosphate amorphous form

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-K alpha radiation, the X-ray powder diffraction pattern is substantially as shown in fig. 9.

Example 10: pharmacokinetic experiments of the salts or crystalline forms of the salts of the invention

The inventors have performed pharmacokinetic evaluations in Beagle dogs of the salts of the present invention or of the crystalline forms thereof. Wherein, the animal information is detailed in table 1.

Table 1: the invention relates to an information table for tested animals

Germling

Grade

Sex

Body weight

Age (age)

Source

Beagle dog

Common stage

Male sex

8～12kg

6-12 months

BEIJING MARSHALL BIOTECHNOLOGY Co.,Ltd.

Experimental methods

The test sample (i.e., the salt of the invention or crystalline form thereof, or the compound of formula (I) of the invention) is filled into capsules for oral administration. Animals were fasted for 12h before dosing and had free access to water. Capsules containing test samples were administered orally at a dose of 5mg/kg, and after administration, venous blood sampling (blood volume taken about 0.15mL) was performed at the following time points: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours, EDTA-K is added in advance in the blood sampling tube₂As an anticoagulant, blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃.

The collected plasma samples were processed (frozen plasma was thawed at room temperature, vortexed for 5min, 20. mu.L of plasma was taken, 120. mu.L of acetonitrile solution containing an internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. mu.L of supernatant was taken, and 130. mu.L of methanol-water (V/V: 1/1) was added and mixed), and then a standard curve in an appropriate range was established according to the concentration of the sample to be tested, and the concentration of the sample to be tested in the plasma samples was measured in MRM mode using LC-MS/MS model AB SCIEX API5500 and subjected to quantitative analysis. According to the drug concentration-time curve, pharmacokinetic parameters are calculated by adopting a WinNonLin 6.3 software non-compartmental model method.

Experiments prove that the salt or the crystal form thereof disclosed by the embodiment of the invention has better pharmacokinetic properties in Beagle dogs.

Example 11: stability test of the salt of the present invention or the Crystal form thereof

(1)High temperature experiment: taking a proper amount of a batch of samples to be tested, putting the samples into a flat weighing bottle, spreading the samples into a thin layer with the thickness less than or equal to 5mm, putting the weighing bottle into a constant temperature box with the temperature of 40 +/-2 ℃/75 +/-5% RH and/or 60 +/-2 ℃/75 +/-5% RH, standing for 30 days, sampling on the 5 th, 10 th and 30 th days, and detecting according to the key stability investigation items: observing the color change of the sample, detecting the purity of the sample by HPLC, and analyzing the structure by X-ray powder diffraction.

(2)High humidity experiment: a proper amount of a batch of samples to be tested are put into a flat weighing bottle, spread into a thin layer with the thickness less than or equal to 5mm, placed for 30 days at 25 ℃ under the conditions of 75% +/-5% RH and/or 90% +/-5% RH, sampled on the 5 th, 10 th and 30 th days, detected according to the key stability investigation items, the color change of the samples is observed, the purity of the samples is detected by HPLC, and the structure is analyzed by X-ray powder diffraction.

(3)Illumination experiment: taking a proper amount of sample to be tested, placing into a flat weighing bottle, spreading into a thin layer with thickness less than or equal to 5mm, placing into an illumination box (with ultraviolet lamp) with an opening, wherein the illumination is 4500 + -500 lx, and the ultraviolet light is more than or equal to 0.7 w.h/m²Was left for 30 days, sampled on

days

5, 10 and 30, and examined according to stability stress examination items: observing the color change of the sample, detecting the purity of the sample by HPLC, and analyzing the structure by X-ray powder diffraction.

Example 12: hygroscopicity assay of the salts or crystalline forms thereof of the invention

The experimental method comprises the following steps:

1) placing a dried glass weighing bottle with a plug (outer diameter of 50mm, height of 15mm) in a constant temperature drier (ammonium chloride saturated solution placed at the lower part) at 25 + -1 deg.C in the previous day, and precisely weighing₁)。

2) Taking a proper amount of sample, spreading in the weighing bottle to obtain a sample with thickness of 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, and precision weighing is carried out (m)₃) And calculating: percent weight gain [ (% m)₃-m₂)/(m₂-m₁)×100％

5) The results of hygroscopicity were shown in Table 2.

Table 2: judgment of hygroscopicity result

Experiments prove that the salt or the crystal form thereof provided by the embodiment of the invention has no or almost no hygroscopicity, and is not easy to deliquesce under the influence of high humidity.

Example 13: solubility testing of the salts of the invention or crystalline forms thereof

Placing a sample to be tested in 37 ℃ organic ultrapure water to prepare a supersaturated solution, shaking for 24h, filtering by using a water system filter membrane to obtain a filtrate, and detecting the solubility of the target sample in the water by using an HPLC method.

Experiments prove that the salt or the crystal form thereof disclosed by the embodiment of the invention has higher solubility in water, so that the salt or the crystal form thereof has better drug forming property and is suitable for preparation development.

The above description is only a basic description of the concept of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall into 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" or the like are intended to 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

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

wherein the salt is an organic acid salt or an inorganic acid salt; wherein the inorganic acid salt is hydrochloride, hydrobromide, phosphate, nitrate or sulfate; the organic acid salt is acetate, succinate, oxalate, fumarate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, salicylate, benzenesulfonate, methanesulfonate or p-toluenesulfonate.

2. The salt of claim 1, wherein the sulfate is sulfate form a, sulfate form B, or sulfate form C, the p-toluenesulfonate is p-toluenesulfonate form a or p-toluenesulfonate form B, the oxalate is oxalate form a, the maleate is maleate form a, and the hydrobromide is hydrobromide form a;

wherein the X-ray powder diffraction pattern of the sulfate form A has diffraction peaks at the following 2 theta angles: 6.37 degrees +/-0.2 degrees, 15.15 degrees +/-0.2 degrees, 18.26 degrees +/-0.2 degrees, 19.08 degrees +/-0.2 degrees, 19.26 degrees +/-0.2 degrees, 21.19 degrees +/-0.2 degrees, 21.44 degrees +/-0.2 degrees, 23.00 degrees +/-0.2 degrees and 25.79 degrees +/-0.2 degrees;

the X-ray powder diffraction pattern of the sulfate crystal form B has diffraction peaks at the following 2 theta angles: 5.62 degrees +/-0.2 degrees, 9.58 degrees +/-0.2 degrees, 13.01 degrees +/-0.2 degrees, 14.70 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.58 degrees +/-0.2 degrees and 22.79 degrees +/-0.2 degrees;

the sulfate form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.87 degrees +/-0.2 degrees, 9.31 degrees +/-0.2 degrees, 11.46 degrees +/-0.2 degrees, 12.65 degrees +/-0.2 degrees, 15.90 degrees +/-0.2 degrees, 17.07 degrees +/-0.2 degrees, 22.05 degrees +/-0.2 degrees, 22.44 degrees +/-0.2 degrees, 23.41 degrees +/-0.2 degrees and 26.78 degrees +/-0.2 degrees;

the crystalline form a of the tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.27 ° ± 0.2 °, 12.79 ° ± 0.2 °, 13.72 ° ± 0.2 °, 15.46 ° ± 0.2 °, 16.80 ° ± 0.2 °, 17.05 ° ± 0.2 °, 17.38 ° ± 0.2 °, 18.05 ° ± 0.2 °, 18.53 ° ± 0.2 °, 19.40 ° ± 0.2 °, 20.84 ° ± 0.2 °, 21.51 ° ± 0.2 °, 22.48 ° ± 0.2 °, 22.79 ° ± 0.2 °, 23.44 ° ± 0.2 °;

the crystalline form B of the tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.00 degrees +/-0.2 degrees, 11.98 degrees +/-0.2 degrees, 15.85 degrees +/-0.2 degrees, 16.64 degrees +/-0.2 degrees, 18.92 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 19.65 degrees +/-0.2 degrees, 20.98 degrees +/-0.2 degrees, 21.38 degrees +/-0.2 degrees, 23.91 degrees +/-0.2 degrees and 24.11 degrees +/-0.2 degrees;

the oxalate form A has an X-ray powder diffraction pattern with diffraction peaks at the following 2 theta angles: 7.71 degrees +/-0.2 degrees, 15.50 degrees +/-0.2 degrees, 23.37 degrees +/-0.2 degrees, 24.90 degrees +/-0.2 degrees, 25.84 degrees +/-0.2 degrees, 29.50 degrees +/-0.2 degrees and 31.35 degrees +/-0.2 degrees;

the maleate form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.37 ° ± 0.2 °, 9.66 ° ± 0.2 °, 12.63 ° ± 0.2 °, 14.65 ° ± 0.2 °, 16.82 ° ± 0.2 °, 18.62 ° ± 0.2 °, 19.07 ° ± 0.2 °, 19.88 ° ± 0.2 °, 24.20 ° ± 0.2 °, 24.53 ° ± 0.2 °, 25.64 ° ± 0.2 °, 26.24 ° ± 0.2 °;

the hydrobromide form A has an X-ray powder diffraction pattern with diffraction peaks at the following 2 theta angles: 6.25 degrees +/-0.2 degrees, 12.47 degrees +/-0.2 degrees, 13.99 degrees +/-0.2 degrees, 18.28 degrees +/-0.2 degrees, 18.75 degrees +/-0.2 degrees, 19.24 degrees +/-0.2 degrees, 22.42 degrees +/-0.2 degrees, 24.16 degrees +/-0.2 degrees and 28.25 degrees +/-0.2 degrees.

3. The salt according to claim 2, wherein,

the X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the following 2 theta angles: 6.37 +/-0.2 °, 7.91 +/-0.2 °, 9.25 +/-0.2 °, 10.65 +/-0.2 °, 12.13 +/-0.2 °, 12.75 +/-0.2 °, 13.61 +/-0.2 °, 15.15 +/-0.2 °, 15.93 +/-0.2 °, 16.57 +/-0.2 °, 18.26 +/-0.2 °, 19.08 +/-0.2 °, 19.26 +/-0.2 °, 21.19 +/-0.2 °, 21.44 +/-0.2 °, 21.98 +/-0.2 °, 22.58 +/-0.2 °, 23.00 +/-0.2 °, 23.96 +/-0.2 °, 24.60 +/-0.2 °, 25.79 +/-0.2 °, 26.23 +/-0.2 °, 27.49 +/-0.2 °, 27.85 +/-0.27 ° ± 0.9 ° ± 0.28 °, 2.9 +/-0.9 ° ± 2 °, 2.9 +/-0.9 ° ± 2 °, 2.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 2.3 ° ± 2 °, 2.2 ° ± 3 ° ± 0.2.2.2 ° ± 3 ° ± 0.2 °, 2.2 °,2 ° ± 3.2.2 °,2 ° ± 3 ° ± 0.9 ° ± 0.2 ° ± 3 ° ± 0.2 °, 2.2 °,2 ° ± 0.2 ° ± 3 ° ± 0.2 °, 2.2 ° ± 0.2 °;

the X-ray powder diffraction pattern of the sulfate crystal form B has diffraction peaks at the following 2 theta angles: 5.62 degrees +/-0.2 degrees, 9.58 degrees +/-0.2 degrees, 10.02 degrees +/-0.2 degrees, 12.17 degrees +/-0.2 degrees, 13.01 degrees +/-0.2 degrees, 14.70 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.58 degrees +/-0.2 degrees, 18.48 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 20.13 degrees +/-0.2 degrees, 21.51 degrees +/-0.2 degrees, 22.79 degrees +/-0.2 degrees, 24.32 degrees +/-0.2 degrees and 26.61 degrees +/-0.2 degrees;

the sulfate form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.87 ° ± 0.2 °, 9.31 ° ± 0.2 °, 9.52 ° ± 0.2 °, 11.46 ° ± 0.2 °, 12.65 ° ± 0.2 °, 14.57 ° ± 0.2 °, 15.36 ° ± 0.2 °, 15.90 ° ± 0.2 °, 17.07 ° ± 0.2 °, 17.71 ° ± 0.2 °, 18.63 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.55 ° ± 0.2 °, 20.80 ° ± 0.2 °, 21.56 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.44 ° ± 0.2 °, 23.41 ° ± 0.2 °, 23.70 ° ± 0.2 °, 24.20 ° ± 0.2 °, 2.2 °, 24.66 ° ± 0.2 °, 25.00 ° ± 0.2 °, 25.55 ° ± 0.2 ± 0.82 ° ± 0.26 °, 2.0.0.9 ° ± 0.9 °, 2.9 ° ± 0.2 °, 2.9 ° ± 0.2.2 °, 2.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9.9 °, 2.9 ° ± 0.9 °, 2.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9.9 °, 2.9 ° ± 0.9 ° ± 0.2.2.2.2 °, 2.9 ° ± 0.2.2 °, 2.2.2 °,2 °, 2.2 °, 2.9.9 ° ± 0.9 ° ± 0.9.9 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2.9 ° ± 0.2 °, 2.2.9 ° ± 0.2.9 ° ± 0.2.2.2.2.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.2 °,2 °, 2.2.2 °,2 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °, 2.2.2 °,2 °, 2.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.2 °,2 ° ± 0.9 ° ± 0.2.9.9 ° ± 0.9 ° ± 0.2.2.2 °,2 °, 2.2.2.9 ° ± 0.2.2.2.9 ° ± 0.9 ° ± 0.2 °, 2.2.2 ° ± 0.2.2.2.9 ° ± 0.9 ° ± 0.2 °,2 ° ± 0.2.2.2 °, 2.2.9.9 ° ± 0.9 ° ± 0.2.9 ° ± 0.9 ° ± 0.2 ° ± 0.2.9 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.2.9 ° ±;

the crystalline form a of the tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 0.2, 15.46, 0.2, 16.11, 0.2, 16.36, 0.2, 16.80, 0.2, 17.05, 0.2, 18.05, 0.2, 18.53, 0.2, 19.40, 0.2, 19.99, 0.2, 20.49, 0.2, 20.84, 0.2, 21.51, 0.2, 22.48, 0.2, 22.79, 0.2, 23.44, 0.2, 23.68, 0.2, 24.94, 0.2, 0.26, 0.2, 0.9, 0.2, 0, 0.2, 0.9, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0, 0.2, 0;

the crystalline form B of the tosylate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.26 +/-0.2 DEG, 8.00 +/-0.2 DEG, 9.50 +/-0.2 DEG, 11.98 +/-0.2 DEG, 12.48 +/-0.2 DEG, 13.55 +/-0.2 DEG, 14.11 +/-0.2 DEG, 14.55 +/-0.2 DEG, 15.37 +/-0.2 DEG, 15.85 +/-0.2 DEG, 16.64 +/-0.2 DEG, 17.41 +/-0.2 DEG, 17.87 +/-0.2 DEG, 18.92 +/-0.2 DEG, 19.28 +/-0.2 DEG, 19.65 +/-0.2 DEG, 20.53 +/-0.2 DEG, 20.98 +/-0.2 DEG, 21.38 +/-0.2 DEG, 22.82 +/-0 DEG, 2 DEG, 23 +/-0.23 +/-0.2 DEG, 23.35 +/-0.2 DEG, 23.91 +/-0.2.11 +/-0.24 +/-0.2 DEG, 2.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27 +/-0.27 DEG, 2 DEG, 2.27.27 +/-0.27 DEG, 2 DEG, 2.27 DEG, 2 DEG, 2.27 +/-0.9 DEG, 2 DEG, 2.9.9 DEG, 2 DEG, 2.9 +/-0.9 DEG, 30 DEG, 2.27 DEG, 0.27 +/-0.27 DEG, 2.9 DEG, 2 DEG, 0.27 DEG, 0.9 DEG, 0.27 DEG, 0.9 +/-0.9 DEG, 0.9 +/-0.27 DEG, 0 +/-0.9 DEG, 0 +/-0.27 DEG, 0.9 DEG, 0.27 DEG, 0 +/-0 DEG, 0 +/-0.27 DEG, 0.9 DEG, 0.27 DEG, 0.9 DEG, 0.27 DEG, 0 +/-0.27 DEG, 0.27 +/-0.27 DEG, 0 +/-0.27 DEG, 0 +/-0.27 DEG, 0.9 +/-0.27 DEG, 0 +/-0.27 DEG, 0.27 +/-0 +/-0.9 DEG, 0.9 +/-0 +/-0.9 DEG, 0 +/-0.27 DEG, 35.37 degrees +/-0.2 degrees and 37.63 degrees +/-0.2 degrees;

the oxalate form A has an X-ray powder diffraction pattern with diffraction peaks at the following 2 theta angles: 7.71 ° ± 0.2 °, 11.43 ° ± 0.2 °, 13.50 ° ± 0.2 °, 14.36 ° ± 0.2 °, 15.50 ° ± 0.2 °, 16.91 ° ± 0.2 °, 17.67 ° ± 0.2 °, 19.01 ° ± 0.2 °, 21.20 ° ± 0.2 °, 22.31 ° ± 0.2 °, 23.37 ° ± 0.2 °, 24.90 ° ± 0.2 °, 25.84 ° ± 0.2 °, 26.17 ° ± 0.2 °, 26.49 ° ± 0.2 °, 27.33 ° ± 0.2 °, 28.66 ° ± 0.2 °, 29.50 ° ± 0.2 °, 31.35 ° ± 0.2 °, 32.10 ° ± 0.2 °;

the maleate form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 0.2, 14.65, 0.2, 0.75, 0.2, 15.27, 0.2, 16.41, 0.2, 16.82, 0.2, 18.62, 0.2, 19.07, 0.2, 19.42, 0.2, 19.88, 0.2, 20.54, 0.2, 21.27, 0.2, 22.47, 0.2, 23.56, 0.2, 24.20, 0.2, 24.53, 0.2, 25.12, 0.2, 0.24, 0.26, 0.2, 0.9, 2, 0.9, 0.2, 0.9, 0.2, 0, 0.2, 0, 0.2, 0, 0.9, 0.2, 0, 0.9, 0, 0.2, 0.9, 0, 0.2, 0.9, 0.2, 0.9, 0.2, 0, 0.2, 0, 0.9, 0, 0.2, 0, 0.9, 0.2, 0.9, 0.2, 0, 0.9, 0.2, 0, 0.2, 0.9, 0, 0.9, 0.2, 0.9, 0, 0.2;

the hydrobromide form A has an X-ray powder diffraction pattern with diffraction peaks at the following 2 theta angles: 6.25 +/-0.2 °, 6.85 +/-0.2 °, 9.15 +/-0.2 °, 10.05 +/-0.2 °, 12.47 +/-0.2 °, 13.99 +/-0.2 °, 14.45 +/-0.2 °, 14.85 +/-0.2 °, 15.83 +/-0.2 °, 16.73 +/-0.2 °, 17.58 +/-0.2 °, 18.28 +/-0.2 °, 18.75 +/-0.2 °, 19.24 +/-0.2 °, 19.58 +/-0.2 °, 20.15 +/-0.2 °, 20.46 +/-0.2 °, 21.01 +/-0.2 °, 21.90 +/-0.2 °, 22.42 +/-0.2 °,2 °, 22.98 +/-0.2 °, 23.61 +/-0.2 °, 24.16 +/-0.2.01 +/-0.2 °, 2.0.2 °,2 ° +/-0.28 °, 2.28 +/-0.2 °,2 °, 2.2.2 °, 2.2 ° +/-2.2 °,2 ° +/-2 °, 2.2 ° +/-2.2 °,2 °, 2.2.2 ° +/-0.2 °,2 °, 2.2 ° +/-0.2 °, 2.2 °,2 °, 2.2.2 ° +/-0.2 °,2 °, 2.2.2.2 °,2 ° +/-0.2 °,2 ° +/-0.2.2 °, 2.2 °,2 °, 2.0.2 °, 2.2.2 ° +/-0.2 °, 2.2 °,2 ° +/-0.2 °,2 °, 2.2.0.2 °, 2.0.2 ° +/-of the angle of.

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

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

the sulfate salt form B has an X-ray powder diffraction pattern substantially as shown in figure 2;

the sulfate form C has an X-ray powder diffraction pattern substantially as shown in figure 3;

said crystalline form a of the p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in figure 4;

said crystalline form B of p-toluenesulfonate having an X-ray powder diffraction pattern substantially as shown in figure 5;

the oxalate form A has an X-ray powder diffraction pattern substantially as shown in FIG. 6;

said maleate form A has an X-ray powder diffraction pattern substantially as shown in figure 7;

the hydrobromide form A having an X-ray powder diffraction pattern substantially as shown in figure 8.

5. The salt according to claim 2, wherein,

a differential scanning calorimetry trace of form B of the sulfate salt comprising endothermic peaks at 136.19 ℃ ± 3 ℃ and 185.76 ℃ ± 3 ℃;

a differential scanning calorimetry trace of form C of the sulfate salt comprising endothermic peaks at 69.42 ℃ ± 3 ℃, 103.78 ℃ ± 3 ℃ and 190.00 ℃ ± 3 ℃;

a differential scanning calorimetry trace of said crystalline form A of tosylate comprising an endothermic peak at 190.50 ℃ ± 3 ℃;

said differential scanning calorimetry trace of form B of the tosylate salt comprises an endothermic peak at 228.21 ℃ ± 3 ℃;

a differential scanning calorimetry trace of form A of the oxalate salt comprising an endothermic peak at 205.92 ℃ ± 3 ℃;

a differential scanning calorimetry trace of said maleate form A comprising an endothermic peak at 183.15 ℃ ± 3 ℃;

the differential scanning calorimetry trace of the hydrobromide form A contained an endothermic peak at 243.26 ℃. + -. 3 ℃.

6. The salt of claim 2 or 5, wherein,

said sulfate form B having a differential scanning calorimetry trace substantially as shown in figure 10;

said sulfate polymorph form C having a differential scanning calorimetry pattern substantially as shown in figure 11;

said crystalline form a of tosylate having a differential scanning calorimetry pattern substantially as shown in figure 12;

said crystalline form B of tosylate having a differential scanning calorimetry pattern substantially as shown in figure 13;

the oxalate form a has a differential scanning calorimetry pattern substantially as shown in figure 14;

said maleate form a having a differential scanning calorimetry pattern substantially as shown in figure 15;

the hydrobromide form a has a differential scanning calorimetry trace substantially as shown in figure 16.

7. A pharmaceutical composition comprising a salt of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of a salt according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for preventing, treating or alleviating the symptoms of 5-HT in a patient_1FA receptor associated disease.

9. The use according to claim 8, wherein said treatment is with 5-HT_1FThe receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

10. RightsUse of a salt according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for activating 5-HT_1FA receptor.