CN108948018B

CN108948018B - Benzodiazepine derivatives, their salts and related crystalline forms, preparation and use

Info

Publication number: CN108948018B
Application number: CN201810424060.4A
Authority: CN
Inventors: 刘钢; 唐建川; 胡昊; 唐毅; 梁勇; 于华; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2017-05-17
Filing date: 2018-05-07
Publication date: 2021-03-30
Anticipated expiration: 2038-05-07
Also published as: CN108948018A

Description

Benzodiazepine derivatives, their salts and related crystalline forms, preparation and use

Technical Field

The invention relates to 3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f)][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

-4-yl) propionic acid methyl ester (hereinafter referred to as "compound of formula (I)") and its S-configuration compound 3(S) -3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

-4-yl) methyl propionate (hereinafter "compound of formula (Ia)"), salts of this compound and crystalline forms thereof, processes for its preparation, pharmaceutical compositions containing it and its use in the manufacture of a medicament for sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant.

Background

Benzodiazepines

The derivatives (benzodiazepines) are short-acting central nervous system inhibitors and have sedative, hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. Such drugs can be used for intravenous administration in the following clinical treatment regimens: such as preoperative sedation, anxiolysis and amnesia during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; and ICU sedation, etc.

Benzodiazepines commonly used clinically

Derivatives of classThere are more than 20 organisms. Although they are structurally similar, the clinical indications vary from derivative to derivative. Midazolam (midazolam) was used as the first benzodiazepine with water solubility in the early 80 s of the 20 th century

The compounds are introduced into the market and as intravenous agents provide a means of sedation and anesthesia for short-term surgery or intensive care units. However, midazolam produces active in vivo metabolites, resulting in a longer time required for the patient to become awake from the midazolam-induced sedated, anesthetized state. In addition, since midazolam metabolism is dependent on the liver enzyme cytochrome P4503a4, if administered to patients with impaired liver function, problems of drug-drug interactions may arise.

Therefore, it is desirable to develop benzodiazepines with shorter onset of action, shorter duration of drug action, and shorter recovery time, thereby reducing the incidence of cardiovascular suppressive adverse reactions

Short-acting Central Nervous System (CNS) -like inhibitors, and have been developed to obtain crystals and salts thereof which are suitable for the preparation of pharmaceutical preparations.

Disclosure of Invention

One aspect of the present invention provides a crystalline form of a compound of formula (I) as shown below:

another aspect of the invention provides a crystalline form of a compound of formula (Ia) as shown below:

the compounds of the above formula (I) or formula (Ia) and their preparation and use are described in International patent No. PCT/CN2016/110075 filed by the applicantIn the application. The above international patent application is incorporated herein by reference in its entirety. The compound not only retains p-GABA_AThe high affinity and selectivity of the receptor, and has the following advantages: the predictable quick attack time, the effective action time and the awakening time of the sedation anesthesia are achieved, thereby reducing the adverse inhibition reaction on the cardiovascular system and the respiratory system and reducing the side effects on the nervous system of a patient, such as sleepiness, dizziness and other problems.

The crystals of the compound of formula (I) or formula (Ia) provided by the present invention not only have the above advantages, but also exhibit other advantageous physical properties (e.g., good solubility, low hygroscopicity, and good solid state stability, etc.) and pharmacokinetic properties (e.g., increased dissolution rate and increased bioavailability due to different crystal lattice energies), etc.

Another aspect of the present invention provides methods for preparing crystals of the compound of formula (I) or formula (Ia), including, but not limited to, gas-solid permeation, anti-solvent crystallization, room temperature suspension stirring, high temperature suspension stirring, gas-liquid permeation, room temperature slow volatilization, slow cooling, and the like.

Another aspect of the present invention provides a salt of a compound of formula (Ia) as shown above, for example a hydrochloride, maleate, succinate, adipate, sulfate, phosphate, fumarate, malate, glycolate, mucate, lactate, gentisate, benzenesulfonate, edisylate, napadisylate, methanesulfonate, tartrate, hippurate, citrate, nicotinate, lactate, oxalate, malonic acid, nicotinamide and p-toluenesulfonate salt of a compound of formula (Ia), in particular a hydrochloride, oxalate and malonate of a compound of formula (Ia), more in particular a hydrochloride crystal, oxalate crystal and malonate crystal of a compound of formula (Ia).

The salts of the compounds of formula (Ia) provided by the present invention have good manufacturability (ease of manufacture), low solvent residue in the crystalline form of the various salts, and no significant difference between the products made from the various batches. The acid used for salifying in the invention has higher safety and can not cause undesirable toxicity. In addition, the various salts and crystalline forms thereof of the present invention are more readily prepared in large quantities at high purity, and thus are more suitable for use in the preparation of pharmaceutical formulations, but may also exhibit other advantageous physical properties (e.g., good solubility, low hygroscopicity, and good solid state stability, etc.) as well as pharmacokinetic properties (e.g., increased dissolution rate and increased bioavailability due to different crystal lattice energies), etc.

Another aspect of the present invention provides a method for preparing a salt of the compound of formula (Ia), which comprises reacting the compound of formula (Ia) in any solid form with an inorganic or organic acid to precipitate a solid, and then separating and drying the precipitated solid. The method for separating out the solid includes but is not limited to a gas-solid permeation method, an anti-solvent crystallization method, a room temperature suspension stirring method, a high temperature suspension stirring method, a gas-liquid permeation method, a room temperature slow volatilization method, a slow cooling method and the like.

Another aspect of the invention provides a pharmaceutical composition comprising a crystal of a compound of formula (I) as described above, a crystal of a compound of formula (Ia) or a salt of a compound of formula (Ia) (in particular a hydrochloride, oxalate or malonate salt of a compound of formula (Ia), more in particular a hydrochloride, oxalate or malonate crystal of a compound of formula (Ia)) or any combination thereof, and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides a method for sedation, hypnosis, anxiolysis, muscle relaxation, or anticonvulsant in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the crystals of the compound of formula (I) described above, crystals of the compound of formula (Ia), or a salt of the compound of formula (Ia) (particularly a hydrochloride, oxalate, or malonate salt of the compound of formula (Ia), more particularly crystals of a hydrochloride, oxalate, or malonate salt of the compound of formula (Ia)), or any combination thereof.

Another aspect of the present invention provides crystals of the compound of formula (I) above, crystals of the compound of formula (Ia) or a salt of the compound of formula (Ia) (in particular a hydrochloride, oxalate or malonate salt of the compound of formula (Ia), more in particular a hydrochloride, oxalate or malonate crystal of the compound of formula (Ia)) or any combination thereof for use in sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant.

Another aspect of the present invention provides the use of crystals of the compound of formula (I) above, crystals of the compound of formula (Ia) above, or a salt of the compound of formula (Ia) (in particular a hydrochloride, oxalate or malonate salt of the compound of formula (Ia), more in particular a hydrochloride, oxalate or malonate crystal of the compound of formula (Ia)) or any combination thereof, for the manufacture of a medicament for sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant.

The crystals of the compound of formula (I) or formula (Ia) or a salt thereof of the present invention have one or more of the following advantageous properties:

i) high solubility, high dissolution rate, low hygroscopicity, high flowability and significantly improved viscosity.

ii) excellent physicochemical stability including, but not limited to, light stability, thermal stability, resistance to high humidity, etc. For example, good photostability ensures the reliability of the crystals during storage and transportation, thus ensuring the safety of the formulation; the crystal does not need to be specially packaged for preventing the crystal from being influenced by illumination, so that the cost is reduced; so that the crystal can not be degraded under the influence of illumination, thereby improving the safety of the preparation and the effectiveness after long-term storage; and so that patients taking the crystals do not worry about the formulation's photosensitizing response upon exposure to sunlight. Good thermal stability enables the crystals to remain stable for long periods of time and to be suitable for standard formulation manufacturing processes. Good physicochemical stability the crystals are easy to prepare and more suitable for the preparation of formulations.

iii) improved metabolism, increased bioavailability, reduced toxicity and increased safety.

iv) suitability and convenience for mass preparation, and cost saving.

Drawings

Figure 1 shows an XRPD pattern of crystal B of the compound of formula (Ia).

FIG. 2 shows a DSC spectrum of crystal B of the compound of formula (Ia).

Figure 3 shows an XRPD pattern of crystal C of the compound of formula (I).

FIG. 4 shows a DSC spectrum of crystal C of the compound of formula (I).

Figure 5 shows an XRPD pattern of the hydrochloride salt crystals of the compound of formula (Ia).

FIG. 6 shows a DSC spectrum of the hydrochloride crystal of the compound of formula (Ia).

FIG. 7 shows an XRPD pattern for oxalate crystal A of the compound of formula (Ia).

FIG. 8 shows a DSC spectrum of oxalate crystal A of the compound of formula (Ia).

Figure 9 shows the XRPD pattern of oxalate crystal B of the compound of formula (Ia).

FIG. 10 shows a DSC spectrum of oxalate crystals B of the compound of formula (Ia).

FIG. 11 shows an XRPD pattern for oxalate crystal C of the compound of formula (Ia).

FIG. 12 shows a DSC spectrum of oxalate crystal C of the compound of formula (Ia).

FIG. 13 shows an XRPD pattern for oxalate crystal D of the compound of formula (Ia).

FIG. 14 shows a DSC spectrum of oxalate crystals D of the compound of formula (Ia).

Figure 15 shows an XRPD pattern of malonate salt crystal a of the compound of formula (Ia).

FIG. 16 shows a DSC spectrum of malonate salt crystal A of the compound of formula (Ia).

Figure 17 shows an XRPD pattern of malonate salt crystal B of the compound of formula (Ia).

FIG. 18 shows a DSC spectrum of malonate salt crystal B of the compound of formula (Ia).

Detailed Description

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

The terms "comprising," "including," "having," "containing," or "involving," as used herein, and other variants thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The word "about" as used herein means within an acceptable standard error of the stated value, e.g., ± 0.05, ± 0.1, ± 0.2, ± 0.3, ± 1, ± 2 or ± 3, etc., as deemed by one of ordinary skill in the art.

The term "salt of a compound of formula (Ia)" as used herein includes inorganic or organic acid salts of a compound of formula (Ia). The inorganic acid is selected from the group consisting of, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and any combination thereof; and the organic acid is selected from the group consisting of, but not limited to, formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, enanthic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid, nicotinic acid, orotic acid, methylsulfate, dodecylsulfate, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 1, 5-naphthalenedisulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid, and any combination thereof.

The term "solid form" as used herein includes all solid state forms, e.g. crystalline forms or amorphous forms, of the compound of formula (I), the compound of formula (Ia) and salts of the compound of formula (Ia).

The term "amorphous" as used herein refers to any solid substance that is not ordered in three dimensions. In some cases, the amorphous solid can be characterized by known techniques, including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids produce a diffuse XRPD pattern, which typically includes one or two broad peaks (i.e., peaks having a basal width of about 5 ° 2 θ or greater).

The term "crystalline form" or "crystalline" as used herein refers to any solid substance exhibiting a three-dimensional ordering, as opposed to an amorphous solid substance, which results in a characteristic XRPD pattern having well-defined peaks.

The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to an experimentally observed diffraction pattern or parameters derived therefrom. XRPD patterns are generally characterized by peak position (abscissa) and/or peak intensity (ordinate).

The term "2 θ" as used herein refers to the peak position in degrees set up by experiments based on X-ray diffraction experiments, and is typically in abscissa units in the diffraction pattern. If the reflection is diffracted when the incident beam makes an angle theta with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2 theta. It should be understood that reference herein to particular 2 theta values for particular crystalline forms is intended to refer to 2 theta values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-K α (C: (C))

1.540598 and

1.544426) as a radiation source.

The term "thermogravimetric analysis (TGA) profile" as used herein refers to the curve recorded by a thermogravimetric analyzer.

The term "Differential Scanning Calorimetry (DSC) profile" as used herein refers to the curve recorded by a differential scanning calorimeter.

As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions means that representative peak positions and intensity variations are taken into account. For example, those skilled in the art will appreciate that the peak position (2 θ) will show some variation, typically as much as 0.1-0.2 degrees, and that the instrument used to measure diffraction will also show some variation. In addition, one skilled in the art will appreciate that relative peak intensities will show variations from instrument to instrument and due to the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered as qualitative measurements only. Similarly, "substantially the same" for DSC profiles and TGA profiles, as used herein, is also intended to encompass variations known to those skilled in the art relating to these analytical techniques. For example, for well-defined peaks, there will typically be a variation of up to ± 0.2 ℃ in the differential scanning calorimetry spectrum, and even greater for broad peaks (e.g. up to ± 1 ℃).

The term "good solvent" as used herein means a solvent for dissolving the compound of (I) or the salt of the compound of (I) of the present invention.

The term "anti-solvent" as used herein means a solvent for reducing the solubility of the substance to be crystallized in a good solvent.

The term "anti-solvent crystallization method" as used herein means a method of using a good solvent in combination with an anti-solvent, thereby reducing the solubility of a substance to be crystallized in the good solvent. The antisolvent crystallization method can be classified into an antisolvent addition method and an antisolvent addition method according to the order of addition of the solvent. The antisolvent addition method is a method of dissolving a material to be crystallized in a good solvent and then adding an antisolvent thereto to crystallize, and the antisolvent addition method is a method of dissolving a material to be crystallized in a good solvent and then adding the resulting solution to an antisolvent to crystallize.

The term "hydrocarbon" as used herein preferably means a hydrocarbon having 1 to 10 carbon atoms, including alkanes, haloalkanes, alkenes, alkynes, and aromatics, including but not limited to dichloromethane, chloroform (chloroform), n-hexane, n-heptane, and toluene.

The term "alcohol" as used herein preferably means an alcohol having 1 to 10 carbon atoms, which includes, but is not limited to, methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol, and tert-butanol.

The term "ethers" as used herein preferably means ethers having 2 to 6 carbon atoms, which include chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxanes), and specifically include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxyethane.

The term "nitrile" as used herein preferably means a nitrile having 2 to 6 carbon atoms, including but not limited to acetonitrile and propionitrile.

The term "ketones" as used herein preferably means ketones having 2 to 6 carbon atoms, including but not limited to acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone.

The term "esters" as used herein preferably means esters having 3 to 10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropanoate, dimethyl carbonate and butyl acetate.

The term "organic acids" as used herein preferably means organic acids having 1 to 10 carbon atoms, including but not limited to formic acid and acetic acid.

The term "sulfones" as used herein preferably means sulfones or sulfoxides with 2 to 10 carbon atoms, including but not limited to dimethyl sulfoxide.

The term "amide" as used herein preferably means an amide having 1 to 10 carbon atoms, including but not limited to dimethylformamide or dimethylacetamide.

The term "nitrogen heterocycles" as used herein preferably means nitrogen-containing heterocycles having 3 to 10 carbon atoms and at least one nitrogen atom, including but not limited to N-methylpyrrolidone.

As used herein, a numerical range (e.g., "1-10") and sub-ranges thereof (e.g., "2-10", "2-6", "3-10"), etc., encompass any number (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or 10) of the numerical range.

The crystalline form of the compound of formula (I) or formula (Ia) prepared, the salt of the compound of formula (Ia) or crystalline forms thereof may be recovered by a process including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solids recovery under pressure or under reduced pressure. The recovered solids may optionally be dried. "drying" in the context of the present invention is carried out under reduced pressure (preferably under vacuum) until the residual solvent content is reduced to within the limits given in the International Conference on harboration of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The residual solvent content depends on the type of solvent, but does not exceed about 5000ppm, or preferably about 4000ppm, or more preferably about 3000 ppm. The drying may be performed in a tray dryer, vacuum oven, air oven, cone vacuum dryer (cone vacuum dryer), rotary vacuum dryer, fluidized bed dryer, spin flash dryer, or the like. The drying may be carried out at a temperature of less than about 100 ℃, less than about 80 ℃, less than about 60 ℃, less than about 50 ℃, less than about 30 ℃ or any other suitable temperature, under atmospheric or reduced pressure (preferably vacuum) for any desired time (e.g., about 1, 2,3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired results, so long as the quality of the product is not degraded. The drying may be carried out any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a size reduction operation to produce the desired particle size. The milling or micronization may be carried out before or after the drying of the product is completed. Techniques that may be used to reduce particle size include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.

The term "anhydrous crystalline form" as used herein preferably means a crystalline form which does not contain water molecules as a structural element.

Crystals of a compound of formula (I) or formula (Ia) and a process for their preparation

It is an object of the present invention to provide a crystalline form of the compound of formula (Ia) shown below,

according to one embodiment of the present invention, there is provided crystal B of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.8 ± 0.2 °, 11.5 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 22.0 ± 0.2 °. In a preferred embodiment, the XRPD pattern of crystal B of the compound of formula (Ia) comprises characteristic peaks at diffraction angles (2 θ) of 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 17.1 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °. In a more preferred embodiment, the XRPD pattern of crystal B of the compound of formula (Ia) comprises characteristic peaks at diffraction angles (2 θ) of 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 17.1 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 20.6 ± 0.2 °, 21.5 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °, 23.6 ± 0.2 °, 24.6 ± 0.2 °, 25.3 ± 0.2 °, 26.1 ± 0.2 °, 27.4 ± 0.2 °, 27.8 ± 0.2 °, 28.3 ± 0.2 °, 29.4 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of crystal B of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		6.8	24.6
10.1	25.3
		11.5	26.1
14.4	27.4
		15.4	27.8
17.1	28.3
		19.4	29.4
19.9	30.5
		20.6	30.8
21.5	32.2
		22.0	32.9
22.6	37.3
		23.6

in a particularly preferred embodiment, the XRPD pattern of crystal B of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 θ):

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			6.8	12.9	33.2
10.1	8.7	7.0
			11.5	7.7	15.5
14.4	6.1	10.6
			15.4	5.8	11.3
17.1	5.2	12.7
			19.4	4.6	68.2
19.9	4.5	38.3
			20.6	4.3	6.1
21.5	4.1	13.7
			22.0	4.0	100.0
22.6	3.9	25.8
			23.6	3.8	9.2
24.6	3.6	4.3
			25.3	3.5	10.7
26.1	3.4	5.0
			27.4	3.3	6.3
27.8	3.2	10.0
			28.3	3.2	7.9
29.4	3.0	7.1
			30.5	2.9	6.2
30.8	2.9	6.7
			32.2	2.8	5.4
32.9	2.7	1.3
			37.3	2.4	10.7

In a particularly preferred embodiment, the XRPD pattern of crystal B of the compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 1. In a particularly preferred embodiment, the XRPD peak positions of crystal B of the compound of formula (Ia) are substantially the same as shown in figure 1.

In a preferred embodiment, the DSC profile of crystal B of the compound of formula (Ia) according to the invention comprises a characteristic peak at about 160.9 ± 0.2 ℃. In a more preferred embodiment, the DSC profile of said crystal B of the compound of formula (Ia) comprises characteristic peaks at substantially the same temperatures as shown in figure 2. In a particularly preferred embodiment, the characteristic peak positions of the DSC pattern of said crystal B of the compound of formula (Ia) are substantially the same as shown in figure 2.

In a particularly preferred embodiment, the crystalline B of the compound of formula (Ia) of the present invention is a non-solvate. In a more preferred embodiment, the crystalline form B of the compound of formula (Ia) of the present invention is in anhydrous crystalline form.

It is another object of the present invention to provide a crystalline form of the compound of formula (I) shown below,

according to one embodiment of the present invention, there is provided crystalline C of the compound of formula (I) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 8.4 ± 0.2 °, 14.0 ± 0.2 °, 16.7 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± 0.2 °. In a preferred embodiment, the XRPD pattern of crystal C of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± 0.2 °. In a more preferred embodiment, the XRPD pattern of crystal C of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 20.3 ± 0.2 °, 21.2 ± 0.2 °, 21.8 ± 0.2 °, 22.4 ± 0.2 °, 22.7 ± 0.2 °, 23.5 ± 0.2 °, 24.5 ± 0.2 °, 25.2 ± 0.2 °, 26.6 ± 0.2 °, 28.1 ± 0.2 °, 29.2 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of crystal C of said compound of formula (I) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		8.4	21.2
9.3	21.8
		9.6	22.4
11.0	22.7
		13.2	23.5
14.0	24.5
		15.3	25.2
16.7	26.6
		17.9	28.1
18.5	29.2
		19.4	33.1
20.3	36.2

in a particularly preferred embodiment, the XRPD pattern of crystal C of said compound of formula (I) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				8.4	41.5	21.2	8.8
9.3	11.9	21.8	11.3
				9.6	9.0	22.4	17.0
11.0	2.1	22.7	40.8
				13.2	13.5	23.5	6.9
14.0	43.1	24.5	6.5
				15.3	21.9	25.2	100.0
16.7	63.1	26.6	13.8
				17.9	8.6	28.1	18.1
18.5	9.3	29.2	11.4
				19.4	37.9	33.1	6.6
20.3	3.7	36.2	2.5

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			8.4	10.6	41.5
9.3	9.5	11.9
			9.6	9.2	9.0
11.0	8.0	2.1
			13.2	6.7	13.5
14.0	6.3	43.1
			15.3	5.8	21.9
16.7	5.3	63.1
			17.9	5.0	8.6
18.5	4.8	9.3
			19.4	4.6	37.9
20.3	4.4	3.7
			21.2	4.2	8.8
21.8	4.1	11.3
			22.4	4.0	17.0
22.7	3.9	40.8
			23.5	3.8	6.9
24.5	3.6	6.5
			25.2	3.5	100.0
26.6	3.3	13.8
			28.1	3.2	18.1
29.2	3.1	11.4
			33.1	2.7	6.6
36.2	2.5	2.5

In a particularly preferred embodiment, the XRPD pattern of crystal C of said compound of formula (I) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 3. In a particularly preferred embodiment, the XRPD peak positions of crystal C of the compound of formula (I) are substantially the same as shown in figure 3.

In a preferred embodiment, the DSC profile of the crystalline C of the compound of formula (I) according to the invention comprises a characteristic peak at about 185.5 ± 0.2 ℃. In a more preferred embodiment, the DSC profile of crystal C of said compound of formula (I) comprises characteristic peaks at substantially the same temperatures as shown in figure 4. In a particularly preferred embodiment, the characteristic peak positions of the DSC profile of the crystalline C of said compound of formula (I) are substantially the same as those shown in figure 4.

In a particularly preferred embodiment, the crystalline C of the compound of formula (I) of the present invention is a non-solvate. In a more preferred embodiment, the crystalline form C of the compound of formula (I) of the present invention is in anhydrous crystalline form.

It is another object of the present invention to provide a process for preparing crystal B of the above compound of formula (Ia) or crystal C of the compound of formula (I), which includes but is not limited to: gas-solid permeation method, anti-solvent crystallization method, room temperature suspension stirring method, high temperature suspension stirring method, gas-liquid permeation method, room temperature slow volatilization method, slow cooling method and the like.

According to some embodiments of the invention, crystals are prepared by a gas-solid permeation process comprising placing a first container containing a compound of formula (I) or formula (Ia) in a second container containing a solvent, wherein the compound of formula (I) or formula (Ia) in solid form is not in direct contact with the solvent, sealing the second container, and placing to obtain crystals. In some embodiments where the crystals are prepared using a gas-solid permeation method, the solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, amides, sulfones, ketones, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxanes)), nitriles, and esters such as methanol, ethanol, isopropanol, chloroform, acetone, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and the like). In some embodiments wherein the crystals are prepared by a gas-solid permeation method, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to solvent is about (1-20):1, preferably (2-10): 1. In some embodiments wherein the crystals are prepared by gas-solid permeation, said standing crystallization comprises standing or stirring crystallization, preferably standing crystallization.

According to some embodiments of the present invention, the crystals are prepared using an anti-solvent addition method, which includes, but is not limited to, dissolving a compound of formula (I) or formula (Ia) in a good solvent to form a clear solution, optionally filtering the solution to obtain a clear solution, and then adding an anti-solvent to the clear solution, and precipitating crystals by stirring (the stirring may be performed at room temperature or at reduced temperature (e.g., reduced to 0-20 deg.C, preferably 0-10 deg.C, such as 0 deg.C, 5 deg.C, or 10 deg.C), or by standing (e.g., standing at room temperature) (preferably while slowly evaporating the solvent) to precipitate crystals Ethers (including chain ethers and cyclic ethers such as furans (including tetrahydrofurans) and dioxanes), sulfones, esters, amides, and organic acids such as methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide, N-methylpyrrolidone, methyl ethyl ketone, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, toluene, dichloromethane, and the like. In some embodiments where the crystals are prepared using an anti-solvent addition method, the anti-solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., hydrocarbons (selected from alkanes, alkenes, alkynes), such as n-hexane, n-heptane, cyclohexane, and the like). In some embodiments where the crystals are prepared by an anti-solvent addition method, the volume ratio of the good solvent to the anti-solvent is 1 (1-60), preferably 1 (1-40). In some embodiments, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to good solvent is (1-80):1, preferably (1-40): 1.

According to some embodiments of the invention, the crystals are prepared using a room temperature suspension stirring method, including, but not limited to, adding the compound of formula (I) or formula (Ia) to a solvent to obtain a suspension, stirring at room temperature, and isolating the crystals. In some embodiments, in which the crystals are prepared using a room-temperature suspension stirring method, the solvent includes, but is not limited to, an inorganic solvent (e.g., water) and an organic solvent (e.g., alcohols, ketones, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxane)), esters, nitriles, amides, and organic acids such as methyl tert-butyl ether, isopropanol, isobutyl acetate, methanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, toluene, or a mixed solvent of two or more selected from the above solvents). In some embodiments, wherein the crystals are prepared using a room temperature suspension stirring method, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to the solvent is (1-80):1, preferably (1-50): 1.

According to some embodiments of the invention, the crystals are prepared using a high temperature suspension stirring method, including, but not limited to, adding a compound of formula (I) or formula (Ia) to a solvent to obtain a suspension, stirring the suspension by heating (e.g., to 40-100 ℃, preferably 40-80 ℃, e.g., 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, or 70 ℃) and then isolating the crystals. In some embodiments, in which the high-temperature suspension stirring method is used to prepare crystals, the solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, ketones, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxane)), esters, nitriles, sulfones, amides, and nitrogen heterocycles, such as methyl ethyl ketone, isobutanol, isobutyl acetate, methanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, 2-methyl tetrahydrofuran, chloroform, ethyl acetate, toluene, n-hexane, etc.), or a mixed solvent selected from two or more of the above solvents. In some embodiments in which the crystals are prepared using a high temperature suspension stirring method, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to solvent is (1-80):1, preferably (5-60): 1.

According to some embodiments of the present invention, crystals are prepared using a gas-liquid permeation method, which comprises dissolving a compound of formula (I) or formula (Ia) in a good solvent in a first vessel to form a clear solution (the solution may be filtered to obtain a clear solution if necessary), charging an anti-solvent into a second vessel, placing the first vessel in the second vessel with an opening, sealing the second vessel and standing, and filtering the precipitated solid to obtain crystals.

In some embodiments of the method for preparing crystals by gas-liquid permeation, the good solvent includes, but is not limited to, organic solvents, such as hydrocarbons (selected from haloalkanes and aromatics), alcohols, ketones, ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes)), esters, nitriles, sulfones, amides, and nitrogen heterocycles, and the like, specifically, methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, isopropanol, methyl isobutyl ketone, isopropyl acetate, methyl t-butyl ether, 1, 4-dioxane, anisole, cyclopentyl methyl ether, toluene, chloroform, or a mixed solvent formed from two or more of the above solvents. In some embodiments where the crystals are prepared by a gas-liquid infiltration method, the anti-solvent includes, but is not limited to, an inorganic solvent (e.g., water) and an organic solvent (e.g., a hydrocarbon (selected from alkanes, alkenes, alkynes), such as n-hexane, n-heptane, cyclohexane, etc.), or a mixed solvent formed from two or more of the above solvents. In some embodiments wherein the crystals are prepared by a gas-liquid infiltration method, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to the good solvent is about (1-80):1, preferably (10-60): 1. In some embodiments, the volume ratio of the anti-solvent to the good solvent is 1 (1-20), preferably 1 (1-10). In some embodiments, the sealing and standing of the second container may be performed at room temperature.

According to some embodiments of the invention, the crystals are prepared using a slow volatilization at room temperature process comprising dissolving a compound of formula (I) or formula (Ia) in a solvent in a container to form a clear solution (optionally the solution is filtered to obtain the clear solution), sealing the container (e.g., using a sealing membrane), leaving a small hole or gap at the seal, and allowing the clear solution to stand to evaporate the solvent to obtain the crystals. In some embodiments where the crystals are prepared using a room temperature slow evaporation method, the solvent includes, but is not limited to, an inorganic solvent (e.g., water) and an organic solvent (e.g., alcohols, amides, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxane)), ketones, nitriles, or esters, such as, specifically, isopropanol, methyl ethyl ketone, isopropyl acetate, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, methanol, acetone, acetonitrile, ethyl acetate, n-hexane, tetrahydrofuran, dichloromethane, and the like), or a mixed solvent formed from two or more of the above solvents. In some embodiments in which the crystals are prepared using a slow volatilization method at room temperature, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to solvent is (1-50):1, preferably (1-30): 1. In some embodiments, the placing can be performed at room temperature.

According to some embodiments of the invention, the crystals are prepared by a slow cooling method, which comprises adding the compound of formula (I) or formula (Ia) to a solvent, heating and stirring to dissolve, allowing the resulting clear solution (which may optionally be filtered to obtain a clear solution) to stand, and slowly cooling to obtain the crystals. In some embodiments where the slow cooling method is used to prepare crystals, the solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, ketones, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxane)), nitriles, amides, and esters, such as, specifically, methyl isobutyl ketone, isobutanol, isobutyl acetate, methanol, tetrahydrofuran, ethanol, 2-methyl tetrahydrofuran, n-hexane, and the like), or mixed solvents formed from two or more of the above solvents. In some embodiments where the slow cooling method is used to prepare the crystal, the slow cooling rate is 0.1-0.5 ℃/min, preferably 0.1-0.3 ℃/min, and more preferably 0.1 ℃/min. In some embodiments, the heating temperature is from 30 to 80 ℃, preferably from 40 to 70 ℃, e.g., 45 ℃, 50 ℃, 55 ℃ or 60 ℃. In some embodiments, the temperature at the end of the cooling is room temperature or 0-10 ℃, e.g., 3 ℃,5 ℃, or 7 ℃. In some embodiments where crystals are prepared using a slow cooling method, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to solvent is (2-100):1, preferably (10-80): 1.

According to some embodiments of the invention, crystals are prepared using an anti-solvent addition method, which includes, but is not limited to, dissolving a compound of formula (I) or formula (Ia) in a good solvent to form a clear solution (which may optionally be filtered to obtain a clear solution), then adding the clear solution to an anti-solvent, precipitating crystals under stirring (which may be performed at room temperature or under heating conditions (e.g., heating to 30-100 ℃, preferably 30-80 ℃, more preferably 35-65 ℃, such as 45 ℃, 50 ℃, 55 ℃ or 60 ℃), or standing (e.g., standing at room temperature) (preferably while slowly evaporating the solvent) to precipitate crystals. In some embodiments where the anti-antisolvent addition method is used to prepare crystals, the good solvent includes, but is not limited to, organic solvents such as alcohols, ketones, hydrocarbons (selected from haloalkanes and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxanes)), sulfones, amides, and organic acids, such as N-methylpyrrolidone, ethanol, acetone, acetonitrile, tetrahydrofuran, dichloromethane, methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, toluene, and the like. In some embodiments of crystals prepared using the anti-solvent addition method, the anti-solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., hydrocarbons (selected from alkanes, alkenes, alkynes), such as cyclohexane, n-hexane, n-heptane, and the like. in some embodiments of crystals prepared using the anti-solvent addition method, the volume ratio of the good solvent to the anti-solvent is (1-20):1, preferably (1-10): 1. in some embodiments, the weight to volume ratio (mg/mL) of the compound of formula (I) or formula (Ia) to the good solvent is (1-80):1, preferably (1-50): 1.

Salts of compounds of formula (Ia), crystals and processes for their preparation

It is another object of the present invention to provide the hydrochloride salt of the compound of formula (Ia). Preferably, in the hydrochloride salt of the compound of formula (Ia), the molar ratio of the compound of formula (Ia) to hydrochloric acid is 1: 1.

According to one embodiment of the present invention, there is provided a crystal of the hydrochloride salt of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.4 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °. In a preferred embodiment, the XRPD pattern for the hydrochloride salt crystals of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 17.5 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °. In a more preferred embodiment, the XRPD pattern for the hydrochloride salt crystals of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 15.3 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 17.5 ± 0.2 °, 18.0 ± 0.2 °, 18.7 ± 0.2 °, 20.3 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 27.5 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of the hydrochloride salt crystals of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

in a particularly preferred embodiment, the XRPD pattern of the hydrochloride salt crystals of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				5.4	63.0	18.7	52.3
7.7	14.2	20.3	31.7
				9.3	68.4	22.1	43.5
10.8	74.0	23.0	50.3
				13.2	31.4	25.0	30.1
15.3	11.6	25.4	14.1
				16.2	100.0	27.5	25.8
17.0	58.5	30.0	18.7
				17.5	17.5	30.9	13.3
18.0	18.2

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			5.4	16.3	63.0
7.7	11.5	14.2
			9.3	9.5	68.4
10.8	8.2	74.0
			13.2	6.7	31.4
15.3	5.8	11.6
			16.2	5.5	100.0
17.0	5.2	58.5
			17.5	5.1	17.5
18.0	4.9	18.2
			18.7	4.7	52.3
20.3	4.4	31.7
			22.1	4.0	43.5
23.0	3.9	50.3
			25.0	3.6	30.1
25.4	3.5	14.1
			27.5	3.2	25.8
30.0	3.0	18.7
			30.9	2.9	13.3

In a particularly preferred embodiment, the XRPD pattern of the hydrochloride salt crystals of the compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 5. In a particularly preferred embodiment, the XRPD peak positions of the hydrochloride salt crystals of the compound of formula (Ia) are substantially the same as shown in figure 5.

In a preferred embodiment, the DSC profile of the hydrochloride salt crystals of the compound of formula (Ia) of the present invention comprises a characteristic peak at about 185.2 ± 0.2 ℃. In a more preferred embodiment, the DSC profile of the hydrochloride salt crystals of the compound of formula (Ia) comprises characteristic peaks at substantially the same temperatures as shown in figure 6. In a particularly preferred embodiment, the DSC profile of the hydrochloride salt crystals of the compound of formula (Ia) has characteristic peak positions substantially the same as shown in figure 6.

In a particularly preferred embodiment, the crystalline hydrochloride salt of the compound of formula (Ia) of the present invention is a non-solvate. In a more preferred embodiment, the crystalline hydrochloride salt of the compound of formula (Ia) of the present invention is in an anhydrous crystalline form.

It is another object of the present invention to provide the oxalate salt of the compound of formula (Ia). Preferably, in the oxalate salt of the compound of formula (Ia), the molar ratio of the compound of formula (Ia) to oxalic acid is 1: 1.

According to one embodiment of the present invention, there is provided oxalate crystal a of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 8.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 24.7 ± 0.2 °. In a preferred embodiment, the XRPD pattern of oxalate crystal a of said compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 23.0 ± 0.2 °, 24.7 ± 0.2 °. In a more preferred embodiment, the XRPD pattern for oxalate crystal A of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 8.5. + -. 0.2 °, 13.5. + -. 0.2 °, 14.0. + -. 0.2 °, 17.8. + -. 0.2 °, 20.3. + -. 0.2 °, 20.5. + -. 0.2 °, 20.9. + -. 0.2 °, 22.1. + -. 0.2 °, 22.8. + -. 0.2 °, 23.0. + -. 0.2 °, 24.1. + -. 0.2 °, 24.7. + -. 0.2 °, 25.3. + -. 0.2 °, 25.8. + -. 0.2 °, 26.5. + -. 0.2 °, 28.2. + -. 0.2 °. In a particularly preferred embodiment, the XRPD pattern of oxalate crystal a of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		8.5	23.0
13.5	24.1
		14.0	24.7
17.8	25.3
		20.3	25.8
20.5	26.5
		20.9	28.2
22.1	34.6
		22.8

in a particularly preferred embodiment, the XRPD pattern of oxalate crystal a of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				8.5	100.0	23.0	13.2
13.5	6.1	24.1	8.5
				14.0	61.0	24.7	29.6
17.8	15.9	25.3	8.2
				20.3	18.0	25.8	9.0
20.5	8.9	26.5	9.2
				20.9	26.7	28.2	2.1
22.1	6.8	34.6	2.1
				22.8	15.7

in a particularly preferred embodiment, the XRPD pattern of oxalate crystal a of said compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 7. In a particularly preferred embodiment, the XRPD peak positions of oxalate crystal a of the compound of formula (Ia) are substantially the same as shown in figure 7.

In a preferred embodiment, the DSC pattern of the oxalate crystals A of the compound of formula (Ia) of the present invention includes characteristic peaks at about 178.6 ℃. + -. 0.2 ℃ and 213.6 ℃. + -. 0.2 ℃. In a more preferred embodiment, the DSC profile of the oxalate crystal a of said compound of formula (Ia) comprises characteristic peaks at substantially the same temperatures as shown in figure 8. In a particularly preferred embodiment, the compound of formula (Ia) has a DSC profile for oxalate crystals a having characteristic peak positions substantially the same as those shown in figure 8.

In a particularly preferred embodiment, the crystalline a oxalate salt of the compound of formula (Ia) of the present invention is a non-solvate. In a more preferred embodiment, the crystalline oxalate form a of the compound of formula (Ia) of the present invention is in the anhydrous crystalline form.

According to one embodiment of the present invention, there is provided oxalate crystal B of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 °, 23.3 ± 0.2 °. In a preferred embodiment, the XRPD pattern for the oxalate crystal B of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.0. + -. 0.2 °, 7.7. + -. 0.2 °, 8.2. + -. 0.2 °, 8.4. + -. 0.2 °, 8.8. + -. 0.2 °, 12.1. + -. 0.2 °, 12.7. + -. 0.2 °, 15.4. + -. 0.2 °, 15.8. + -. 0.2 °, 16.7. + -. 0.2 °, 20.0. + -. 0.2 °, 21.6. + -. 0.2 °, 22.8. + -. 0.2 °, 23.3. + -. 0.2 °. In a more preferred embodiment, the XRPD pattern of oxalate crystal B of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 10.2 ± 0.2 °, 10.7 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 14.0 ± 0.2 °, 15.4 ± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, 17.8 ± 0.2 °, 18.5 ± 0.2 °, 19.1 ± 0.2 °, 20.0 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 25.7 ± 0.2 °, 26.6 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of oxalate crystals B of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		5.0	17.8
7.7	18.5
		8.2	19.1
8.4	20.0
		8.8	20.4
10.2	21.6
		10.7	22.8
12.1	23.3
		12.7	24.3
14.0	24.9
		15.4	25.7
15.8	26.6
		16.7	28.0

in a particularly preferred embodiment, the XRPD pattern of oxalate crystals B of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			5.0	17.5	3.8
7.7	11.4	20.7
			8.2	10.8	82.1
8.4	10.5	55.2
			8.8	10.0	100.0
10.2	8.7	5.6
			10.7	8.3	3.4
12.1	7.3	12.5
			12.7	7.0	16.6
14.0	6.3	4.9
			15.4	5.7	11.4
15.8	5.6	14.4
			16.7	5.3	32.5
17.8	5.0	7.9
			18.5	4.8	7.0
19.1	4.6	7.6
			20.0	4.4	10.5
20.4	4.4	7.1
			21.6	4.1	15.1
22.8	3.9	12.9
			23.3	3.8	29.8
24.3	3.7	6.7
			24.9	3.6	9.1
25.7	3.5	11.8
			26.6	3.3	10.3
28.0	3.2	6.1

In a particularly preferred embodiment, the XRPD pattern of oxalate crystal B of said compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 9. In a particularly preferred embodiment, the XRPD peak positions of the oxalate crystals B of the compound of formula (Ia) are substantially the same as shown in figure 9.

In a preferred embodiment, the DSC pattern of the crystalline B oxalate salt of the compound of formula (Ia) of the present invention comprises characteristic peaks at about 81.9 + -0.2 deg.C, 136.6 + -0.2 deg.C and 166.1 + -0.2 deg.C. In a more preferred embodiment, the DSC profile of the oxalate crystal B of said compound of formula (Ia) comprises characteristic peaks at substantially the same temperatures as shown in figure 10. In a particularly preferred embodiment, the compound of formula (Ia) has a DSC profile for the oxalate salt crystal B with characteristic peak positions substantially the same as those shown in figure 10.

According to one embodiment of the present invention, there is provided oxalate crystal C of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 18.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °. In a preferred embodiment, the XRPD pattern of oxalate crystal C of said compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.0. + -. 0.2 °, 6.4. + -. 0.2 °, 7.7. + -. 0.2 °, 8.5. + -. 0.2 °, 9.1. + -. 0.2 °, 10.7. + -. 0.2 °, 11.9. + -. 0.2 °, 12.9. + -. 0.2 °, 13.2. + -. 0.2 °, 14.0. + -. 0.2 °, 17.8. + -. 0.2 °, 18.3. + -. 0.2 °, 19.3. + -. 0.2 °, 20.3. + -. 0.2 °, 22.2. + -. 0.2 °, 23.2. + -. 0.2 °. In a more preferred embodiment, the XRPD pattern of oxalate crystal C of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 5.0. + -. 0.2 °, 6.4. + -. 0.2 °, 7.7. + -. 0.2 °, 8.5. + -. 0.2 °, 9.1. + -. 0.2 °, 10.7. + -. 0.2 °, 11.9. + -. 0.2 °, 12.9. + -. 0.2 °, 13.2. + -. 0.2 °, 14.0. + -. 0.2 °, 15.5. + -. 0.2 °, 15.8. + -. 0.2 °, 17.3. + -. 0.2 °, 17.8. + -. 0.2 °, 18.3. + -. 0.2 °, 19.3. + -. 0.2 °, 20.3. + -. 0.2 °, 22.2. + -. 0.2 °, 23.2. + -. 0.2 °. In a particularly preferred embodiment, the XRPD pattern of oxalate crystal C of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		5.0	17.3
6.4	17.8
		7.7	18.3
8.5	19.3
		9.1	20.3
10.7	22.2
		11.9	23.2
12.9	24.0
		13.2	24.7
14.0	25.8
		15.5	26.5
15.8

in a particularly preferred embodiment, the XRPD pattern of oxalate crystal C of said compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				5.0	3.3	17.3	9.7
6.4	11.7	17.8	12.0
				7.7	17.3	18.3	35.9
8.5	100.0	19.3	16.9
				9.1	88.3	20.3	23.8
10.7	6.4	22.2	31.8
				11.9	10.6	23.2	27.8
12.9	13.5	24.0	12.4
				13.2	23.7	24.7	11.7
14.0	28.7	25.8	11.2
				15.5	3.6	26.5	11.3
15.8	5.0

in a particularly preferred embodiment, the XRPD pattern of oxalate crystal C of said compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 11. In a particularly preferred embodiment, the XRPD peak positions of oxalate crystal C of said compound of formula (Ia) are substantially the same as shown in figure 11.

In a preferred embodiment, the DSC pattern of the oxalate salt crystal C of the compound of formula (Ia) of the present invention includes characteristic peaks at about 67.5 + -0.2 deg.C, 106.5 + -0.2 deg.C and 168.5 + -0.2 deg.C. In a more preferred embodiment, the DSC profile of the oxalate salt crystal C of the compound of formula (Ia) includes characteristic peaks at substantially the same temperatures as shown in figure 12. In a particularly preferred embodiment, the compound of formula (Ia) has a DSC profile for oxalate crystal C having characteristic peak positions substantially the same as shown in figure 12.

According to one embodiment of the present invention, there is provided oxalate crystal D of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 15.9 ± 0.2 °, 19.9 ± 0.2 °. In a preferred embodiment, the XRPD pattern of the oxalate crystal D of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 13.9 ± 0.2 °, 15.9 ± 0.2 °, 19.9 ± 0.2 °, 22.2 ± 0.2 °. In a more preferred embodiment, the XRPD pattern of the oxalate crystal D of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 7.9. + -. 0.2 °, 8.4. + -. 0.2 °, 8.5. + -. 0.2 °, 9.0. + -. 0.2 °, 12.1. + -. 0.2 °, 12.7. + -. 0.2 °, 13.9. + -. 0.2 °, 15.9. + -. 0.2 °, 16.7. + -. 0.2 °, 17.1. + -. 0.2 °, 19.9. + -. 0.2 °, 21.7. + -. 0.2 °, 22.2. + -. 0.2 °. In a particularly preferred embodiment, the XRPD pattern of the oxalate crystal D of the compound of formula (Ia) comprises characteristic peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		7.9	16.7
8.4	17.1
		8.5	19.9
9.0	20.5
		12.1	21.7
12.7	22.2
		13.9	23.8
15.9	24.8

in a particularly preferred embodiment, the XRPD pattern of the oxalate crystal D of the compound of formula (Ia) comprises characteristic peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			7.9	11.2	21.2
8.4	10.6	36.1
			8.5	10.4	37.0
9.0	9.9	100.0
			12.1	7.3	12.6
12.7	7.0	7.4
			13.9	6.4	7.1
15.9	5.6	34.7
			16.7	5.3	3.4
17.1	5.2	4.3
			19.9	4.5	10.5
20.5	4.3	4.8
			21.7	4.1	10.0
22.2	4.0	20.9
			23.8	3.7	4.1
24.8	3.6	2.5

In a particularly preferred embodiment, the XRPD pattern of the oxalate crystal D of the compound of formula (Ia) includes a peak at diffraction angle (2 θ) substantially the same as shown in figure 13. In a particularly preferred embodiment, the XRPD peak positions of the oxalate crystals D of the compound of formula (Ia) are substantially the same as shown in figure 13.

In a preferred embodiment, the DSC pattern of the crystalline D oxalate salt of the compound of formula (Ia) of the present invention comprises characteristic peaks at about 91.5. + -. 0.2 ℃, 176.0. + -. 0.2 ℃ and 203.7. + -. 0.2 ℃. In a more preferred embodiment, the DSC profile of said oxalate crystal D of the compound of formula (Ia) includes characteristic peaks at substantially the same temperatures as shown in figure 14. In a particularly preferred embodiment, the compound of formula (Ia) has a DSC profile for the oxalate salt crystal D having characteristic peak positions substantially the same as those shown in figure 14.

It is another object of the present invention to provide malonates of the compounds of formula (Ia). Preferably, in the malonate salt of the compound of formula (Ia), the molar ratio of the compound of formula (Ia) to malonic acid is 1: 1.

According to one embodiment of the present invention, there is provided malonate crystal a of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 6.9 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 23.8 ± 0.2 °. In a preferred embodiment, the XRPD pattern for malonate crystal A of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 6.9 ± 0.2 °, 9.7 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, 23.8 ± 0.2 °. In a more preferred embodiment, the XRPD pattern for malonate crystal A of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 6.9 ± 0.2 °, 9.7 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.7 ± 0.2 °, 17.7 ± 0.2 °, 18.7 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, 23.8 ± 0.2 °, 24.2 ± 0.2 °, 25.6 ± 0.2 °, 25.8 ± 0.2 °, 26.6 ± 0.2 °, 27.1 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of malonate crystal a of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		6.9	22.6
9.7	23.0
		12.7	23.5
13.7	23.8
		14.8	24.2
15.7	25.6
		17.7	25.8
18.7	26.6
		19.2	27.1
19.7	29.1
		20.7	29.8
21.0	35.7
		22.1

in a particularly preferred embodiment, the XRPD pattern of malonate crystal a of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				6.9	31.7	22.6	31.2
9.7	7.4	23.0	27.8
				12.7	24.1	23.5	35.1
13.7	38.4	23.8	53.8
				14.8	25.9	24.2	30.9
15.7	8.9	25.6	24.2
				17.7	100.0	25.8	22.6
18.7	16.6	26.6	19.1
				19.2	70.2	27.1	16.1
19.7	20.9	29.1	10.3
				20.7	28.3	29.8	16.9
21.0	57.2	35.7	8.9
				22.1	34.6

in a particularly preferred embodiment, the malonate crystal a of the compound of formula (Ia) has an XRPD pattern comprising peaks at diffraction angles (2 Θ) substantially the same as shown in fig. 15. In a particularly preferred embodiment, the XRPD peak positions of malonate crystal a of said compound of formula (Ia) are substantially the same as shown in figure 15.

In a preferred embodiment, the malonate crystal form a of the compound of formula (Ia) of the present invention has a DSC profile comprising characteristic peaks at about 72.8 ± 0.2 ℃ and 85.8 ± 0.2 ℃. In a more preferred embodiment, the malonate crystal a of the compound of formula (Ia) has a DSC profile comprising characteristic peaks at substantially the same temperatures as shown in figure 16. In a particularly preferred embodiment, the characteristic peak positions of the DSC pattern of the malonate crystal a of the compound of formula (Ia) are substantially the same as those shown in figure 16.

According to one embodiment of the present invention, there is provided malonate crystal B of a compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 23.8 ± 0.2 °. In a preferred embodiment, the XRPD pattern for malonate crystal B of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 14.6 ± 0.2 °, 15.1 ± 0.2 °, 15.8 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 23.8 ± 0.2 °. In a more preferred embodiment, the XRPD pattern for malonate crystal B of the compound of formula (Ia) includes characteristic peaks at diffraction angles (2 θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 14.6 ± 0.2 °, 15.1 ± 0.2 °, 15.8 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 20.4 ± 0.2 °, 20.7 ± 0.2 °, 21.1 ± 0.2 °, 22.5 ± 0.2 °, 23.8 ± 0.2 °. In a particularly preferred embodiment, the XRPD pattern of malonate crystal B of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	2θ(°)±0.2°
		7.0	19.2
9.3	19.7
		9.8	20.4
12.8	20.7
		13.7	21.1
14.0	22.5
		14.6	23.8
15.1	26.7
		15.8	27.0
18.1	35.8

in a particularly preferred embodiment, the XRPD pattern of malonate crystal B of the compound of formula (Ia) comprises peaks at the following diffraction angles (2 Θ):

2θ(°)±0.2°	interplanar spacing (d spacing)	Strength%
			7.0	12.6	100.0
9.3	9.5	37.0
			9.8	9.0	26.2
12.8	6.9	8.1
			13.7	6.5	35.0
14.0	6.3	87.0
			14.6	6.1	16.4
15.1	5.9	17.2
			15.8	5.6	17.2
18.1	4.9	64.9
			19.2	4.6	60.0
19.7	4.5	41.3
			20.4	4.4	21.1
20.7	4.3	23.0
			21.1	4.2	36.4
22.5	4.0	22.2
			23.8	3.7	46.2
26.7	3.3	14.7
			27.0	3.3	10.8
35.8	2.5	3.7

In a particularly preferred embodiment, the XRPD pattern of malonate crystal B of the compound of formula (Ia) comprises peaks at diffraction angles (2 θ) substantially the same as shown in fig. 17. In a particularly preferred embodiment, the XRPD peak positions of the malonate crystal B of the compound of formula (Ia) are substantially the same as shown in figure 17.

In a preferred embodiment, the malonate crystal B of the compound of formula (Ia) of the present invention has a DSC profile comprising a characteristic peak at about 99.4 ± 0.2 ℃. In a more preferred embodiment, the malonate crystal B of the compound of formula (Ia) has a DSC profile comprising characteristic peaks at substantially the same temperatures as shown in figure 18. In a particularly preferred embodiment, the characteristic peak positions of the DSC pattern of the malonate salt crystal B of the compound of formula (Ia) are substantially the same as those shown in figure 18.

It is another object of the present invention to provide a method for preparing hydrochloride, oxalate, malonate and various crystalline forms thereof of the compound of formula (Ia), which comprises reacting the compound of formula (Ia) in any solid form (e.g., crystalline form or amorphous form) with hydrochloric acid, oxalic acid or malonic acid, precipitating a solid, and then separating and drying the precipitated solid.

The method for separating out the solid includes but is not limited to a gas-solid permeation method, an anti-solvent crystallization method, a room temperature suspension stirring method, a high temperature suspension stirring method, a gas-liquid permeation method, a room temperature slow volatilization method, a slow cooling method and the like.

In some embodiments where the solid is precipitated by the antisolvent addition method, the various crystalline forms of the hydrochloride, oxalate, or malonate salt of the compound of formula (Ia) are prepared by: the compound of formula (Ia) in any solid form (e.g. crystalline form or amorphous form) is reacted with hydrochloric acid, oxalic acid or malonic acid in a good solvent, after the reaction is completed, an antisolvent is added thereto, crystals are precipitated under stirring (the stirring may be carried out at room temperature or under a reduced temperature condition (e.g. reduced to 0-20 ℃, preferably 0-10 ℃, such as 0 ℃,5 ℃ or 10 ℃), or the crystals are precipitated by standing (e.g. standing at room temperature) (preferably while slowly volatilizing the solvent), and then the precipitated crystals are separated and dried. The good solvent includes, but is not limited to, organic solvents such as alcohols, ketones, nitriles, hydrocarbons (selected from haloalkanes, aromatic hydrocarbons), ethers (including chain ethers and cyclic ethers such as furans (including tetrahydrofurans) and dioxanes), sulfones, esters, amides, and organic acids such as methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide, N-methylpyrrolidone, methyl ethyl ketone, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, toluene, dichloromethane, and the like. Such anti-solvents include, but are not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., hydrocarbons (selected from alkanes, alkenes, alkynes), such as n-hexane, n-heptane, cyclohexane, and the like). The volume ratio of the good solvent to the anti-solvent is 1 (0.1-60), preferably 1 (0.3-40). The weight-to-volume ratio (mg/mL) of the compound of the formula (Ia) to the good solvent is (1-100):1, preferably (10-60): 1. The molar ratio of the compound of the formula (Ia) to hydrochloric acid, oxalic acid or malonic acid is (1-5) to (1-5), preferably (1-3) to (1-3).

In some embodiments where the solid precipitates by slow volatilization at room temperature, the various crystalline forms of the hydrochloride, oxalate or malonate salt of the compound of formula (Ia) are prepared by: the compound of formula (Ia) in any solid form (e.g. crystalline form or amorphous form) is dissolved and reacted with hydrochloric acid, oxalic acid or malonic acid in a solvent, slowly volatilized at room temperature after the reaction is completed to precipitate crystals, and then the precipitated crystals are separated and dried. The solvent includes, but is not limited to, an inorganic solvent (e.g., water) and an organic solvent (e.g., alcohols, amides, hydrocarbons (including alkanes, haloalkanes, alkenes, alkynes, and aromatics), ethers (including chain ethers and cyclic ethers (e.g., furans (including tetrahydrofurans) and dioxanes)), ketones, nitriles, or esters, specifically, e.g., isopropanol, methyl ethyl ketone, isopropyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, acetone, acetonitrile, ethyl acetate, n-hexane, tetrahydrofuran, dichloromethane, or the like), or a mixed solvent formed of two or more of the above solvents. The weight to volume ratio (mg/mL) of the compound of formula (Ia) to the solvent is (1-100):1, preferably (1-50): 1. The molar ratio of the compound of formula (Ia) to hydrochloric acid, oxalic acid or malonic acid is 1-5:1-5, preferably 1-3: 1-3.

Pharmaceutical composition and use

Another object of the present invention is to provide a pharmaceutical composition comprising:

i) any one or more of the following:

crystalline C of the compound of formula (I) of the present invention;

crystals B of the compound of formula (Ia) of the present invention; or

A salt of a compound of formula (Ia) of the invention, in particular a hydrochloride, oxalate or malonate salt of a compound of formula (Ia), more in particular a solid form of a hydrochloride, oxalate or malonate salt of a compound of formula (Ia), more in particular a crystalline hydrochloride salt of a compound of formula (Ia), a crystalline oxalate salt A, B, C or D of a compound of formula (Ia), or a crystalline malonate salt a or B of a compound of formula (Ia); and

ii) one or more pharmaceutically acceptable carriers.

It is another object of the present invention to provide a method for sedation, hypnosis, anxiolysis, muscle relaxation, or anticonvulsant in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one or more of the following:

crystalline C of the compound of formula (I) of the present invention;

crystals B of the compound of formula (Ia) of the present invention; or

The salts of the compounds of formula (Ia) of the present invention are in particular the hydrochloride, oxalate or malonate salts of the compounds of formula (Ia), more in particular the solid form of the hydrochloride, oxalate or malonate salt of the compounds of formula (Ia), more in particular the crystalline hydrochloride salt of the compound of formula (Ia), the crystalline oxalate salt A, B, C or D of the compound of formula (Ia), or the crystalline malonate salt a or B of the compound of formula (Ia).

It is another object of the present invention to provide any one or more of the following:

crystalline C of the compound of formula (I) of the present invention;

crystals B of the compound of formula (Ia) of the present invention; or

Salts of the compounds of the formula (Ia) according to the invention, in particular hydrochlorides, oxalates or malonates of the compounds of the formula (Ia), more in particular solid forms of hydrochlorides, oxalates or malonates of the compounds of the formula (Ia), more in particular crystalline hydrochlorides of the compounds of the formula (Ia), crystalline oxalates A, B, C or D of the compounds of the formula (Ia), or crystalline malonates A or B of the compounds of the formula (Ia),

it is used for sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant.

It is another object of the present invention to provide the use of any one or more of the following in the manufacture of a medicament for sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant:

crystalline C of the compound of formula (I) of the present invention;

crystals B of the compound of formula (Ia) of the present invention; or

The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the compositions of the present invention may be administered in suitable dosage forms.

The dosage form may be a solid, semi-solid, liquid, or gaseous formulation, including, but not limited to, tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.

The pharmaceutical compositions of the present invention may be prepared by any method known in the art, for example, by mixing, dissolving, granulating, sugar-coating, milling, emulsifying, lyophilizing, and the like.

The term "therapeutically effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The amount or amount of a compound of the invention in a pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially 1-50mg, for example 1.5mg, 2mg, 4mg, 10mg and 25mg etc.

As used herein, unless otherwise specified, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Examples

The present invention will be explained in more detail with reference to the following examples, which are provided for illustrating the technical solutions of the present invention and are not intended to limit the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adjustments, and still fall within the scope of the present invention.

Test instrument information and methods for experimentation

Method 1, XRPD

XRPD patterns were collected on a PANALYTICAL EMPyrean X-ray powder diffraction analyzer, and the X-ray of the XRPD test was Cu-k alpha (X-ray-K-X: (X-ray-X-ray diffraction pattern of Cu-K alpha) (X-ray-X-ray diffraction pattern of Cu-K-X-ray diffraction pattern of Cu-

1.540598；

1.544426K α 2/K α 1 intensity ratio: 0.50).

Method 2, DSC analysis

DSC data were collected on a TAQ200/2000 differential scanning calorimeter.

Method 3, Ion Chromatography (IC)

Ion Chromatography (IC) was used to measure the counter ion content and was used in conjunction with HPLC to determine the molar ratio of compound of formula (Ia) to salt-forming ion in the resulting salt.

Method 4 polarizing microscope (PLM) testing

PLM tests were collected by Axio lab. a1 upright microscope at room temperature.

Method 5 dynamic moisture sorption (DVS)

DVS values were collected on DVS Intrasic in SMS (surface Measurement systems). DVS test for relative humidity at 25 deg.C Using LiCl, Mg (NO)₃)₂And deliquescence point correction of KCl.

Example 1

3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

Preparation of methyl (4-yl) propionate (compound of formula (I))

The first step is as follows: 7-chloro-5- (2-fluorophenyl) -1H-benzo [ e][1,4]Diaza derivatives

Preparation of (E) -2(3H) -thione (Compound B)

Reacting 7-chloro-5- (2-fluorophenyl) -1H-benzo [ e][1,4]Diaza derivatives

-2(3H) -one (Compound A, 5.0g,17.3mmol) was dissolved in tetrahydrofuran (150 mL). Phosphorus pentasulfide (5.77g,6.55mmol) was added and the mixture was heated to 78 ℃ for 2 hours. Filtering, washing for 3 times, adding water into the filtrate, extracting with ethyl acetate for 3 times, drying, concentrating, and purifying by column chromatography to obtain target product 7-chloro-5- (2-fluorophenyl) -1H-benzo [ e][1,4]Diaza derivatives

-2(3H) -thione (Compound B, 4.2g, yield: 79%).

MS m/z(ESI):305[M+H]+

The second step is that: 8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

Preparation of (Compound C)

Reacting 7-chloro-5- (2-fluorophenyl) -1H-benzo [ e][1,4]Diaza derivatives

-2(3H) -Thione (Compound B, 400mg,1.31mmol, see example 7 for synthesis, first step) was dissolved in dioxane (15mL) and cyclopropanecarbohydrazide (394mg,3.93mmol) and mercury acetate (513mg,1.97mmol) were added. The mixture was heated to 100 ℃ and reacted for 5 hours. Cooling, pouring into ice water, extracting with ethyl acetate, washing the organic phase with water for 5 times, drying and concentrating to obtain the target product 8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

(Compound C, 280mg, yield: 68.5%).

MS m/z(ESI):353[M+H]+

The third step: 3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

Preparation of methyl (4-yl) propionate (compound of formula (I))

The compound 8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

(Compound 12b, 150mg,0.43mmol) and methyl acrylate (366mg,4.3mmol) were dissolved in dry THF (2 mL). The mixture was cooled to-15 deg.C and potassium tert-butoxide (95mg,0.86mmol) was added in portions and stirred for 1 hour until LCMS indicated the reaction was complete. Concentrating the reaction solution, and purifying by reversed phase HPLC to obtain the target product 3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f)][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

-4-yl) propionic acid methyl ester (compound of formula (I), 31mg, yield: 16.6%).

MS m/z(ESI):439[M+H]⁺

¹HNMR(400MHz,CDCl₃)δ:7.99(d,J＝8.8Hz,1H),7.87(dd,J＝8.8，6.4Hz,1H),7.66-7.54(m,2H),7.38-7.32(m,2H),7.25-7.20(m,1H),4.25-4.22(m,1H),3.61(s,3H),2.76-2.53(m,4H),2.12-2.08(m,1H),1.17-1.14(m,1H),1.03-0.90(m,3H)。

Example 2

3(S) -3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f)][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

Preparation of methyl (4-yl) propionate (compound of formula (Ia))

The first step is as follows: preparation of methyl (S) -5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -4- ((tert-butoxycarbonyl) amino) -5-oxopentanoate (Compound c)

2-amino-5-chloro-2' -fluorobenzophenone (compound a, 20g,0.083mol, commercially available) and N-tert-butoxycarbonyl-L-glutamic acid-5-methyl ester (compound b, 23g,0.088mol, commercially available) were dissolved in dichloromethane (300 mL). The mixture was cooled to 0 ℃, dicyclohexylcarbodiimide (DCC,18.2g,0.088mmol) was added and stirred for 24 hours. The reaction was complete as indicated by liquid mass spectrometer (LCMS) testing. The reaction was poured into ice water, extracted with ethyl acetate and the organic phase washed 3 times with water, dried and concentrated to give crude methyl (S) -5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -4- ((tert-butoxycarbonyl) amino) -5-oxopentanoate (compound 17c, 50g) which was used directly in the next reaction.

The second step is that: preparation of methyl (S) -4-amino-5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -5-oxopentanoate (Compound d)

Methyl (S) -5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -4- ((tert-butoxycarbonyl) amino) -5-oxopentanoate (compound c, 50g) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (TFA,100mL) was added and the mixture was heated to 40 ℃ and stirred for 2 hours until LCMS indicated the reaction was complete. The reaction was concentrated to give a crude methyl (S) -4-amino-5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -5-oxopentanoate residue (compound d, 40g) which was used directly in the next reaction.

The third step: (S) -3- (7-chloro-2-oxo-5- (2-fluorophenyl) -2, 3-dihydro-1H-benzo [ e)][1,4]Diaza derivatives

Preparation of methyl (3-yl) propionate (Compound e)

Methyl (S) -4-amino-5- ((2-fluoro-benzoyl-4-chlorophenyl) amino) -5-oxopentanoate (compound d, 40g) was dissolved in methanol (500 mL). Adding NaHCO₃The pH was adjusted to about 10 and stirred for 24 hours. LCMS showed the reaction was complete. The reaction solution was filtered, and the filtrate was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water 3 times, dried and concentrated, and the residue was purified by silica gel column chromatography to give the desired product (S) -3- (7-chloro-2-oxo-5- (2-fluorophenyl) -2, 3-dihydro-1H-benzo [ e ]][1,4]Diaza derivatives

-3-yl) propionic acid methyl ester (compound e, 22g, yield: 73%).

MS m/z(ESI):374[M+H]+

The fourth step: 3(S) -3- (7-chloro-2- ((dimorpholinophosphoryl) oxy) -5- (2-fluorophenyl) -3H-benzo [ e)][1,4]Diaza derivatives

Preparation of methyl (3-yl) propionate (Compound f)

Reacting 3(S) -3- (7-chloro-2-oxo-5- (2-fluorophenyl) -2, 3-dihydro-1H-benzo [ e)][1,4]Diaza derivatives

Methyl (3-yl) propionate (compound e, 6g,0.016mol) was dissolved in dry tetrahydrofuran (100 mL). The mixture was cooled to 0 ℃, NaH (963mg,0.024mol) was added, and stirred for 30 minutes. Morpholine chlorophosphate (8.21g,0.032mmol) was then added and stirred for 1 hour until LCMS indicated the reaction was complete. The reaction was poured into ice water, extracted with ethyl acetate, and the organic phase was washed 3 times with water, dried and concentrated to give crude 3(S) -3- (7-chloro-2- ((dimorpholinophosphoryl) oxy) -5- (2-fluorophenyl) -3H-benzo [ e ] ne][1,4]Diaza derivatives

Methyl-3-yl) propionate (compound f, 12g), which was used directly in the next reaction.

The fifth step: (S) -3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f)][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

Preparation of methyl (4-yl) propionate (compound of formula (Ia))

Mixing (S) -3- (7-chloro-2- ((dimorpholinphosphoryl) oxy) -5- (2-fluorophenyl) -3H-benzo [ e)][1,4]Diaza derivatives

Methyl (3-yl) propionate (compound f, 13.0g) was dissolved in 1, 4-dioxane (150 mL). Cyclopropanecarbohydrazide (4.81g,0.048mol) was added, heated to 100 ℃ and stirred for 14 h. LCMS showed the reaction was complete. Concentrating the reaction solution, and purifying the residue by preparative HPLC to obtain the target product 3(S) -3- (8-chloro-1-cyclopropyl-6- (2-fluorophenyl) -4H-benzo [ f [ ]][1,2,4]Triazole [4,3-a ]][1,4]Diaza derivatives

-4-yl) propionic acid methyl ester (compound of formula (Ia), 2.8g, yield 30%).

MS m/z(ESI):439[M+H]⁺

¹HNMR(400MHz,CDCl₃)δ:7.99(d,J＝8.8Hz,1H),7.87(dd,J＝8.8,6.4Hz,1H),7.66-7.54(m,2H),7.38-7.32(m,2H),7.25-7.20(m,1H),4.25-4.22(m,1H),3.61(s,3H),2.76-2.53(m,4H),2.12-2.08(m,1H),1.17-1.14(m,1H),1.03-0.90(m,3H)。

Example 3

Preparation and characterization of Crystal B of the Compound of formula (Ia)

Crystalline B of the compound of formula (Ia) is prepared according to the following method:

example 3.1 gas-solid permeation method

Approximately 15mg of each compound of formula (Ia) was weighed and added to a 3mL vial. About 2mL of the solvent shown in the following table was added to the 20mL bottle, the 3mL vial was placed open in the 20mL vial, and the 20mL vial was sealed. The solid was collected after standing at room temperature for 13 days. The results of the experiments are shown in the following table.

Solvent(s)	The obtained solid
		Water (W)	Crystal B
Ethanol	Crystal B
		Isopropanol (I-propanol)	Crystal B

The resulting solid was subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 1. The obtained solid was subjected to DSC analysis according to method 2, and the obtained DSC pattern was as shown in FIG. 2.

EXAMPLE 3.2 antisolvent addition method

Approximately 15mg of each compound of formula (Ia) was weighed and added to a 20mL vial. After dissolving in 0.5mL of a good solvent as shown in the following table, the corresponding anti-solvent as shown in the following table was added dropwise to the resulting clear solution, and the mixture was stirred while dropwise adding until a solid precipitated. Suspending and stirring the clear solution at 5 ℃ overnight if no solid is separated after about 15mL of the anti-solvent is added; if no solid is precipitated, the clear liquid is slowly volatilized at room temperature for crystallization. The precipitated solid was collected and the experimental results are shown in the following table.

The XRPD pattern and DSC pattern of the resulting solid were substantially the same as those in example 3.1, indicating that crystal B was obtained.

Example 3.3 Room temperature suspension stirring method

About 15mg of each of the compounds of the formula (Ia) was weighed out, added to a 1.5mL glass vial, and 0.6mL of the solvents shown in the following table were added thereto, respectively, to give a suspension. After the resulting suspension was stirred at room temperature for 14 days, the solid was collected by centrifugation and the experimental results are shown in the following table.

Solvent(s)	The obtained solid
		Methyl tert-butyl ether	Crystal B
Methanol/water (1:2)	Crystal B
		Acetone/water (1:2)	Crystal B
Acetonitrile/water (1:2)	Crystal B
		Dimethyl sulfoxide/water (1:2)	Crystal B
2-Methyltetrahydrofuran/Hexane (1:2)	Crystal B
		Ethyl acetate/n-hexane (1:2)	Crystal B
Toluene/n-hexane (1:2)	Crystal B

Example 3.4 high temperature suspension agitation

About 15mg of each of the compounds of the formula (Ia) was weighed, added to a 1.5mL glass vial, and 0.6mL of the solvents as listed in the following table, respectively, was added thereto to give a suspension. After the resulting suspension was stirred at 50 ℃ for 14 days, the solid was collected by centrifugation and the experimental results are shown in the following table.

Solvent(s)	The obtained solid
		Methyl tert-butyl ether	Crystal B
Methanol/water (1:2)	Crystal B
		Acetone/water (1:2)	Crystal B
Dimethyl sulfoxide/water (1:2)	Crystal B
		2-Methyltetrahydrofuran/Hexane (1:2)	Crystal B
Ethyl acetate/n-hexane (1:2)	Crystal B
		Toluene/n-hexane (1:2)	Crystal B

Example 3.5 gas-liquid infiltration method

About 15mg of each of the compound of the formula (Ia) was weighed, added to a 3mL vial, and 0.5mL of a good solvent shown in the following table was added thereto to dissolve. Another 20mL vial was charged with about 3mL of the corresponding anti-solvent as shown in the following table, and the 3mL vial was placed open in the 20mL vial, sealed, and allowed to stand at room temperature. When the precipitation of the solid was observed, the solid was taken out, and the experimental results are shown in the following table.

Example 3.6 Slow volatilization at room temperature

Approximately 15mg of each compound of formula (Ia) was weighed and added to a 3mL vial. 1.0mL of each of the solvents shown in the following table was added thereto, and the samples were allowed to dissolve completely by sonication or shaking to obtain clear solutions. Covering the small bottle filled with the clear solution by using a sealing film, pricking 3-4 small holes on the sealing film, and slowly volatilizing at room temperature. The resulting solid was collected and the results of the experiment are shown in the table below.

Solvent(s)	The obtained solid
		Isopropanol (I-propanol)	Crystal B
Methyl ethyl ketone	Crystal B
		Acetic acid isopropyl ester	Crystal B
2-methyltetrahydrofuran	Crystal B
		Cyclopentyl methyl ether	Crystal B
Methanol/water (4:1)	Crystal B
		Acetone/water (4:1)	Crystal B
Acetonitrile/water (4:1)	Crystal B
		Ethyl acetate/n-hexane (4:1)	Crystal B
Tetrahydrofuran/hexane (4:1)	Crystal B
		Dichloromethane/n-hexane (4:1)	Crystal B

Example 3.7 Slow Cooling method

An amount of the compound of formula (Ia) was weighed, added to a 3mL vial, 1.0mL of the solvent shown in the following table was added thereto, and magnetically stirred at 800RPM for 3 hours at 50 ℃. Filtering with 0.45 μm PTFE filter membrane, and collecting supernatant. Cooling the obtained supernatant from 50 deg.C to 5 deg.C at a speed of 0.1 deg.C/min, and keeping the temperature at 5 deg.C. The precipitated solid was collected and the experimental results are shown in the following table.

Solvent(s)	The obtained solid
		Methyl tert-butyl ether	Crystal B
Isobutanol	Crystal B
		Isobutyl acetic acid	Crystal B
Methanol/water (1:1)	Crystal B
		Acetone/water (1:1)	Crystal B
Ethanol/n-hexane (1:1)	Crystal B
		2-Methyltetrahydrofuran/Hexane (1:1)	Crystal B

Example 3.8 anti-solvent addition

Approximately 15mg of each compound of formula (Ia) was weighed out, added to a 20mL vial and dissolved in 0.5mL of a good solvent as shown in the following table to give a clear solution. The resulting clear solution was quickly added to a 5mL vial containing 4mL of the corresponding anti-solvent shown in the table below while magnetically stirring. After a few minutes of equilibration, the solid was collected and the results of the experiment are shown in the table below.

Example 4

Preparation and characterization of Crystal C of the Compound of formula (I)

Room temperature suspension stirring method

About 15mg of each of the compounds of the formula (I) was weighed, added to a 1.5mL glass vial, and 0.6mL of the solvents shown in the following Table were added thereto, respectively, to give a suspension. After the resulting suspension was left to stir at room temperature for 14 days, the solid was collected by centrifugation. The results of the experiments are shown in the following table.

Solvent(s)	The obtained solid
		Isopropanol (I-propanol)	Crystal C

The resulting solid was subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 3. The obtained solid was subjected to DSC analysis according to method 2, and the obtained DSC pattern was as shown in FIG. 4.

Example 5

Preparation and characterization of the Crystal of the hydrochloride salt of the Compound of formula (Ia)

Slow volatilization method at room temperature

200.1mg of the compound of the formula (Ia) were weighed out, charged into a 20mL glass vial and dissolved by adding 1.5mL of ethyl acetate. To the resulting solution was added 3.6mL of a diluted hydrochloric acid solution (obtained by diluting 76. mu.L of hydrochloric acid (37%, 12mol/L) with 6.0mL of ethyl acetate), and the mixture was stirred at room temperature for 22 hours and then slowly evaporated at room temperature. The solid was collected by filtration and dried under vacuum at 50 ℃.

According to method 3, the molar ratio of the compound of formula (Ia) to hydrochloric acid in the hydrochloride of the compound of formula (Ia) was found to be 1: 1. The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 5. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern was as shown in fig. 6. The crystals obtained were subjected to the PLM test according to method 4, and the obtained crystals were small in size, with an average particle size of <10 μm, very fluid and convenient for formulation.

Example 6

Preparation and characterization of oxalate crystals A of the Compound of formula (Ia)

6.1. Antisolvent addition process

Crystalline oxalate salt a of a compound of formula (Ia) is prepared by:

299.5mg of the compound of formula (Ia) and 97.2mg of oxalic acid are weighed out and added to a 20mL glass vial. To the glass bottle was added 7.5mL of acetone to dissolve it. To the resulting solution was then added 11.0mL of n-heptane. After stirring at room temperature for 24 hours, the solid was collected by centrifugation.

The molar ratio of the compound of formula (Ia) to oxalic acid in the oxalate salt of the compound of formula (Ia) was determined to be 1:1 according to method 3. The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 7. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern is shown in fig. 8. According to method 4, the obtained crystals are subjected to PLM test, and the obtained crystals are rod-shaped solids, have small crystal particles, have the average particle size of less than 10 micrometers, have very good fluidity and are convenient to prepare.

6.2. Slow volatilization method at room temperature

About 299.5mg of each of the compound of formula (Ia) and 97.2mg of oxalic acid were weighed out and added to a 20mL glass vial. 10mL of ethyl acetate was added to dissolve the mixture, and after stirring at room temperature for 3 days, the mixture was slowly evaporated at room temperature to obtain a solid. The resulting solid was collected by centrifugation and dried in vacuo at room temperature.

The XRPD pattern and DSC pattern of the resulting solid were substantially the same as those in example 6.1, indicating that oxalate crystal a of the compound of formula (Ia) was obtained.

Example 7

Preparation and characterization of oxalate crystals B of the Compound of formula (Ia)

Slow volatilization method at room temperature

About 299.5mg of each of the compound of formula (Ia) and 97.2mg of oxalic acid were weighed out and added to a 20mL glass vial. 10mL of acetone was added to dissolve the mixture, and the mixture was stirred at room temperature for 3 days and then slowly evaporated at room temperature to obtain a solid. The resulting solid was collected by centrifugation and dried in vacuo at room temperature.

The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 9. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern is shown in fig. 10.

Example 8

Preparation and characterization of oxalate Crystal C of Compound of formula (Ia)

Slow volatilization method at room temperature

About 299.5mg of each of the compound of formula (Ia) and 97.2mg of oxalic acid were weighed out and added to a 20mL glass vial. 10mL of tetrahydrofuran/water (V/V, 19:1) was added to dissolve the mixture, and after stirring at room temperature for 3 days, the mixture was slowly evaporated at room temperature to obtain a solid. The solid was collected by centrifugation and dried in vacuo at room temperature.

The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 11. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern is shown in fig. 12.

Example 9

Preparation and characterization of oxalate crystals D of the Compound of formula (Ia)

Slow volatilization method at room temperature

About 299.5mg of each of the compound of formula (Ia) and 97.2mg of oxalic acid were weighed out, added to a 20mL glass vial, dissolved by adding 10mL of ethyl acetate, and left to stir at room temperature for 12 hours, followed by slow volatilization at room temperature to obtain a solid. The solid was collected by centrifugation and dried under vacuum at 50 ℃.

The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in fig. 13. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern is shown in fig. 14.

Example 10

Preparation and characterization of malonate Crystal A of Compound of formula (Ia)

Antisolvent addition method:

200.2mg of the compound of the formula (Ia) and 50.7mg of malonic acid are weighed out and introduced into a 20mL glass vial. To the glass bottle was added 4.5mL of ethyl acetate to dissolve it, and then 4.0mL of n-heptane was added to the resulting solution. After stirring at room temperature for 24 hours, the solid was collected by centrifugation and dried under vacuum at 50 ℃.

According to method 3, the molar ratio of the compound of formula (Ia) to malonic acid in the malonate salt of the compound of formula (Ia) was determined to be 1: 1. The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 15. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern is shown in fig. 16. The crystals obtained were subjected to the PLM test according to method 4, and the crystals obtained were granular solids with small crystal particles having an average particle size of <20 μm, had very good flowability and were convenient for formulation.

Example 11

Preparation and characterization of malonate Crystal B of Compound of formula (Ia)

Slow volatilization method at room temperature

200.2mg of the compound of the formula (Ia) and 50.7mg of malonic acid are weighed out and introduced into a 20mL glass vial. To the glass bottle was added 4.5mL of ethyl acetate, and after stirring for 12 hours, the mixture was slowly evaporated at room temperature to give a solid. The solid was collected by centrifugation and dried under vacuum at 50 ℃.

The crystals obtained were subjected to XRPD analysis according to method 1, and the resulting XRPD pattern is shown in figure 17. The obtained crystals were subjected to DSC analysis according to method 2, and the obtained DSC pattern was as shown in fig. 18.

Examples of the experiments

EXAMPLE 1 equilibrium solubility test

An appropriate amount of crystal B of the compound of formula (Ia) was magnetically stirred in water at 500RPM at room temperature to form a suspension. After 24 hours of equilibration, the suspension was centrifuged and filtered through a 0.45 micron PTFE filter. And (4) respectively carrying out concentration determination and crystal form verification on the separated supernatant and the residual solid.

The experimental result shows that the solubility of the crystal B of the compound of the formula (Ia) in water can reach 0.084mg/mL at room temperature, which is better than that of the amorphous and other crystal forms of the compound of the formula (Ia). And separating the residual solid after magnetic stirring, wherein XRPD analysis shows that the crystal form of the residual solid is not changed, remains as the crystal B of the compound of the formula (Ia), and no other impurities are generated and is not converted into other crystal forms. This experiment shows that crystal B of the compound of formula (Ia) has excellent solubility and stability, with excellent kinetically stable properties. Furthermore, this property of the crystals B of the compound of formula (Ia) also makes it very advantageous for formulation, enabling stability during formulation.

Experimental example 2 hygroscopicity and solid State stability test

DVS characterization was performed according to method 5 on crystal B of the compound of formula (Ia), crystal of hydrochloride of the compound of formula (Ia), crystal a of oxalate of the compound of formula (Ia), and crystal a of malonate of the compound of formula (Ia), respectively, to investigate hygroscopicity and solid state stability thereof at different humidities.

The results of the experiments are shown in the following table:

from the above results, it is understood that the weight change of the crystalline form of the present invention due to moisture absorption under the high humidity condition of 80% is less than 1%, indicating that it is almost free from hygroscopicity. Further, XRPD analysis shows that the crystal form does not change XRPD data under high humidity conditions, and the crystal form has excellent properties in hygroscopicity and solid state stability. In particular, the crystal B of the compound of formula (Ia) of the present invention has a weight change of only 0.1% under a high humidity condition of 80%, indicating that it is almost free from hygroscopicity. This indicates that the crystal B of the compound of formula (Ia) of the present invention is very stable to high humidity conditions and its hygroscopicity is significantly superior to other crystal forms of the compound of formula (Ia).

EXAMPLE 3 physicochemical stability test

3.1. Physicochemical stability test of crystals of the Compound of the present invention and salts thereof

The physicochemical stability of a compound of formula (Ia) according to the present invention and a crystal form of a salt thereof, which are shown in the following table, was examined under the following 3 conditions, respectively, in an appropriate amount: 80 ℃ closed for 24 hours, 25 ℃/60% RH open for 1 week and 40 ℃/75% RH open for 1 week. The samples shown in the table were then subjected to XRPD and HPLC analysis, respectively, to determine crystal form and purity changes. The results of the experiments are shown in the following table:

it should be noted that the "relative purity" indicated in the table above is the ratio relative to the starting HPLC purity.

From the above results, it is clear that the crystal of the compound of the present invention and the salt thereof has very little change in purity under high temperature and/or high humidity conditions, and particularly, the crystal B of the compound of the formula (Ia) of the present invention and the malonate salt form a of the compound of the formula (Ia) have no change in purity under high temperature and/or high humidity conditions at all. Also, XRPD analysis showed that the crystals of the compound of formula (Ia) and the salt thereof of the present invention did not undergo crystal form change after standing, which indicates that the crystals of the compound of formula (Ia) and the salt thereof of the present invention are not only stable to high-humidity conditions and/or high-temperature conditions, but also stable to air (e.g., oxygen) under such conditions, and have very excellent physicochemical stability. The above experimental results show that the crystal of the compound of formula (Ia) of the present invention has no special requirements for transportation conditions, does not require special conditions such as sealing, light shielding, low temperature, etc., and can ensure the quality safety of transportation and storage even under high humidity and high temperature conditions. Particularly, the crystal B of the compound of the formula (Ia) and the malonate crystal form A of the compound of the formula (Ia) have more outstanding physical and chemical stability, can ensure that the crystal B does not generate impurities even being placed for a long time under high temperature and/or high humidity conditions, and ensures the safety of clinical medication.

3.2. Physicochemical stability test of salts of the Compounds of the invention

Respectively weighing appropriate amount of hydrochloride crystal of the compound of the formula (Ia), oxalate crystal A of the compound of the formula (Ia) and malonate crystal A of the compound of the formula (Ia), and detecting crystal form change of the compound of the formula (Ia) under heating condition by XRPD. The results of the experiments are shown in the following table:

from the above results, it can be seen that the crystal of the salt of the compound of formula (Ia) of the present invention has no crystal form or purity change under extreme high temperature conditions, which indicates that the crystal has good physicochemical stability under both normal temperature and high temperature conditions, and the above experiment also shows that the crystal of the salt of the compound of formula (Ia) of the present invention has good photostability.

Experimental example 4 dynamic solubility test

Hydrochloride crystals of the compound of formula (Ia), oxalate crystals a of the compound of formula (Ia) and malonate crystals a of the compound of formula (Ia) were each formulated as a suspension (about 10mg solids per ml solvent) in an aqueous environment, an SGF (artificial gastric fluid) environment, a FaSSIF (simulation of intestinal fluid in the small intestine under hunger conditions before meals in humans), a FeSSIF (simulation of intestinal fluid in the small intestine under satiating conditions after meals in humans) and mixed at room temperature (25 rpm) by a rotating disk. During the course of the rotary equilibration, samples were taken after 1 hour each, and the supernatant was filtered to determine the concentration and the XRPD pattern of the solid. The results of the experiments are shown in the following table.

From the above results, it can be seen that: the crystals of the salt of the compound of formula (Ia) of the present invention have good solubility in water environment, SGF environment, FaSSIF environment, FeSSIF, and the solubility of the crystals of the salt of the compound of formula (Ia) of the present invention in water, FaSSIF and SGF is significantly improved compared to the free base of the compound of formula (Ia). And no crystal form change occurs in the crystal in the detection process through XRPD detection. The above experimental results show that the crystal of the salt of the compound of formula (Ia) of the present invention can be rapidly dissolved in vivo after administration, facilitating absorption of the drug.

Experimental example 5

Test for inducing disappearance of righting reflex in mouse by Compound of the present invention

Kunming mice (male, 18-25 g) are randomly grouped, and after single administration by rapid bolus injection through tail vein, the latency period and duration of disappearance of righting reflex of the mice are recorded. The results of the experiments are shown in tables 1 and 2 below.

TABLE 1 incubation results for the effect of positive reflection on mice turnover

As can be seen from table 1 above, the compounds of the present invention have a shorter latency than the control, indicating that the compounds of formula (Ia) have a short onset of action, a fast onset of action, and a very good onset of action.

TABLE 2 duration results on the effect of positive reflection on mice turnover

Compound (dose) (60mg/kg)	Duration (min)
		A compound of the formula (Ia)Article (A)	25.61

The data in table 2 above show that the compounds of the invention have a very suitable duration of anaesthesia and recovery, thus indicating that the compounds of formula (Ia) have an excellent duration of anaesthesia, a specific effect which is critical for the clinical use of anaesthetics.

Experimental example 6

Whole-cell patch clamp detection of influence of compound of the invention on GABA (Gamma amino acid butyric acid) activation current of cells

The test compound was dissolved in external solution (NaCl 140mM, KCl 4.7mM, HEPES 10mM, CaCl)₂2mM, 11mM glucose, MgCl₂1mM, pH 7.4). HEK 293T cells highly expressing human GABAa receptor were seeded on coverslips in DMEM medium at 37 ℃ and 5% CO₂Culturing for 24h under the condition.

GABA Cl^-The current was recorded whole cell using a HEKA EPC 10USB patch clamp amplifier. 1 μ M GABA for exciting Cl^-The current and the membrane potential are clamped at-60 mV. Cells were treated with different concentrations of test compound simultaneously with 1 μ M GABA and Cl recorded for the same cells^-Induction Effect of Current, percentage of maximum enhancement of Current (E)_max) And the concentration of the compound to be tested (EC) at which the maximum enhancement percentage of the current reaches half₅₀)。

Table 3: e at a Compound concentration of 10. mu.M_max

Test Compound (concentration 10. mu.M)	E_max
		A compound of formula (Ia)	346.8％

Percent maximum enhancement of current E for vehicle control group_maxCalculated as 100%, E of the compound of the formula (Ia) at 10. mu.M_maxGreater than 100% indicates that the compounds of formula (Ia) have good activation of the human GABAa receptor.

TABLE 4 EC of Compounds₅₀

Compound (I)	EC₅₀(μM)
		A compound of formula (Ia)	0.47

EC of the Compound of formula (Ia)₅₀A value of less than 1 μ M with a very small EC₅₀The concentration indicates that the compound of formula (Ia) has good activation on human GABAa receptors.

Tables 3 and 4 above show that the compounds of the present invention have excellent anesthetic action and a definite mechanism of action.

Experimental example 7

Cynomolgus monkey safety test of the Compound of the present invention

After the cynomolgus monkeys were randomly grouped, different doses (4mg/kg, 6mg/kg, 8mg/kg) of the compound of formula (Ia) were administered to each group of cynomolgus monkeys. Then, general symptoms, duration of anesthetic action and anesthetic condition of the cynomolgus monkey were observed. Before and after administration, II-lead electrocardiogram is detected by a large animal noninvasive physiological signal remote measuring system (emkaPACK4G), arterial blood pressure (systolic pressure, diastolic pressure and mean arterial pressure) is measured by an intelligent noninvasive sphygmomanometer, anal temperature is detected by a TH-212 intelligent digital thermometer, and pulse oxyhemoglobin saturation is monitored by a monitor (SpO 2).

The results indicate that the compounds of formula (Ia) have a more suitable effect both in the latency and duration of anesthesia. No significant fluctuations were found in parameters such as respiratory rate, body temperature, blood pressure and blood oxygen saturation. No significant change in QTc was seen for most of the time period after dosing. This indicates that after administration of the compound of formula (Ia) to cynomolgus monkeys, no significant side effects were seen in both cardiovascular and respiratory systems.

In addition, the compound of formula (Ia) shows good safety and tolerance to mice, rats, monkeys and sheep in tolerance and toxicity tests under single-dose high-dose conditions.

The above embodiments are further described in detail. However, it should be understood that the scope of the above subject matter is not limited to the following examples, and any technical solutions implemented based on the disclosure of the present invention are within the scope of the present invention.

Claims

1. Crystals B of a compound of formula (Ia):

the XRPD pattern of crystal B of the compound of formula (Ia) comprises characteristic peaks at diffraction angles (2 θ) of 6.8 ± 0.2 °, 11.5 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 22.0 ± 0.2 °.

2. The XRPD pattern of crystal B of the compound of formula (Ia) of claim 1 comprising characteristic peaks at diffraction angles (2 Θ) of 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 17.1 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °.

3. The XRPD pattern for crystal B of the compound of formula (Ia) according to claim 1 includes characteristic peaks at diffraction angles (2 θ) of 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 17.1 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 20.6 ± 0.2 °, 21.5 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °, 23.6 ± 0.2 °, 24.6 ± 0.2 °, 25.3 ± 0.2 °, 26.1 ± 0.2 °, 27.4 ± 0.2 °, 27.8 ± 0.2 °, 28.3 ± 0.2 °, 29.4 ± 0.2 °.

4. The XRPD pattern of crystal B of the compound of formula (Ia) according to claim 1 comprising characteristic peaks as shown in figure 1.

5. A process for preparing crystals B of a compound of formula (Ia) according to any one of claims 1 to 4 selected from the group consisting of gas-solid permeation, anti-solvent crystallization, room temperature suspension stirring, high temperature suspension stirring, gas-liquid permeation, room temperature slow volatilization and slow cooling.

6. A crystal C of a compound of formula (I):

the XRPD pattern of crystal C of the compound of formula (I) includes characteristic peaks at diffraction angles (2 θ) of 8.4 ± 0.2 °, 14.0 ± 0.2 °, 16.7 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± 0.2 °.

7. The XRPD pattern for crystal C of the compound of formula (I) according to claim 6 including characteristic peaks at diffraction angles (2 θ) of 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± 0.2 °.

8. The XRPD pattern for crystal C of the compound of formula (I) according to claim 6 includes characteristic peaks at angles (2 θ) of 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 20.3 ± 0.2 °, 21.2 ± 0.2 °, 21.8 ± 0.2 °, 22.4 ± 0.2 °, 22.7 ± 0.2 °, 23.5 ± 0.2 °, 24.5 ± 0.2 °, 25.2 ± 0.2 °, 26.6 ± 0.2 °, 28.1 ± 0.2 °, 29.2 ± 0.2 °.

9. The XRPD pattern of crystal C of the compound of formula (I) of claim 6 including characteristic peaks as shown in figure 3.

10. A process for the preparation of crystals C of a compound of formula (I) according to any one of claims 6 to 9, selected from the group consisting of gas-solid permeation, anti-solvent crystallization, room temperature suspension stirring, high temperature suspension stirring, gas-liquid permeation, room temperature slow volatilization and slow cooling.

11. A salt of a compound of formula (Ia):

the salt is an organic acid salt or an inorganic acid salt of the compound of formula (Ia).

12. The salt of the compound of formula (Ia) according to claim 11, which is a hydrochloride, maleate, succinate, adipate, sulfate, phosphate, fumarate, malate, glycolate, mucate, lactate, gentisate, besylate, edisylate, napadisylate, mesylate, tartrate, hippurate, citrate, nicotinate, lactate, oxalate, malonate, nicotinamide and tosylate of the compound of formula (Ia).

13. Salts of the compounds of formula (Ia) according to claim 11 are the hydrochloride, oxalate and malonate salts of the compounds of formula (Ia).

14. A process for the preparation of a salt of a compound of formula (Ia) according to any one of claims 11 to 13, which comprises reacting a compound of formula (Ia), optionally in solid form, with the mineral acid or the organic acid to precipitate a solid, and subsequently separating and drying the precipitated solid.

15. The salt of the compound of formula (Ia) according to claim 11, which is the hydrochloride salt of the compound of formula (Ia).

16. The hydrochloride salt of the compound of formula (Ia) of claim 15, wherein the molar ratio of the compound of formula (Ia) to hydrochloric acid is 1: 1.

17. The salt of the compound of formula (Ia) according to claim 15 or 16, which is a crystalline hydrochloride salt of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 5.4 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °.

18. The XRPD pattern of the crystalline hydrochloride salt of the compound of formula (Ia) according to claim 17 comprising characteristic peaks at diffraction angles (2 Θ) of 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 17.5 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °.

19. The XRPD pattern of the crystalline hydrochloride salt of the compound of formula (Ia) according to claim 17 comprising characteristic peaks at diffraction angles (2 Θ) of 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 15.3 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 17.5 ± 0.2 °, 18.0 ± 0.2 °, 18.7 ± 0.2 °, 20.3 ± 0.2 °, 22.1 ± 0.2 °, 23.0 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 27.5 ± 0.2 °.

20. The XRPD pattern of the crystalline hydrochloride salt of the compound of formula (Ia) according to claim 17 comprising characteristic peaks as shown in figure 5.

21. A process for the preparation of a salt of a compound of formula (Ia) according to claims 15 to 20, which comprises reacting a compound of formula (Ia), optionally in solid form, with hydrochloric acid to precipitate a solid, and subsequently separating and drying the precipitated solid.

22. A salt of the compound of formula (Ia) according to claim 11, which is the oxalate salt of the compound of formula (Ia).

23. The salt of the compound of formula (Ia) according to claim 22, wherein the molar ratio of the compound of formula (Ia) to oxalic acid is 1: 1.

24. The salt of the compound of formula (Ia) according to claim 22 or 23, which is oxalate salt of the compound of formula (Ia) crystalline a having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 8.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 24.7 ± 0.2 °.

25. The compound of formula (Ia) according to claim 24 having the oxalate crystal a an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 23.0 ± 0.2 °, 24.7 ± 0.2 °.

26. The compound of formula (Ia) according to claim 24 having an oxalate crystal a with an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.5 ± 0.2 °, 20.9 ± 0.2 °, 22.1 ± 0.2 °, 22.8 ± 0.2 °, 23.0 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.3 ± 0.2 °, 25.8 ± 0.2 °, 26.5 ± 0.2 °, 28.2 ± 0.2 °.

27. The XRPD pattern of oxalate crystal a of the compound of formula (Ia) according to claim 24 includes characteristic peaks as shown in figure 7.

28. A salt of the compound of formula (Ia) according to claim 22 or 23, which is oxalate crystal B of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 °, 23.3 ± 0.2 °.

29. The XRPD pattern of oxalate crystal B of the compound of formula (Ia) according to claim 28 comprising characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 15.4 ± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, 20.0 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °.

30. The XRPD pattern of oxalate crystal B of the compound of formula (Ia) according to claim 28 includes characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 10.2 ± 0.2 °, 10.7 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 14.0 ± 0.2 °, 15.4 ± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, 17.8 ± 0.2 °, 18.5 ± 0.2 °, 19.1 ± 0.2 °, 20.0 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 25.7 ± 0.2 °, 26.6 ± 0.2 °.

31. The XRPD pattern of oxalate crystal B of the compound of formula (Ia) according to claim 28 includes characteristic peaks as shown in figure 9.

32. A salt of the compound of formula (Ia) according to claim 22 or 23, which is oxalate crystal C of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 18.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °.

33. The XRPD pattern of oxalate crystal C of the compound of formula (Ia) according to claim 32 including characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 10.7 ± 0.2 °, 11.9 ± 0.2 °, 12.9 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 18.3 ± 0.2 °, 19.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °.

34. The XRPD pattern of oxalate crystal C of the compound of formula (Ia) according to claim 32 including characteristic peaks at diffraction angles (2 Θ) of 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 10.7 ± 0.2 °, 11.9 ± 0.2 °, 12.9 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.5 ± 0.2 °, 15.8 ± 0.2 °,17.3 ± 0.2 °, 17.8 ± 0.2 °, 18.3 ± 0.2 °, 19.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °.

35. The XRPD pattern of oxalate crystal C of the compound of formula (Ia) according to claim 32 including the characteristic peaks shown in figure 11.

36. The salt of the compound of formula (Ia) according to claim 22 or 23, which is crystalline D oxalate salt of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 Θ) of 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 15.9 ± 0.2 °, 19.9 ± 0.2 °.

37. The XRPD pattern of oxalate crystal D of the compound of formula (Ia) according to claim 36, includes characteristic peaks at diffraction angles (2 θ) of 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 13.9 ± 0.2 °, 15.9 ± 0.2 °, 19.9 ± 0.2 °, 22.2 ± 0.2 °.

38. The XRPD pattern of oxalate crystal D of the compound of formula (Ia) according to claim 36, including characteristic peaks at diffraction angles (2 Θ) of 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 13.9 ± 0.2 °, 15.9 ± 0.2 °, 16.7 ± 0.2 °, 17.1 ± 0.2 °, 19.9 ± 0.2 °, 21.7 ± 0.2 °, 22.2 ± 0.2 °.

39. The XRPD pattern of oxalate crystal D of the compound of formula (Ia) according to claim 36 includes the characteristic peaks shown in figure 13.

40. A process for the preparation of a salt of a compound of formula (Ia) as claimed in any one of claims 22 to 39, which comprises reacting the compound of formula (Ia), in any solid form, with oxalic acid to precipitate a solid, and subsequently isolating and drying the precipitated solid.

41. The salt of the compound of formula (Ia) according to claim 11, which is a malonate salt of the compound of formula (Ia).

42. The malonate salt of a compound of formula (Ia) of claim 41, wherein the molar ratio of the compound of formula (Ia) to malonic acid is 1: 1.

43. The salt of the compound of formula (Ia) according to claim 41 or 42, which is malonate crystal A of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.9 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 23.8 ± 0.2 °.

44. The XRPD pattern for malonate crystal A of the compound of formula (Ia) according to claim 43 comprising characteristic peaks at diffraction angles (2 θ) of 6.9 ± 0.2 °, 9.7 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, 23.8 ± 0.2 °.

45. The XRPD pattern for malonate crystal A of the compound of formula (Ia) according to claim 43 comprising characteristic peaks at diffraction angles (2 θ) of 6.9 ± 0.2 °, 9.7 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 15.7 ± 0.2 °, 17.7 ± 0.2 °, 18.7 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, 23.8 ± 0.2 °, 24.2 ± 0.2 °, 25.6 ± 0.2 °, 25.8 ± 0.2 °, 26.6 ± 0.2 °, 27.1 ± 0.2 °.

46. The XRPD pattern of malonate crystal a of the compound of formula (Ia) according to claim 43, comprising characteristic peaks as shown in figure 15.

47. The salt of the compound of formula (Ia) according to claim 41 or 42, which is malonate crystal B of the compound of formula (Ia) having an XRPD pattern comprising characteristic peaks at diffraction angles (2 θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 23.8 ± 0.2 °.

48. The XRPD pattern for malonate crystal B of the compound of formula (Ia) according to claim 47 includes characteristic peaks at diffraction angles (2 θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 14.6 ± 0.2 °, 15.1 ± 0.2 °, 15.8 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 23.8 ± 0.2 °.

49. The XRPD pattern for malonate crystal B of the compound of formula (Ia) according to claim 47 includes characteristic peaks at diffraction angles (2 θ) of 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 14.6 ± 0.2 °, 15.1 ± 0.2 °, 15.8 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 20.4 ± 0.2 °, 20.7 ± 0.2 °, 21.1 ± 0.2 °, 22.5 ± 0.2 °, 23.8 ± 0.2 °.

50. The XRPD pattern of malonate crystal B of the compound of formula (Ia) according to claim 47, comprising characteristic peaks as shown in figure 17.

51. A process for the preparation of a salt of a compound of formula (Ia) according to any one of claims 41 to 50, which comprises reacting the compound of formula (Ia), in any solid form, with malonic acid to precipitate a solid, followed by isolation and drying of the precipitated solid.

52. A pharmaceutical composition comprising:

i) any one or more of the following:

crystals B of a compound of formula (Ia) according to any one of claims 1 to 4;

crystal C of a compound of formula (I) according to any one of claims 6 to 9; or

A salt of a compound of formula (Ia) according to any one of claims 11-13, 15-20, 22-39, and 41-50; and

ii) one or more pharmaceutically acceptable carriers.

53. Use of any one or more of the following in the manufacture of a medicament for sedation, hypnosis, anxiolysis, muscle relaxation or anticonvulsant:

crystals B of a compound of formula (Ia) according to any one of claims 1 to 4;

A salt of a compound of formula (Ia) according to any one of claims 11 to 13, 15 to 20, 22 to 39 and 41 to 50.