VMAT2 inhibitor, method for preparing the same, and use thereof

Abstract

The present invention relates to a group of compounds that function as VMAT2 inhibitors, specifically compounds of formula (I): [Formula 1] The present invention relates to a compound represented by TIFF2022547390000135.tif49170 or a stereoisomer or pharmaceutically acceptable salt thereof, a method for preparing the same, and a use of the same in preparing a drug for treating a disease associated with VMAT2.

Description

Technical Field

[0001] The present invention relates to a group of compounds that function as VMAT2 inhibitors or stereoisomers or pharmaceutically acceptable salts thereof, and their use in the field of diseases related to VMAT2.

Background Art

[0002] Tardive dyskinesia (TD), also known as tardive hyperkinetic disorder, is a disease first proposed by Faurbye in 1964. This disease often occurs in patients who have taken large amounts of antipsychotics over a long period of time. Clinically, this disease is mainly characterized by involuntary, rhythmic, repetitive, and stereotypical movements, which often involve the jaw, lips, and tongue. Other drugs such as drugs (levodopa) for treating Parkinson's disease can also cause tardive dyskinesia.

[0003] Vesicular monoamine transporter 2 (VMAT2) is a transporter located in the vesicular membrane inside the presynaptic membrane, and this function is for the reuptake and delivery of monoamine neurotransmitters such as dopamine (DA) or 5-hydroxytryptamine into vesicles to prevent these monoamine neurotransmitters from being metabolized in the cytoplasm. A VMAT2 inhibitor can antagonize the reuptake function of VMAT2, and as a result, dopamine is reuptaken and delivered into vesicles by VMAT2 and metabolized by enzymes in the cytoplasm. Therefore, the release of dopamine in the synaptic cleft is reduced, thereby further achieving the purpose of treating tardive dyskinesia.

[0004] Tetrabenazine (TBZ) is the first commercially available selective VMAT2 inhibitor, and its metabolite in vivo, trans(2,3)-dihydrotetrabenazine (DHTBZ), also has selective VMAT2 inhibitory activity. In April 2017, valbenazine (VBZ) was approved by the FDA for the treatment of adult tardive dyskinesia. Valbenazine is prepared by esterification of the metabolite DHTBZ of tetrabenazine, has a longer half-life compared to tetrabenazine, does not require frequent dosing, has definite efficacy and reliable stability, and shows good tolerance.

Chemical formula

Summary of the Invention

Problems to be Solved by the Invention

[0005] Tetrabenazine has problems such as a short half-life and multiple doses. There are a number of tetrabenazine metabolites that cause severe adverse reactions and lead to black box warnings regarding adverse reactions such as depression and suicidal tendencies. Many people have tardive dyskinesia, but only a few drugs are commercially available. Therefore, in this field, there is still a need for VMAT2 inhibitors with better activity to meet a wide range of clinical needs.

Means for Solving the Problems

[0006] Based on the problems existing in the prior art, the present invention provides a compound represented by formula (I)

Chemical formula

Chemical formula

[0007] In some embodiments of the present disclosure, R2 of the compound of formula (I) is unsubstituted C 2~10 alkyl, C 3~6 cycloalkyl-C 1~6 alkyl, or C 2~10 alkyl substituted with one, two, or three R3s, and is selected from C 2~10 alkyl, preferably C 2~5 alkyl unsubstituted or substituted with 2 to 3 R3s, and is C 2~5 alkyl; R3 is F, and the other variable elements are as defined in the present invention.

[0008] In some embodiments of the present invention, R2 of the compound of formula (I) is selected from ethyl, propyl, isobutyl, monofluorobutyl, monofluoropentyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluorofluoroethyl, or cyclopropanemethylene, preferably trifluoroethyl or cyclopropanemethylene, and the other variable elements are as defined in the present invention.

[0009] In some embodiments of the present invention, R1 of the compound of formula (I) is methyl; "---" is a single bond and R is OH or

Chemical formula

[0010] In some embodiments of the present invention, in the 3- to 6-membered heterocycloalkyl described for the compound of formula (I) or in C 1~6 The heteroatom in the heteroalkyl is O, S, or N; the number of heteroatoms is 1 to 6, preferably one of the heteroatoms is O; and C 1~6 The number of C atoms in the heteroalkyl is 2 to 6, or 3 to 6, or 2 to 5, or 3 to 5, or 4 to 6, or 4 to 5.

[0011] The present invention also relates to a compound having a structure represented by formula (II)

Chemical formula

[0012] In some embodiments of the present invention, R2 of the compound of formula (II) is unsubstituted C 2~10 alkyl, C 3~6 cycloalkyl-C 1~6Alkyl, or C 2~10 Alkyl, which is C substituted with one, two, or three R3s 2~10 Selected from alkyl, preferably C 2~5 Alkyl, which is unsubstituted or substituted with two to three R3s and is C 2~5 Alkyl; R3 is F.

[0013] In some embodiments of the present invention, R2 of the compound of formula (II) is selected from ethyl, propyl, isobutyl, monofluorobutyl, monofluoropentyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl, or cyclopropanemethylene, preferably trifluoroethyl or cyclopropanemethylene.

[0014] In some embodiments of the present invention, for the compound of formula (II), the C 1~6 The heteroatom in heteroalkyl is O, S, or N; the number of heteroatoms is from 1 to 6, preferably one of the heteroatoms is O.

[0015] The present invention also relates to a compound having the structure represented by formula (III)

Chemical formula

[0016] In some embodiments of the present invention, R2 of the compound of formula (III) is unsubstituted C 2~10 alkyl, C 3~6 cycloalkyl-C 1~6 alkyl, or C 2~10 alkyl substituted with one, two, or three R3s, selected from C 2~10 alkyl, preferably C 2~5 alkyl, which is unsubstituted or substituted with two to three R3s, C 2~5 alkyl; R3 is F.

[0017] In some embodiments of the present invention, R2 of the compound of formula (III) is selected from ethyl, propyl, isobutyl, monofluorobutyl, monofluoropentyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl, or cyclopropanemethylene, preferably trifluoroethyl or cyclopropanemethylene.

[0018] In some embodiments of the present invention, for the compound of formula (III), the heteroatom in C 1~6 heteroalkyl is O, S, or N; the number of heteroatoms is 1 to 6, preferably one of the heteroatoms is O.

[0019] The present invention relates to a compound having a structure represented by formula (IV)

Chemical formula

[0020] In some embodiments of the present invention, R2 of the compound of formula (IV) is unsubstituted C 2~10 alkyl, C 3~6 cycloalkyl-C 1~6 alkyl, or C 2~10 alkyl substituted with one, two, or three R3s, selected from C 2~10 alkyl, preferably C 2~5 alkyl that is unsubstituted or substituted with 2 - 3 R3s, and is C 2~5 alkyl; R3 is F.

[0021] In some embodiments of the present invention, R2 of the compound of formula (IV) is selected from ethyl, propyl, isobutyl, monofluorobutyl, monofluoropentyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl, or cyclopropanemethylene, preferably trifluoroethyl or cyclopropanemethylene.

[0022] In some embodiments of the present invention, regarding the compound of formula (IV), the heteroatom in C 1~6 heteroalkyl is O, S, or N; the number of heteroatoms is 1 - 6, and preferably one of the heteroatoms is O.

[0023] In some embodiments of the present invention, similarly provided is the following structure:

Chemical formula

Chemical formula

[0024] In some embodiments of the present invention, similarly provided is valine ester and the following structure:

Chemical formula

[0025] In some embodiments of the present invention, similarly provided is the following structure:

Chemical formula

[0026] The present invention also provides a p-toluenesulfonate of any one of the above compounds, and the p-toluenesulfonate preferably has the following structure:

Chemical formula

[0027] The present invention also provides five crystal forms of compound 11-P4S.

[0028] In some embodiments of the present invention, crystal form A of 11-P4S belongs to the orthorhombic P21212 space group, and the unit cell parameters are a = a = 27.14408(13) Å, b = 16.24056(7) Å, c = 6.13775(3) Å, α = 90°, β = 90°, γ = 90°, V = 2705.74(2) , and Z = 4.

[0029] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A of 11-P4S obtained by Cu-Kα radiation includes characteristic peaks determined by the following 2θ reflection angles: 6.33 ± 0.2°, 10.87 ± 0.2°, and 18.89 ± 0.2°.

[0030] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form A of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.33 ± 0.2°, 10.87 ± 0.2°, 16.61 ± 0.2°, 18.89 ± 0.2°, 19.27 ± 0.2°, and 22.19 ± 0.2°.

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form A of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.33 ± 0.2°, 10.87 ± 0.2°, 13.77 ± 0.2°, 16.61 ± 0.2°, 18.20 ± 0.2°, 18.89 ± 0.2°, 19.27 ± 0.2°, 20.05 ± 0.2°, 22.19 ± 0.2°, 24.60 ± 0.2°, and 24.77 ± 0.2°.

[0032] In some embodiments of the present invention, crystalline form A of 11-P4S has an X-ray powder diffraction pattern substantially shown in FIG. 2-1 with Cu-Kα radiation.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form B of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.32 ± 0.2°, 5.42 ± 0.2°, and 10.85 ± 0.2°.

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form B of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.32 ± 0.2°, 5.42 ± 0.2°, 10.85 ± 0.2°, 16.60 ± 0.2°, 18.88 ± 0.2°, and 22.02 ± 0.2°.

[0035] In some embodiments of the present invention, crystalline form B of 11-P4S has an X-ray powder diffraction pattern substantially shown in FIG. 3-1 with Cu-Kα radiation.

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form C of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 5.81 ± 0.2°, 6.33 ± 0.2°, and 12.86 ± 0.2°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form C of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 5.81 ± 0.2°, 6.33 ± 0.2°, 7.99 ± 0.2°, 12.86 ± 0.2°, 19.09 ± 0.2°, and 23.17 ± 0.2°.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form C of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 5.81 ± 0.2°, 6.33 ± 0.2°, 7.99 ± 0.2°, 10.31 ± 0.2°, 11.63 ± 0.2°, 12.86 ± 0.2°, 18.16 ± 0.2°, 19.09 ± 0.2°, 23.17 ± 0.2°, 24.00 ± 0.2°, and 27.32 ± 0.2°.

[0039] In some embodiments of the present invention, crystalline form C of 11-P4S has an X-ray powder diffraction pattern substantially shown in FIG. 4-1 with Cu-Kα radiation.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form D of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.02 ± 0.2° and 23.91 ± 0.2°.

[0041] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form D of 11-P4S obtained with Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 5.31 ± 0.2°, 6.02 ± 0.2°, 18.88 ± 0.2°, 22.12 ± 0.2°, and 23.91 ± 0.2°.

[0042] In some embodiments of the present invention, the crystalline form D of 11-P4S has an X-ray powder diffraction pattern substantially shown in FIG. 5-1 by Cu-Kα radiation.

[0043] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form E of 11-P4S obtained by Cu-Kα radiation includes characteristic peaks determined at the following 2θ reflection angles: 6.06 ± 0.2°, 18.32 ± 0.2°, and 30.79 ± 0.2°.

[0044] In some embodiments of the present invention, the crystalline form E of 11-P4S has an X-ray powder diffraction pattern substantially shown in FIG. 6-1 by Cu-Kα radiation.

[0045] The present invention also provides a crystalline form of p-toluenesulfonate of 19P2 (abbreviated as 19P2S), which belongs to the orthorhombic P212121 space group. The unit cell parameters are a = 6.28880(10) Å, b = 15.7958(3) Å, c = 27.9234(6) Å, α = 90°, β = 90°, γ = 90°, V = 2773.82(9) Å3, and Z = 4.

[0046] The present invention also provides a pharmaceutical composition comprising any one of the above compounds or its stereoisomers or pharmaceutically acceptable salts, or a crystalline form of any one of the above compounds, and a pharmaceutically acceptable carrier. This pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms (for example, tablets, capsules, oral liquid preparations, granules, injections, or various sustained-release preparations and controlled-release preparations). This pharmaceutical composition can be administered orally or by a parenteral mode (for example, intravenous, subcutaneous, or topical). The dosage can be appropriately adjusted according to the age, gender, and type of disease of the patient, and the daily dosage is generally about 10 to 100 mg / day.

[0047] The present invention also provides the use of any one of the above compounds or a stereoisomer or pharmaceutically acceptable salt thereof, or a crystalline form of any one of the above compounds, or a pharmaceutical composition, in the preparation of a drug for the treatment of a disease associated with VMAT2.

[0048] The present invention also provides the use of the above compound or a stereoisomer or pharmaceutically acceptable salt thereof, or a crystalline form of any one of the above compounds, or a pharmaceutical composition, in the preparation of a drug for the treatment of hyperkinetic disorders, preferably, the hyperkinetic disorder includes Huntington's disease, tardive dyskinesia, Tourette syndrome, or spasm.

[0049] The present invention also provides a method for preparing a compound of formula (II), comprising the following preparation steps: Step 1:

Chemical formula

Chemical formula

Chemical formula

[0050] The present invention also provides a method for preparing a compound of formula (III), comprising the following steps:

Chemical formula

[0051] The present invention also provides a method for preparing a compound of formula (IV), comprising the following steps:

Chemical formula

[0052] The present invention also provides a method for preparing a stereoisomer of a compound of formula (I), and this method is specifically configured as follows:

Chemical formula

Chemical formula

[0053] The compounds provided by the present invention have any one or more of the following advantages: strong affinity for VMAT2, higher exposure in vivo, higher concentration in the brain, longer half-life, and strong efficacy, etc.

[0054] Unless otherwise stated, the following terms and phrases used in this specification are intended to have the following meanings. Specific terms or phrases should not be considered uncertain or unclear unless specifically defined, and should be understood in their ordinary meanings. When a trade name is indicated in this specification, this trade name is intended to refer to the corresponding product or active ingredient.

[0055] The term "pharmaceutically acceptable", as used in this specification, refers to compounds, materials, compositions, and / or dosage forms that do not exhibit excessive toxicity, irritation, allergic reaction, or other problems or complications when used in contact with human and animal tissues within the scope of sound medical judgment, and this use is commensurate with a reasonable benefit / risk ratio.

[0056] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which salts are prepared from compounds having the specific substituents found in the present invention together with relatively low toxicity acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base, either in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid, either in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Certain compounds of the present invention contain both basic and acidic functional groups and can thus be converted to any base addition or acid addition salt.

[0057] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid or base radicals by conventional chemical methods. Generally, the methods for preparing such salts involve reacting this compound in the free acid or free base form with a stoichiometric amount of a suitable base or acid, either in water, or in an organic solvent, or in a mixture of both, to prepare the salt.

[0058] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds (e.g., cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention). Additional asymmetric carbons can be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0059] Unless otherwise stated, the term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0060] Unless otherwise stated, the term "diastereomer" refers to stereoisomers that are stereoisomers and in which the molecule has two or more chiral centers and are not mirror images of each other.

[0061] Unless otherwise stated, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.

[0062] Unless otherwise stated, the solid wedge line

Chem.

Chem.

[0063] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared using chiral synthesis, or chiral reagents, or other conventional techniques. When a specific enantiomer of the compounds of the present invention is required, this enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting mixture of diastereomers can be separated, and the auxiliary group can be cleaved to obtain the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), diastereomeric salts can be formed with an appropriate optically active acid or base, and subsequently, the diastereomers can be resolved using conventional methods known in the art, and then the pure enantiomer can be recovered. In addition, the separation of enantiomers and diastereomers is often achieved by using chromatography with a chiral stationary phase, optionally in combination with a chemical derivatization method (e.g., formation of a carbamate from an amine). The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting this compound. For example, this compound can be radiolabeled with a radioactive isotope (e.g., tritium (3H), iodine-125 (125I), or C-14 (14C)). In another example, hydrogen can be replaced with deuterium to form a deuterated agent. The bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon. Compared with the non-deuterated agent, the deuterated agent has reduced toxic side effects, increased drug stability, enhanced efficacy, extended biological half-life of the drug, and other advantages. All isotope variations of the compounds of the present invention are intended to be encompassed within the scope of the present invention, whether radioactive or not.

Brief Description of the Drawings

[0064]

Figure 1

Figure 2-1-2-3

Figure 3-1-3-3

Figure 4-1-4-3

Figure 5-1-5-3

Figure 6-1-6-3

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Mode for Carrying Out the Invention

[0065] Example 1 Fragment 1: [Chemical formula] Preparation of Synthetic route: [Chemical formula] 1. Compound a (5.0 g, 32.9 mmol) was dissolved in DMF (50 mL). Benzyl bromide (6.2 g, 35.8 mmol) and potassium carbonate (6.8 g, 49.1 mmol) were added. The reaction mixture was reacted overnight at room temperature with stirring. Water (100 mL) was added to the reaction system. A solid precipitated, and suction filtration was carried out to obtain 7.2 g of white solid b.

[0066] 2. Compound b (5.4 g, 22.3 mmol) was dissolved in nitromethane (50 mL). Ammonium acetate (0.86 g, 11.2 mmol) was added, and the reaction mixture was heated to 100 °C and reacted for 3 hours with stirring. The reaction system was cooled to room temperature. Water (100 mL) was added to the reaction system. A solid precipitated, and suction filtration was carried out to obtain 6.0 g of yellow solid c.

[0067] 3. Under nitrogen protection, lithium aluminum hydride (2.0 g, 52.6 mmol) was slowly added to anhydrous tetrahydrofuran (50 mL). The reaction mixture was cooled to 0 °C. c (5.0 g, 17.5 mmol) was slowly added dropwise. Then, the reaction system was warmed to 60 °C and reacted for 2 hours with stirring. The reaction mixture was cooled to 0 °C, and the reaction was quenched with water. The resulting mixture was suction filtered, the filtrate was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.2 g of pale yellow oily liquid d. This product was used directly in the next step of the reaction without purification. MS m / z (ESI): 258.2 [M + 1]

[0068] 4. Crude d (2.7 g, 10.5 mmol) was dissolved in glacial acetic acid (16 mL). Trifluoroacetic acid (4 mL) was added, followed by urotropin (3.0 g, 21.0 mmol). The reaction mixture was warmed to 80 °C and reacted for 2 hours with stirring. The reaction mixture was cooled to room temperature. Crushed ice (50 g) was added, and then the pH of the reaction mixture was adjusted to 8 with 20% sodium hydroxide solution. The reaction solution was extracted with dichloromethane (50 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2.4 g of crude product e. This product was used directly in the next step of the reaction without purification. MS m / z (ESI): 268.1 [M+1]

[0069] 5. Crude e (2.0 g, 5.1 mmol) was dissolved in a system of ethanol (20 mL) and water (20 mL). Benzyltriethylammonium chloride (0.43 g, 1.3 mmol) was added, and the mixture was heated to reflux and reacted for 5 hours with stirring. The solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Then, this crude product was recrystallized from ethanol to obtain 0.8 g of white solid compound F. MS m / z (ESI): 394.2 [M+H] + ; 1H NMR (600 MHz, CDCl3): δ 7.43 - 7.28 (m, 5H), 6.64 (s, 1H), 6.57 (s, 1H), 5.11 (s, 2H), 3.82 (s, 3H), 3.48 (dd, 1H), 3.26 (dd, 1H), 3.13 - 3.00 (m, 2H), 2.90 (dd, 1H), 2.77 - 2.61 (m, 2H), 2.60 - 2.48 (m, 2H), 2.33 (t, 1H), 1.83 - 1.75 (m, 1H), 1.70 - 1.58 (m, 1H), 1.06 - 0.98 (m, 1H), 0.90 (m, 6H).

[0070] 6. Compound f (0.5 g, 1.3 mmol) was dissolved in methanol (20 mL). Palladium on carbon (0.05 g) was added, and the resulting mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to obtain 0.47 g of a pale yellow powder (i.e., fragment 1). MS m / z (ESI): 304.2 [M+1].

[0071] Compound 1:

Chemical formula

Chemical formula

[0072] Example 2: [Chemical formula] Synthetic route: [Chemical formula] Fragment 1 compound (150 mg, 0.50 mmol) was dissolved in DMF (2 mL). 1-Bromo-4-fluorobutane (85 mg, 0.55 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added, and the mixture was warmed to 60 °C and reacted with stirring for 5 hours. After cooling, water (8 mL) was added to the reaction system, and then the reaction mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Compound 2 (115 mg, pale yellow oily liquid). MS m / z (ESI): 378.2 [M+H] + ; 1 H NMR (600 MHz, CDCl3): δ 6.64 (s, 1H), 6.54 (s, 1H), 4.57 (t, 1H), 4.45 (t, 1H), 4.07 (t, 2H), 3.80 (s, 3H), 3.48 (dd, 1H), 3.26 (dd, 1H), 3.15 - 3.02 (m, 2H), 2.88 (dd, 1H), 2.77 - 2.61 (m, 2H), 2.60 - 2.48 (m, 2H), 2.33 (t, 1H), 1.96 - 1.90 (m, 3H), 1.88 - 1.75 (m, 2H), 1.70 - 1.58 (m, 1H), 1.06 - 0.98 (m, 1H), 0.89 (m, 6H).

[0073] Example 3: [Chemical formula] Synthetic route: [Chemical formula] Fragment 1 The compound (150 mg, 0.50 mmol) was dissolved in DMF (2 mL). Bromomethylcyclopropane (74 mg, 0.55 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added, and the mixture was warmed to 60 °C and reacted with stirring for 5 hours. After cooling, water (8 mL) was added to the reaction system, and then the reaction mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Compound 3 (107 mg, pale yellow wax-like solid). MS m / z (ESI): 358.2 [M+H] + ; 1 H NMR (600 MHz, CDCl3): δ 6.61 (s, 1H), 6.54 (s, 1H), 3.82 - 3.79 (m, 5H), 3.48 (dd, 1H), 3.28 (dd, 1H), 3.15 - 3.02 (m, 2H), 2.89 (dd, 1H), 2.77 - 2.61 (m, 2H), 2.60 - 2.48 (m, 2H), 2.33 (t, 1H), 1.82 - 1.75 (m, 1H), 1.70 - 1.58 (m, 1H), 1.06 - 0.98 (m, 1H), 0.89 (m, 6H), 0.65 - 0.59 (m, 2H), 0.35 - 0.30 (m, 2H).

[0074] Example 4:

Chemical formula

Chemical formula

[0075] Example 5:

Chemical formula

Chemical formula

[0076] Example 6:

Chemical formula

Chemical formula

[0077] Synthetic Route 2:

Chemical Structure

[0078] Step 2: Intermediate 1 (0.07 g, 0.270 mmol) was dissolved in a mixed solution of ethanol (1 mL) and water (1 mL). 3-Dimethylamino Methyl -5-methyl-2-hexanone (0.06 g, 0.324 mmol) and benzyltriethylammonium chloride (0.02 g, 0.081 mmol) were added. The mixture was heated to 95 °C and reacted for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Compound 6 (10 mg, off-white solid), and the yield was 10%.

[0079] Synthetic Route 3:

Chemical Structure

[0080] Step 2: The same as Synthetic Route 1.

[0081] Example 7:

Chemical Structure

Chemical Structure

[0082] Example 8:

Chemical formula

Chemical formula

[0083] Example 9:

Chemical Structure

Chemical Structure

[0084] Example 10:

Chem.

Chem.

[0085] Example 11:

Chem.

Chem.

[0086] Examples 12 - 20: Examples 12 - 20 were synthesized by using a method similar to that of Example 11.

[0087]

Table 1

[0088]

Table 2

[0089] Example 21:

Chemical Structure

Chemical Structure

[0090] 2. Compound 21a (1.13 g, 1.92 mmol) was dissolved in a 1,4-dioxane solution (15 ml, 4 M concentration). The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated. The solid was washed with diethyl ether (10 ml × 1 time) to obtain a crude product. The crude product was dissolved in water (30 mL). The mixture was adjusted to pH = 7 - 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 ml × 3 times). The organic phases were combined. The dichloromethane phase was washed with water (10 ml × 1 time) and saturated sodium chloride (10 ml × 1 time) respectively. The dichloromethane phase was dehydrated with anhydrous sodium sulfate. The mixture was filtered to remove solids. The dichloromethane phase was concentrated to obtain compound 21 (720 mg). MS m / z (ESI): 487.3 [M+H] +; 1H NMR (400 MHz, CD3OD) δ 6.76 (s, 1H), 6.74 (s, 1H), 4.65 - 4.74 (m, 1H), 4.38 - 4.45 (m, 2H), 3.77 (s, 3H), 3.25 - 3.27 (m, 1H), 2.97 - 3.12 (m, 3H), 2.61 - 2.74 (m, 2H), 2.47 - 2.51 (m, 1H), 1.94 - 2.16 (m, 3H), 1.63 - 1.75 (m, 1H), 1.43 - 1.51 (m, 1H), 1.27 - 1.37 (m, 1H), 1.01 - 1.08 (m, 2H), 0.88 - 1.00 (m, 12H).

[0091] Examples 22 - 25: Examples 22 - 25 were synthesized by using a method similar to the method of Example 21.

[0092]

Table 3

[0093] Examples 26 - 28: Compounds 26 - 28 were synthesized by using a method similar to the method of Example 11.

[0094]

Table 4

[0095] Example 29

Chemical Structure

[0096] Step 2: Synthesis of Compound 11: In a 1 L single-neck flask, intermediate I (38.46 g, 100 mmol, 1 eq) and tetrahydrofuran (150 mL) were added. Under an ice bath, sodium borohydride (4.56 g, 120 mmol, 1.2 eq) was added, followed by anhydrous methanol (150 ml), and the mixture was stirred under an ice bath for 2 hours. After completion of the reaction, the reaction was quenched with 1N HCl (300 mL, 300 mmol, 3 eq) in a nitrogen atmosphere under an ice bath. Under the ice bath, saturated sodium carbonate solution (300 mL) was added dropwise to obtain a pale yellow solid. The mixture was filtered and the solid was recovered. The solid was washed three times in total with water (300 mL). After drying, 39 g of a pale yellow solid was obtained. This solid was dissolved in ethyl acetate (300 mL) at a temperature of 80°C. Then, petroleum ether (100 mL) was added. The mixture was allowed to cool naturally for 4 hours. A white solid precipitated. The solid was recovered and washed three times in total with a mixed solution of ethyl acetate (50 mL) and petroleum ether (50 mL). After drying, Compound 11 (23.07 g, white solid) was obtained, and the yield was 59.6%. MS m / z (ESI): 388.2 [M + H] + ; 11H NMR (600 MHz, CDCl3): δ 6.71 (s, 1H), 6.70 (s, 1H), 4.38 - 4.31 (m, 2H), 3.82 (s, 3H), 3.41 - 3.35 (m, 1H), 3.13 - 2.96 (m, 4H), 2.64 - 2.54 (m, 2H), 2.47 - 2.40 (m, 1H), 2.04 - 1.94 (m, 1H), 1.75 - 1.66 (m, 3H), 1.61 - 1.45 (m, 2H), 1.08 - 1.02 (m, 1H), 0.92 - 0.90 (m, 6H).

[0097] Step 3: Resolution of Compound 11 12.33 g of Compound 11 was weighed. Using Daicel Preparative chromatography and a Daicel chiral column, the chiral isomers were separated by HPLC method. The corresponding components were recovered and subjected to rotary evaporation to remove the solvent, thereby obtaining pure optical isomers. The separation method and detection results can be found in Tables 3 - 4.

[0098] [Table 5]

[0099] [Table 6]

[0100] The components of 11 - P4 (retention time: 4.994 min) and 11 - P3 (retention time: 6.109 min) were recovered respectively. The solvent was removed by rotary evaporation to obtain Sample 11 - P4 (6.1448 g) and 11 - P3 (5.7844 g) respectively. The analysis method and results can be found in Tables 5 - 8.

[0101] [Table 7]

[0102] [Table 8]

[0103]

Table 9

[0104]

Table 10

[0105] MS, 1 HNMR, and 13 CNMR of Compounds 11-P4 and 11-P3 are identical: MS m / z (ESI): 388.2 [M+H] + ; 1 HNMR (600 MHz, CDCl3): δ 6.72 (s, 1H), 6.71 (s, 1H), 4.33 - 4.37 (q, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.37 - 3.40 (m, 1H), 3.12 - 3.14 (d, J = 12.0 Hz, 1H), 3.06 - 3.08 (m, 1H), 3.02 - 3.05 (m, 1H), 2.98 - 3.00 (m, 1H), 2.60 - 2.63 (m, 1H), 2.55 - 2.58 (m, 1H), 2.45 - 2.46 (m, 1H), 1.95 - 1.99 (t, J = 12.0 Hz, 1H), 1.72 - 1.74 (m, 1H), 1.68 - 1.71 (m, 1H), 1.55 - 1.60 (m, 1H), 1.47 - 1.53 (m, 1H), 1.03 - 1.07 (m, 1H), 0.91 - 0.92 (d, J = 6.0 Hz, 3H), 0.93 - 0.94 (d, J = 6.0 Hz, 3H). 13 CNMR (150 Hz, CDCl3): δ 148.5, 145.53, 132.85, 126.84, 120.80 - 126.34, 117.66, 109.29, 74.46, 67.66 - 68.36, 60.94, 59.99, 56.09, 51.74, 41.51, 40.44, 39.64, 28.83, 25.33, 24.15, 21.74。

[0106] Example 30 I. Crystal Form A of Compound 11-P4S Step 1: Formation of Mono-p-Toluenesulfonate from Compound 11-P4: [Chemical formula] 11-P4 (0.20 g, 0.52 mmol) was dissolved in ethyl acetate (5 ml). A solution of p-toluenesulfonic acid monohydrate (0.12 g, 0.62 mmol) in ethyl acetate was added dropwise to precipitate a white solid. The mixture was stirred at room temperature for 12 hours and filtered by suction. The filter cake was washed with ethyl acetate (5 mL × 3 times) and dried to obtain Compound 11-P4S as a white solid (0.22 g) with a yield of 78%.

[0107] Step 2: Method for Growing Single Crystals of Compound 11-P4S Crystal Form A 1) 9 mg of 11-P4S was weighed and placed in a 1.5 mL HPLC vial. 2) Ethanol (450 μL) was added to this solid. The temperature was raised to 40 °C and then kept constant at 40 °C until the solid completely dissolved to obtain a clear solution. 3) This solution was cooled to 25 °C at a rate of 0.3 °C / min while standing still. 4) Crystals precipitated, and this reaction vial was observed under a microscope. The crystals were quantified and an XRSD experiment was performed.

[0108] Step 3: XRSD Experiment of Compound 11-P4S Crystal Form A 3.1 Instrument Parameters and Data Collection: 3.1.1 Instrument Parameters: Single crystal diffractometer: Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer Detector: HyPix-6000HE flat panel detector; Low-temperature system: Oxford Cryostream 800; Light source: Cu target microfocus light source; λ = 1.54184 Å, 50 W; Distance between crystal and CCD detector: d = 35 mm; Tube voltage: 50 kV; Tube current: 1 mA

[0109] 3.1.2 Data collection In this diffraction experiment, 48459 diffraction points were collected, among which 4803 independent diffraction points were included (Rint = 0.0672), the diffraction collection range: 2θ = 6.342~133.2°, and the diffraction index range: -32 ≤ h ≤ 32, -19 ≤ k ≤ 19, -7 ≤ l ≤ 6. Structure analysis was performed using SHELXT (Sheldrick, G.M. 2015. Acta Cryst. A71, 3 - 8), and (for F 2 ) structure refinement was performed using SHELXL (Sheldrick, G.M. 2015. Acta Cryst. C71, 3 - 8). Among the 4803 independent diffraction points, the number of parameters involved in structure refinement was 348. After refinement, S = 1.046, R1 = 0.0318, and wR2 = 0.0828. The residual electron density values were 0.26 and -0.32 eÅ -3 .

[0110] 3.2. The data lists can be found in Tables 9 and 10.

[0111]

Table 11

[0112]

Table 12

[0113] 3.3 Conclusion The crystalline form A of compound 11 - P4S was a colorless block (0.20×0.10×0.10 mm 3 ) and belonged to the orthorhombic P21212 space group. Unit cell parameters: a = 27.14408(13) Å, b = 16.24056(7) Å, c = 6.13775(3) Å, α = 90°, β = 90°, γ = 90°, V = 2705.74(2) Å 3 , Z = 4. The calculated density: Dc = 1.374 g / cm 3, Number of electrons in the unit cell: F(000) = 1184.0, Linear absorption coefficient of the unit cell: μ(CuKα) = 1.613 mm -1 , and Diffraction experiment temperature: T = 99.99(11) K.

[0114] The elliptical graph of the molecular structure of 11-P4S can be found in Figure 1. The structure of this compound is [Chemical formula] as follows.

[0115] Step 4: Characterization of Compound 11-P4S Crystal Form A 4.1 XPRD Characterization 4.1.1 Characterization method: XRPD was obtained using an X-ray powder diffractometer manufactured by PANalytical, and the scanning parameters were as shown in Table 11 below.

[0116] [Table 13]

[0117] 4.1.1 Results: The XPRD spectrum can be found in Figure 2-1, and the analysis data of this spectrum can be found in Table 12.

[0118] [Table 14]

[0119] 4.2 TGA / DSC Characterization 4.2.1 Characterization method: The TGA spectrum and DSC spectrum were obtained using a TA Q5000 / 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters can be found in Table 13.

[0120] [Table 15]

[0121] 4.2.2 Results: The TGA / DSC spectrum of crystalline form A of Compound 11-P4S was found in Figure 2-2. From this result, after heating the sample to 200 °C, the weight loss was 1.6%, and it was shown that there were two endothermic peaks (peak temperatures) at 215.4 °C and 246.2 °C.

[0122] 4.3 1 H NMR 4.3.1 Method: The liquid-state nuclear magnetic resonance spectrum was obtained using a Bruker 400M nuclear magnetic resonance spectrometer, with DMSO-d6 used as the solvent.

[0123] 4.3.2 Results: 1 The H NMR spectrum was found in Figure 2-3. From this result, in this sample, the molar ratio of p-toluenesulfonic acid to the free base was 1.0:1.0, the molar ratio of MTBE to the free base was 0.02:1.0, the mass fraction of p-toluenesulfonate was 30.7%, and the mass fraction of MTBE was 0.3% were shown.

[0124] II. Crystalline Form B of Compound 11-P4S Step 1. Preparation Method 109 mg of crystalline form A of Compound 11-P4S was dissolved in MeOH (2 mL). Then, 18 mL of THF, a poor solvent, was added. This mixture was placed at -20 °C, stirred, and filtered to separate the solid. This solid was placed at room temperature and air-dried to obtain crystalline form B of Compound 11-P4S.

[0125] Step 2. Characterization of the Crystal 2.1 Characterization Method: The characterization methods of XPRD, TGA / DSC, and 1 the H NMR were the same as those of crystalline form A of Compound 11-P4S.

[0126] 2.2 Experimental Results 2.2.1 XPRD The XPRD spectrum can be found in Figure 3-1, and the analysis data of this spectrum can be found in Table 14.

[0127]

Table 16

[0128] 2.2.2 TGA / DSC The TGA / DSC spectrum of crystalline form B of Compound 11-P4S can be found in Figure 3-2. From this spectrum, it was shown that when the sample was heated up to 200 °C, the weight loss was 6.8%, and there were three endothermic peaks (peak temperatures) at 120.5 °C, 221.8 °C, and 252.6 °C.

[0129] 2.2.3 1 H NMR 1 The 1H NMR spectrum can be found in Figure 3-3. From this spectrum, it was shown that for this sample, the molar ratio of p-toluenesulfonic acid to the free base was 1.0:1.0, the molar ratio of THF to the free base was 0.5, the corresponding weight loss was 6.5%, and no residual methanol was detected.

[0130] III. Crystalline Form C of Compound 11-P4S Step 1. Preparation Method 121.2 mg of crystalline form A of Compound 11-P4S was weighed and dissolved in MeOH (2.2 mL). Then, DCM (75 mL) was added to give a clear solution. This solution remained transparent even after stirring for 2 hours at room temperature. The solution was transferred to room temperature and air-dried to obtain crystalline form C of Compound 11-P4S.

[0131] Step 2. Characterization of the Crystal 2.1 Characterization Method: The characterization methods of XPRD, TGA / DSC, and 1 1H NMR were the same as those of crystalline form A of Compound 11-P4S.

[0132] 2.2 Experimental Results 2.2.1 XPRD The XPRD spectrum can be found in Figure 4-1, and the analysis data of this spectrum can be found in Table 15.

[0133]

Table 17

[0134] 2.2.2 TGA / DSC The TGA / DSC spectrum of crystalline form C of Compound 11-P4S can be found in Figure 4-2. From this spectrum, it was shown that when the sample was heated up to 200 °C, the weight loss was 17.4%, and there were three endothermic peaks (peak temperatures) at 112.5 °C, 210.7 °C, and 249.6 °C.

[0135] 2.2.3 1 H NMR 1 The 1H NMR spectrum can be found in Figure 4-3. From this spectrum, it was shown that for this sample, the molar ratio of p-toluenesulfonic acid to the free base was 1.0:1.0, the molar ratio of DCM to the free base was 0.2, the mass fraction of the solvent was 3.1%, and no residual methanol was detected.

[0136] IV. Crystalline Form D of Compound 11-P4S Step 1. Preparation Method 93.3 mg of crystalline form A of Compound 11-P4S was weighed. To this, 1,4-dioxane (3 mL) was added. The mixture was placed at room temperature and stirred for 4 days. Then, the sample was suction filtered. The filter cake was placed at 150 °C and heated for about 5 minutes to obtain crystalline form D of Compound 11-P4S.

[0137] Step 2. Characterization of the Crystal 2.1 Characterization Method: The characterization methods of XPRD, TGA / DSC, and 1 1H NMR were the same as those of crystalline form A of Compound 11-P4S.

[0138] 2.2 Experimental Results 2.2.1 XPRD The XPRD spectrum can be found in Figure 5-1, and the analysis data of this spectrum can be found in Table 16.

[0139]

Table 18

[0140] 2.2.2 TGA / DSC The TGA / DSC spectrum of crystalline form D of Compound 11-P4S can be found in Figure 5-2. From this spectrum, it was shown that when the sample was heated up to 200 °C, the weight loss was 1.3%, and there was one endothermic peak (peak temperature) at 249.9 °C and one exothermic peak (peak temperature) at 188.0 °C.

[0141] 2.2.3 1H NMR The 1H NMR can be found in Figure 5-3. From this, it was shown that in this sample, the molar ratio of p-toluenesulfonic acid to the free base was 1.0:1.0, and no residue of 1,4-dioxane was detected.

[0142] V. Crystalline Form E of Compound 11-P4S Step 1. Preparation Method 62.1 mg of crystalline form A of Compound 11-P4S was weighed. To this, IPA (10 mg ) was added. This mixture was left at 50 at °C for 2 hours with stirring. The filtrate was slowly cooled (from 50 °C to 5 °C, 0.1 °C / min) to precipitate an appropriate amount of solid. Then suction filtration was carried out to obtain crystalline form E of Compound 11-P4S.

[0143] Step 2. Characterization of the Crystal 2.1 Characterization Methods: XPRD, TGA / DSC, and 1The characterization method of 1H NMR was the same as that of crystalline form A of compound 11-P4S.

[0144] 2.2 Experimental Results 2.2.1 XPRD The XPRD spectrum can be found in Figure 6-1, and the analysis data of this spectrum can be found in Table 17.

[0145]

Table 19

[0146] 2.2.2 TGA / DSC The TGA / DSC spectrum of crystalline form E of compound 11-P4S can be found in Figure 6-2. From this spectrum, it was shown that when the sample was heated to 200 °C, the weight loss was 2.8%, and there was one endothermic peak (peak temperature) at 244.6 °C.

[0147] 2.2.3 1 1H NMR 1 The 1H NMR spectrum can be found in Figure 6-3. From this spectrum, it was shown that for this sample, the molar ratio of p-toluenesulfonic acid to free base was 1.0:1.0, and no residual MTBE was detected.

[0148] VI. Crystalline Forms of Compound 11-P3S Step 1: Formation of Mono-p-toluenesulfonate from Compound 11-P3:

Chemical Formula

[0149] Step 2: Method for growing single crystal of compound 11-P3S: 1) Weighed 11.6 mg of 11-P3S and placed it in a 1.5 mL HPLC vial. 2) Added ethanol (348 μL) to this solid. Raised the temperature to 60 °C and then maintained it at 60 °C until the solid completely dissolved to obtain a clear solution. 3) Cooled this solution to 25 °C at 0.5 °C / min while keeping it still. 4) Crystals precipitated, and this reaction vial was observed under a microscope. The crystals were quantified and XRSD experiments were performed.

[0150] Step 3: XRSD experiment of single crystal of 11-P3S: 3.1 Instrument parameters and data collection 3.1.1 Instrument parameters: The same as those in Section 3.1.1 of Crystal Form A of Compound 11-P4S

[0151] 3.1.2 Data collection: In this diffraction experiment, 36655 diffraction points were collected, where 4793 independent diffraction points were included (R int = 0.0525), diffraction collection range: 2θ = 6.342~133.17°, and diffraction index range: -32 ≤ h ≤ 30, -19 ≤ k ≤ 16, -7 ≤ l ≤ 7. Structure analysis was performed using SHELXT (Sheldrick, G.M. 2015. Acta Cryst. A71, 3-8), and structure refinement was performed using SHELXL (Sheldrick, G.M. 2015. Acta Cryst. C71, 3-8) (for F 2 ). Among the 4793 independent diffraction points, the number of parameters involved in structure refinement was 348. After refinement, S = 1.041, R1 = 0.0324, and wR2 = 0.0824. The residual electron density values were 0.32 and -0.26 eÅ -3 .

[0152] 3.2 The list of data can be found in Tables 18 and 19.

[0153]

Table 20

[0154]

Table 21

[0155] 3.3 Conclusion The crystal form of compound 11-P3S was a colorless mass (0.20×0.20×0.10 mm 3 ), and it belonged to the orthorhombic P21212 space group. Unit cell parameters: a = 27.1619(4) Å, b = 16.2359(2) Å, c = 6.13160(10) Å, α = 90°, β = 90°, γ = 90°, V = 2704.02(7) Å3, Z = 4. Calculated density: Dc = 1.375 g / cm 3 , number of electrons in the unit cell: F(000) = 1184.0, linear absorption coefficient of the unit cell: μ(CuKα) = 1.614 mm -1 , and diffraction experiment temperature: T = 99.99(11) K. The elliptical graph of the molecular structure of compound 11-P3S can be found in Figure 7, and the structure of this compound was

Chemical formula

[0156] Example 31

Chemical formula

[0157] Compound Em1-11P4a (1.13 g, 1.92 mmol) was dissolved in 15 ml of a 4M HCl solution in 1,4-dioxane. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated. The solid was washed with diethyl ether (10 ml×1 time) to obtain a crude product. This crude product was dissolved in water (30 mL). The mixture was adjusted to pH = 7 - 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 ml×3 times). The organic phases were combined. The dichloromethane phase was washed with water (10 ml×1 time) and saturated sodium chloride (10 ml×1 time) respectively. The dichloromethane phase was dehydrated with anhydrous sodium sulfate. The mixture was filtered to remove the solid. The dichloromethane phase was concentrated to obtain compound 21-P3 (720 mg) with a yield of 76.8%. MS m / z (ESI): 487.3 [M+H] + 。

[0158] Example 32

Chemical formula

[0159]

Table 22

[0160]

Table 23

[0161] 19P2 (retention time: 5.397 minutes) and other components were each recovered to obtain 5.11 g of Compound 19P2, and the purity of the product was 98.15%. MS m / z (ESI): 360.2 [M+H] + ; 1 1H NMR (600 MHz, CDCl3): δ 6.63 (s, 1H), 6.56 (s, 1H), 3.83 - 3.79 (m, 5H), 3.49 - 3.46 (m, 1H), 3.42 - 3.35 (m, 1H), 3.28 - 3.02 (m, 4H), 2.89 (dd, 1H), 2.77 - 2.61 (m, 2H), 2.60 - 2.48 (m, 2H), 2.33 (t, 1H), 1.82 - 1.75 (m, 1H), 1.70 - 1.58 (m, 1H), 1.06 - 0.99 (m, 1H), 0.93 - 0.87 (m, 6H), 0.64 - 0.59 (m, 2H), 0.36 - 0.31 (m, 2H).

[0162] Example 33 Step 1: Formation of mono-p-toluenesulfonate from Compound 19P2:

Chem.

[0163] Step 2. Single crystal growth of Compound 19P2S 10 mg of 19P2S was weighed and placed in a 1.5 mL HPLC vial. Ethanol (500 μL) was added to this solid. The temperature was raised to 40 °C and then kept constant at 40 °C until the solid completely dissolved to obtain a clear solution. This solution was cooled to 25 °C at 0.3 °C / min while standing still. Crystals precipitated and the reaction vial was observed under a microscope. The crystals were quantified and an XRSD experiment was performed.

[0164] Step 3: Single crystal XRSD experiment of 19P2S: (1) Instrument parameters: The same as those in Section 3.1.1 of Crystal Form A of Compound 11-P4S.

[0165] (2) Data collection In this diffraction experiment, 24,167 diffraction points were collected, among which 4,899 independent diffraction points were included (Rint = 0.0646), the diffraction collection range: 2θ = 6.33~133.182°, and the diffraction index range: -7 ≤ h ≤ 5, -18 ≤ k ≤ 17, -33 ≤ l ≤ 33. Structure analysis was performed using SHELXT (Sheldrick, G.M. 2015. Acta Cryst. A71, 3-8), and structure refinement was performed using SHELXL (Sheldrick, G.M. 2015. Acta Cryst. C71, 3-8) for (F 2 For). Among the 4,899 independent diffraction points, the number of parameters involved in structure refinement was 339. After refinement, S = 1.020, R1 = 0.0373, and wR2 = 0.0920. The residual electron density values were 0.38 and -0.33 eÅ -3 respectively.

[0166] (3) The list of data could be found in Tables 22 and 23.

[0167]

Table 24

[0168]

Table 25

[0169] Conclusion: The crystal of compound 19P2S was a colorless block (0.30 × 0.10 × 0.04 mm 3 ) and belonged to the orthorhombic P212121 space group. Unit cell parameters: a = 6.28880(10) Å, b = 15.7958(3) Å, c = 27.9234(6) Å, α = 90°, β = 90°, γ = 90°, V = 2773.82(9) Å3, and Z = 4. Calculated density: Dc = 1.273 g / cm 3 , number of electrons in the unit cell: F(000) = 1144.0, linear absorption coefficient of the unit cell: μ(CuKα) = 1.385 mm -1 , and diffraction experiment temperature: T = 100.00(13) K.

[0170] An elliptical graph of the molecular structure of compound 19P2S could be found in Figure 8. The structure of this compound was

Chemical formula

[0171] Example 34

Chemical formula

[0172] Comparative Example 35:

Chemical Structure

Chemical Structure

[0173] Comparative Example 36:

Chemical formula

Chemical formula

[0174] Comparative Example 37:

Chemical formula

Chemical formula

[0175] 2. 3-Isobutyl-9-3'-fluoropropoxy-10-hydroxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (0.07 g, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (0.06 g, 0.40 mmol) was added and the mixture was stirred for 30 minutes. 1-Bromopropane (0.037 g, 0.30 mmol) was added. Under nitrogen protection, the mixture was warmed to 80 °C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added to quench the reaction. Ethyl acetate (30 mL × 3 times) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (EA:PE = 1:5) to obtain the compound of Comparative Example 37 (0.04 g, white solid). MS m / z (ESI): 392.3 [M+H] +; 1H-NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.61 (s, 1H), 4.77 - 4.69 (t, J = 5.8 Hz, 1H), 4.68 - 4.60 (t, J = 5.8 Hz, 1H), 4.17 - 4.05 (m, 2H), 3.84 - 3.73 (m, 2H), 3.54 - 3.38 (m, 1H), 3.34 - 3.23 (m, 1H), 3.17 - 2.93 (m, 2H), 2.93 - 2.83 (m, 1H), 2.78 - 2.67 (m, 2H), 2.66 - 2.48 (m, 2H), 2.35 (t, J = 11.6 Hz, 1H), 2.25 - 2.13 (m, 2H), 1.86 - 1.74 (m, 1H), 1.73 - 1.61 (d, J = 6.4 Hz, 1H), 1.32 - 1.20 (m, 1H), 1.08 - 0.98 (m, 1H), 0.97 - 0.84 (m, 6H), 0.39 - 0.29 (m, 3H).

[0176] Comparative Example 38: Step 1: Fragment 2

Chemical formula

Chemical formula

[0177] 2. To 67.78 g of compound h, nitromethane (100 mL) and ammonium acetate (13.9 g) were added. The mixture was warmed to 112 °C and reacted for 4 hours. As found by TLC detection, the raw materials had disappeared. The temperature was lowered and nitromethane was removed by evaporation. The residue was washed with water and extracted twice with ethyl acetate. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain 77 g of yellow solid i. This yellow solid i was used in the next step.

[0178] 3. 30 g of lithium aluminum hydride was dissolved in THF (300 mL). The mixture was cooled to 0 °C. 77 g of compound i was dissolved in tetrahydrofuran. The resulting mixture was slowly added dropwise to the reaction vial. After the addition, the reaction mixture was refluxed at 72 °C for 3 hours. As found by TLC detection, the raw materials had disappeared. The temperature was lowered to 0 °C. Water (30 mL), 10% sodium hydride solution (60 mL), and water (90 mL) were added slowly and continuously. The mixture was suction filtered and the filter cake was washed twice with tetrahydrofuran. The organic phases were combined. The organic phase was evaporated to dryness to obtain 79.8 g of a brown oily liquid. This brown oily liquid was dissolved in acetone. The mixture was adjusted to pH = 3 by the addition of oxalic acid, a solid precipitated, and suction filtration was carried out to obtain 40 g of compound j as a yellowish white solid. This compound j was used in the next step.

[0179] 4. 2.9 g of compound j was dissolved in acetic acid (30 mL). Trifluoroacetic acid (10 mL) and urotropin (3.3 g) were added. The mixture was heated to 85 °C and reacted for 4 hours. As found by TLC detection, the raw materials had disappeared. The temperature was lowered. Acetic acid and trifluoroacetic acid were removed by evaporation. Water was added to the residue. The pH was adjusted to 9 using an aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain 2.9 g of brown oily liquid k, which was used directly in the next step.

[0180] 5. 39.2 g of compound k was dissolved in a mixed solution of ethanol (100 mL) and water (100 mL). 3-Dimethylamino Methyl -5-methyl-2-hexanone (27.6 g) and benzyltriethylammonium chloride (10.1 g) were added, and the mixture was heated to 95 °C and reacted for 16 hours. As found by TLC detection, the raw materials had disappeared. The temperature was lowered. Ethanol was removed by evaporation. The residue was extracted three times with ethyl acetate. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain 33.4 product as a brown oily liquid. This product was dissolved in acetone and adjusted to pH = 3 by the addition of p-toluenesulfonic acid. A solid precipitated, and suction filtration was carried out to obtain 12.7 g of a yellowish-white solid l, which was used in the next step.

[0181] 6. 1.5 g of compound l was dissolved in a methanol solution (20 mL). Two portions of palladium carbon were added. The mixture was reacted at room temperature for 10 hours under a hydrogen gas atmosphere. As found by TLC detection, the raw materials had disappeared. The reaction mixture was suction filtered, and the filter cake was washed twice with methanol. The organic phases were combined. The combined organic phases were evaporated to dryness to obtain 1.08 g of a pale yellow solid (i.e., fragment 2).

[0182] Step 2:

Chemical formula

Chemical formula

[0183] Comparative Example 39:

Chemical Structure

Chemical Structure

[0184] Comparative Example 40:

Chem.

Chem.

[0185] Comparative Example 41: Step 1: Fragment 3

Chem.

Chem.

[0186] 2. Compound 3b (9.92 g, 43.5 mmol) was dissolved in DMF (50 mL). Bromoethane (7.11 g, 65.2 mmol) and potassium carbonate (9.00 g, 65.2 mmol) were added. The mixture was warmed to 80 °C and reacted for 5 hours. After cooling, the reaction system was poured into water (500 mL), and then extracted with ethyl acetate (200 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with petroleum ether (150 mL). This mixture was filtered to recover the solid, and Compound 3c (10.0 g, off-white solid) was obtained.

[0187] 3. Compound 3c (10.0 g, 39.1 mmol) was dissolved in nitromethane (50 mL). Ammonium acetate (1.81 g, 23.5 mmol) was added. The mixture was heated to 115 °C and reacted for 3 hours. After cooling, the reaction mixture was concentrated. The residue was washed with water and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 3d (11.6 g, yellow solid).

[0188] 4. Under nitrogen protection and in an ice bath, compound 3d (11.6 g, 38.8 mmol) was dissolved in anhydrous THF (100 mL), and this mixture was added dropwise to a solution of lithium aluminum hydride (4.42 g, 116 mmol) in anhydrous THF (100 mL), and reacted for 1 hour. Then, the mixture was warmed to 60 °C and reacted for an additional 2 hours. The temperature was lowered in an ice bath. Water (4.4 mL) was added dropwise, and then 10% sodium hydroxide solution (8.8 mL) and water (13.2 mL) were added. The mixture was suction filtered, and then the filter cake was washed with ethyl acetate (150 mL × 3 times). The filtrate was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate. An ethyl acetate solution of oxalic acid was added until the pH value showed acidity. The mixture was stirred overnight. The mixture was filtered, and the filter cake was recovered and washed with ethyl acetate (100 mL × 3 times) to obtain compound 3e (11.2 g, white solid).

[0189] 5. Compound 3e (11.2 g, 31.0 mmol) was dissolved in acetic acid (100 mL). The resulting mixture was added to trifluoroacetic acid (30 mL). Urotropin (9.55 g, 68.2 mmol) was added, heated to 85 °C, and reacted for 4 hours. The reaction mixture was cooled to room temperature and concentrated. Water was added to the residue. The resulting mixture was adjusted to pH = 9 with an aqueous sodium hydroxide solution and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3f (8.71 g, brown oil, crude product), and this compound 3f was used directly in the next step without purification. MS m / z (ESI): 282.2 [M+H] +

[0190] 6. Compound 3f (8.71 g, 31.0 mmol) was dissolved in a mixed solution of ethanol (100 mL) and water (100 mL). 3-Dimethylamino Methyl-5-Methyl-2-hexanone (6.36 g, 37.2 mmol) and benzyltriethylammonium chloride (2.12 g, 9.30 mol) were added. The mixture was heated to 95 °C and reacted for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was extracted with ethyl acetate (150 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 3 g (3.78 g, off-white solid) of Compound. MS m / z (ESI): 408.3 [M+H] +

[0191] 7. 3 g (3.78 g, 9.30 mmol) of Compound was dissolved in a methanol solution (50 ml). Palladium-carbon-containing water (10%, 0.5 g) was added and hydrogen was introduced. The mixture was reacted at room temperature for 18 hours. The mixture was suction filtered, the filter cake was washed with methanol (50 mL × 2 times), concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Fragment 3 (2.50 g, off-white solid). MS m / z (ESI): 318.2 [M+H] +

[0192] Step 2:

Chemical formula

Chemical formula

[0193] Comparative Example 42:

Chemical formula

Chemical formula

[0194] Comparative Examples 43 - 44 Regarding the preparation of Comparative Examples 43 - 44, the method of Comparative Example 42 can be referred to, and the compounds of Comparative Examples 43 - 44 were prepared by reduction with a solution of ethanol and sodium borohydride.

[0195] [Table 26]

[0196] Comparative Example 45: [Chemical Formula] Synthesis Route: [Chemical Formula] 1. Under nitrogen protection, Boc-L-valine (651 mg, 3 mmol) was dissolved in dichloromethane (15 mL) under an ice bath. 4-Dimethylaminopyridine (293 mg, 2.4 mmol) and the compound of Comparative Example 7 (760 mg, 1.83 mmol) were added, and the mixture was reacted for 5 minutes while stirring under an ice bath. Dicyclohexylcarbodiimide (618 mg, 3 mmol) was added all at once. The mixture was allowed to warm to room temperature naturally and reacted for 18 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (dichloromethane:methanol = 30:1) to obtain an intermediate compound (780 mg, off-white solid). MS m / z (ESI): 565.4 [M+1]

[0197] 2. The compound obtained in the previous step (780 mg, 1.38 mmol) was dissolved in dichloromethane (10 ml). The resulting mixture was added to a 1,4-dioxane solution (1.7 ml, 4 M concentration) and reacted at room temperature for 2 hours. The reaction solution was concentrated. The solid was washed with diethyl ether (10 ml × 1 time) to obtain a crude product. This crude product was dissolved in water (30 mL). The mixture was adjusted to pH 7-8 with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (10 ml × 3 times). The organic phases were combined. The dichloromethane phase was washed with water (10 ml × 1 time) and saturated sodium chloride (10 ml × 1 time) respectively. The dichloromethane phase was dehydrated with anhydrous sodium sulfate. Filtration was carried out to remove the solid. The dichloromethane phase was concentrated to obtain the compound of Comparative Example 45 (500 mg, off-white solid). MS m / z (ESI): 465.4 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 6.73 -6.75 (m, 2H), 4.56-4.77 (m, 3H), 4.08-4.11 (m, 2H), 3.80 (s, 3H), 3.05-3.32 (m, 4H), 2.50-2.75 (m, 3H), 2.01-2.21 (m, 5H), 1.33-1.77 (m, 3H), 1.06-1.13 (m, 2H), 0.93-1.05 (m, 12H).

[0198] Experimental Example 1 Biological Activity Experiment I. Detection of Radioactivity of Activity of Compounds Binding to VMAT2 in Rats (Binding Assay) 1. Experimental Purpose: To determine the IC 50 and Ki values of the binding of various compounds to VMAT2 in rats, and to evaluate the affinity of the compounds for VMAT2

[0199] 2. Experimental Materials Ligand: [3H]Dihydrotetrabenazine (DHTBZ) (10 nM) Test Compounds: Compounds 1 - 9, 11, 12, 14, 16 - 19, 20, 27, 28, 32, 11 - P3, 11 - P4, and 21 - P3: Prepared according to the corresponding examples above Compounds of Comparative Examples 35 - 43: Prepared according to Comparative Examples 35 - 43 TBZ: Jiangsu Vcare Pharmatech Co., Ltd., Lot Number: TBZ - 113030 DHTBZ: Jiangsu Vcare Pharmatech Co., Ltd., Lot Number: 67 - 25 - 1521 - 59C DHTBZ - X (racemate): Prepared using TBZ as the raw material according to Reaction Scheme 1 of WO2008058261 Pamphlet VBZ: Prepared according to the following method: VBZ xylene sulfonate (0.5 g, 0.65 mmol) was dissolved in water (10 mL). This mixture was adjusted to pH = 8 with saturated NaHCO3 solution and extracted with EA (20 mL × 3 times). The organic phases were combined, dehydrated with anhydrous sulfuric acid, and concentrated to obtain VBZ (0.26 g) as a white solid

[0200] 3. Experimental Procedures and Methods 3.1 Preparation of Rat Brain Membranes Male Wistar rats weighing 175 ± 25 g were selected, and the entire brain (excluding the cerebellum) of these rats was surgically isolated, placed in a pre-cooled sucrose solution (20 mL, 0.32 M), and homogenized with a Teflon breast homogenizer. The homogenate was centrifuged at 1000 g for 12 minutes at 4°C, the supernatant was aspirated, and centrifugation was performed at 22,000 g for an additional 10 minutes at 4°C. The supernatant was discarded, and the resulting precipitate was placed in ice-cold MilliQ water (18 mL, Millipore Corporation, Billerica, MA), incubated for 5 minutes, and subjected to osmotic shock to disrupt the cell membrane. Subsequently, the molar osmotic concentration was restored by adding HEPES solution (25 mM, 2 mL) and potassium tartrate solution (100 mM, 2 mL). The resulting sample was centrifuged at 20,000 g for 20 minutes at 4°C. The supernatant was aspirated, and MgSO4 solution (1 mM, 20 μL) was added. This solution was centrifuged at 100,000 g for 45 minutes at 4°C. The precipitate was collected and resuspended in ice-cold assay buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, 0.1 mM EDTA, and 0.05 mM EGTA, pH 7.5) to obtain a vesicle suspension.

[0201] 3.2 Detection and Analysis In the detection, a 96-well plate was used and duplicate or triplicate wells were arranged. Into each well of this 96-well plate, a solution (50 μL) containing a vesicle suspension (50 μL, containing 32 μg of protein), [3H]dihydrotetrabenazine (DHTBZ) (10 nM), and a test compound (the inhibitor is at a concentration of 1 nM to 1000 nM or other desired concentration) was added and incubated at 25°C for 30 minutes. Nonspecific ligand Ro4-1284 (10 μM) was used to determine and predict nonspecific binding, and tetrabenazine (TBZ), DHTBZ, VBZ, or DHTBZ racemate with clear pharmacological properties was used as a positive control and for comparison with the activity of the new compound. After completion of the incubation, the reaction solution was filtered through a filter plate (bacterial filter and collector, PerkinElmer Life and Analytical Sciences), and subsequently, the filter membrane was washed 5 times with 350 μL of ice-cold buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, and 10 mM NaCl, pH 7.5). This filter plate was dried and the bottom surface was sealed. To each well, 40 μL of scintillation cocktail (MicroScint 20; PerkinElmer Life and Analytical Sciences) was added. The radioactivity on the filter was determined by liquid scintillation spectrometry (TopCount NXT; PerkinElmer Life and Analytical Sciences).

[0202] 3.3 Analysis of Results Based on the above radioactivity assay results, IC 50 and Ki were calculated. IC 50 was calculated by non-linear least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). The Ki value was calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W.H., Biochem. Pharmacol. 22: 3099 - 3108, 1973). The Ki value was calculated from the IC 50and calculated in combination with the past KD in the radioactivity detection method of Eurofins Panlabs.

[0203] The binding inhibition rates, IC 50 values, and Ki values of the compounds of some examples and the compounds of the comparative examples were tested at 20 nM and 100 nM by using the above method, and the results can be found in Tables 25 to 27.

[0204] [Table 27]

[0205] [Table 28]

[0206] [Table 29]

[0207] The experimental results showed that the compounds provided by the present invention have a stronger affinity for VMAT compared with TBZ, DHTBZ, DHTBZ-X, VBZ, and the compounds of the comparative examples. When the group at the 10th position is methyl and the groups at the 9th position are ethyl, cyclopropylmethylene, and 4-fluorobutyl, the binding inhibition activity is the highest. When the group at the 10th position is a long substituent (for example, propyl and butyl), the binding inhibition activity is significantly decreased, or even worse, the activity is hardly detected. In addition, when the group at the 9th position is methyl and the group at the 10th position is a long substituent (for example, ethyl, propyl, and cyclopropylmethylene), the binding inhibition activity is significantly decreased, or even worse, the activity is not detected. That is, the inventors have discovered that the substituents at the 9th and 10th positions bring a significant difference in activity.

[0208] II. Compound and VMAT2 Uptake Assay 1. Purpose Performing the Uptake Assay of Compound VMAT2

[0209] 2. Materials (1) Reagents and Materials 3H-dopamine, sucrose, HEPES, potassium tartrate, EGTA, EDTA, ATP, MgCl2, MgSO4, ascorbic acid, TBZ, BCA Protein Assay Kit Frozen Vesicle Suspension: A vesicle suspension was prepared by extraction using the striatum of SD rats. Under an ice bath, fresh rat striatum was added to a sucrose solution (0.32 M, 28 mL) and homogenized 10 times at 10 seconds per homogenization using a homogenizer. At 4°C, the homogenate was centrifuged at 2000 g for 10 minutes. The supernatant was aspirated and further centrifuged at 10000 g for 30 minutes at 4°C. The precipitate was separated and resuspended in a sucrose solution (4 mL, 0.32 M). MilliQ water (14 mL, under an ice bath) was added and the mixture was subjected to osmotic shock. After 1 minute, HEPES buffer (0.25 M, 1.8 mL) and potassium tartrate solution (1 M, 1.8 mL) were added. At 4°C, the mixture was centrifuged at 20000 g for 30 minutes. The supernatant was collected and further centrifuged at 55000 g for 60 minutes at 4°C. The supernatant was discarded. MgSO4 (200 μL, 10 mM), HEPES (200 μL, 0.25 M), and potassium tartrate (200 μL, 1 M) were added. At 4°C, the mixture was centrifuged at 55000 g for 45 minutes. The precipitate was collected, resuspended in a detection buffer (10 mL, 25 mM HEPES, 100 mM potassium tartrate, 50 μM EGTA, 100 μM EDTA, 20 mM MgCl2, and 2 mM ATP, pH 7.4), sub-packaged at 500 μL / tube, and frozen at -80°C for use.

[0210] (2) Buffers Assay buffer: 25 mM HEPES, 100 mM potassium tartrate, 50 μM EGTA, 100 μM EDTA, 20 mM MgCl2, 1.7 mM ascorbic acid, 2 mM ATP, pH 7.4. Ascorbic acid and ATP were added before the assay. Washing buffer: 25 mM HEPES, 100 mM potassium tartrate, 50 μM EGTA, 100 μM EDTA, pH 7.4.

[0211] (3) Test compound Compounds 11 - 15, 18 - 20, 26 - 28, 32, 11 - P4, and 21 - P3; prepared according to the corresponding examples above DHTBZ, DHTBZ - X, VBZ: the same source as in the above binding assay

[0212] (4) Instruments and consumables Unifilter - 96 GF / B filter plate, Perkin Elmer (catalog number 6005177); 96 - well V - bottom polypropylene plate, Agilent (catalog number 5042 - 1385); TopSeal - A sealing film, Perkin Elmer (catalog number 6050185); MicroBeta2 (PerkinElmer); Cell harvester C961961 (Perkin Elmer); SpectraMax 340PC (Molecular Devices);

[0213] 3. Test method (1) The test sample and TBZ were diluted 4 - fold with DMSO into 8 concentration gradients with a maximum concentration of 0.2 mM and a minimum of 1 μM. 1 μl of the diluted test compound and TBZ was transferred to the detection plate with a pipette. (2) TBZ (1 μl, 2 mM) was added for use as a non - specific binding control (LC), and 1 μl of DMSO was used as a total binding control (HC). (3) 100 μL of the diluted vesicle suspension (containing 15 μL of the stock solution) was placed in a 96-well plate and incubated at 37 °C for 15 minutes. (4) 3H-dopamine (17.92 μM) was diluted to 0.2 μM with assay buffer. 3H-dopamine (100 μL, 0.2 μM) was added to the detection plate to a final concentration of 0.1 μM and incubated at 37 °C for 10 minutes. (5) The reaction mixture was filtered through a GF / B plate in a collector, and the GF / B plate was rinsed 4 times with pre-chilled rinse buffer. (6) The plate was dried at 0 °C for at least 1 hour. (7) After drying, the filter plate was sealed using a Perkin Elmer Unifilter-96 bottom seal tape. 50 μL of Perkin Elmer Microscint 20 cocktail was added. The top of the filter plate was sealed using a Perkin Elmer TopSeal-A sealing film. (8) The number of 3H captured on the filter membrane was counted using a Perkin Elmer MicroBeta2 Reader. (9) The data was analyzed using Prism 5.0 software. The IC 50 was calculated using the model "log(Inhibitor) vs. response - Variable Slope", and the IC 50 was calculated using the equation IC something = IC 90 *(something / (100 - something))1 / slope.

[0214] 4. The test results could be found in Tables 28 - 30.

[0215]

Table 30

[0216]

Table 31

[0217]

Table 32

[0218] From the test results, it was shown that the compounds provided by the present invention have strong in vitro activity compared with DHTBZ, DHTBZ-X, and VBZ.

[0219] Experimental Example 2: Pharmacokinetic evaluation of Compounds 11, 16, 21, 22, and 23, and Comparative Examples 44 and 45 in SD rats 1. Experimental materials a) Test compounds Compounds 11, 16, 21 - 23; Comparative Examples 44 and 45; prepared according to the corresponding examples DHTBZ: Jiangsu Vcare Pharmatech Co., Ltd., lot number 67 - 25 - 1521 - 59C VBZ: Prepared according to the method described in Experimental Example 1 b) Vehicle: 20% solutol solution, solutol lot number BCBQ5646V, Sigma c) Test animals: SD rats, clean grade, male, body weight about 220 g

[0220] 2. Method for pharmacokinetic test in SD rats: Compounds 11, Compound 16, the compound of Comparative Example 44, and DHTBZ were each orally administered to male SD rats by forced administration (4 animals / group). The dosing amount was 10 μmol / kg. Blood samples (about 0.2 mL / time point / rat) were collected into heparinized tubes at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after dosing. Within 30 minutes after collection, the samples were centrifuged to separate plasma, transferred to 1.5 ml EP tubes, and stored at -20 °C for detection.

[0221] 3. Method for distribution test in SD rat brain tissue VBZ, Compound 21, Compound 22, Compound 23, and the compound of Comparative Example 45 were administered orally to male SD rats (3 animals / group). The dosage was 12 μmol / kg. Blood samples (about 1 mL / time point / rat) were collected into heparinized tubes at 0.5 hour, 2 hours, and 6 hours after dosing. Within 30 minutes after collection, the samples were centrifuged to separate plasma, which was transferred to 1.5 mL EP tubes and stored at -20°C for detection. After sacrificing the rats, the brain tissues were excised, washed with physiological saline, and dried with filter paper. The cerebral blood vessels were dissected, and the remaining brain tissues were weighed and stored at -20°C.

[0222] 4. Analysis of Samples For sample pretreatment, a method of precipitating proteins was used, and this method can be briefly described as follows: Protein precipitation was performed with 25 μL of plasma / 50 μL of brain tissue homogenate by using 200 μL / 400 μL of acetonitrile containing an internal standard respectively. After high-speed centrifugation, the supernatant was diluted with water (1:1 (V / V)) and subjected to analysis.

[0223] At 0.5, 2, and 6 hours, by using the LC-MS / MS method, the concentrations of VBZ, Compound 21, Compound 22, Compound 23, and the compound of Comparative Example 45, as well as the concentrations of their metabolites (i.e., DHTBZ, Compound 11, Compound 12, Compound 13, and the compound of Comparative Example 44), were determined in the plasma of SD rats and in the brain tissue homogenate (physiological saline homogenate, 1:4 w / v), and the ratio of the concentration in the brain to the concentration in the plasma at each time point was calculated.

[0224] 5. Test Results 5.1 Pharmacokinetic Test The results of the tests performed in SD rats orally administered with Compound 11, Compound 16, the compound of Comparative Example 44, and DHTBZ can be found in Figure 9, from which it was shown that Compound 11 had a higher exposure than the compound of Comparative Example 44 and DHTBZ.

[0225] 5.2 Brain Tissue Distribution Test 5.2.1 Concentration in the Brain: The distribution of the parent compound in the brain tissue after forced oral administration of VBZ, Compound 21, Compound 22, Compound 23, and Comparative Example 45 in SD rats can be found in Table 10, and the distribution of the active metabolites (DHTBZ, Compound 11, Compound 12, Compound 13, and the compound of Comparative Example 44) in the brain tissue can be found in Figure 11.

[0226] From the experimental results, the following was shown: At 2 hours after administration, the concentrations of Compound 21 and its metabolite Compound 11 in the brain tissue were both significantly higher compared to the concentrations of VBZ and DHTBZ.

[0227] 5.2.2 Brain / plasma ratio The brain / plasma ratio of the parent compound after forced oral administration of VBZ, Compound 21, Compound 22, Compound 23, and Comparative Example 45 in SD rats can be found in Figure 12, and from the experimental results, the following was shown: At various time points after dosing, the brain / plasma ratio of Compound 21 was 3.4 to 6.8 times that of VBZ and was higher compared to the brain / plasma ratios of the other compounds.

[0228] The brain / plasma ratio of the active metabolites (DHTBZ, Compound 11, Compound 12, Compound 13, and the compound of Comparative Example 44) after forced oral administration of VBZ, Compound 21, Compound 22, Compound 23, and Comparative Example 45 in SD rats can be found in Figure 13, and from the experimental results, the following was shown: At various time points after dosing, the brain / plasma ratio of the metabolite of Compound 21 (i.e., Compound 11) was 2.8 to 5.8 times that of DHTBZ.

[0229] Experimental Example 3 Pharmacokinetic Evaluation of Compound 21-P3 and 11-P4 in SD Rats 1. Test materials: a) Test compounds 11-P4: Prepared according to Example 29 21-P3: Prepared according to Example 31 VBZ: Prepared according to the method described in Experimental Example 1 DHTBZ: Jiangsu Vcare Pharmatech Co., Ltd., lot number 67-25-1521-59C b) Vehicle: 20% Sorbitol solution, Sorbitol lot number BCBQ5646V, Sigma c) Test animals: 24 male Sprague-Dawley rats, clean grade, body weight approximately 220 g, randomly divided into groups, 3 rats / group (3 for forced oral administration; 3 for intravenous administration).

[0230] 2. Test method: (1) Preparation of pharmaceutical solutions: Approximately 20 mg of each of 21-P3, 11-P4, VBZ, and DHTBZ was accurately weighed and dissolved in an appropriate amount of vehicle until the concentration of each compound reached 1 μmol / mL.

[0231] (2) Bioavailability test: The forced oral administration dose was 5 mL / kg, the dosing amount was 5 μmol / kg, and each compound was administered to 3 animals; the intravenous administration dose was 2 mL / kg, the dosing amount was 2 μmol / kg, and each compound was administered to 3 animals; the Sprague-Dawley rats were fasted for 12 hours before dosing, but had free access to drinking water and were fed 3 hours after dosing. At each corresponding time point after dosing, blood samples (approximately 1 ml / time point / rat) were collected into heparinized tubes. Within 30 minutes after collection, the samples were centrifuged to separate the plasma, which was transferred to 1.5 ml EP tubes and stored at -20°C for detection.

[0232] 3. Analysis of samples By using the LC-MS / MS method, the concentrations of the compounds VBZ, DHTBZ, 21-P3, and 11-P4 in Sprague-Dawley rat plasma were determined, and in the case of the dosing groups of VBZ and 21-P3, the concentrations of their respective metabolites DHTBZ and 11-P4 were also determined. For the pretreatment of the samples, a method of protein precipitation was used, and protein precipitation was performed on 25 μL of plasma by using 200 μL of acetonitrile containing an internal standard. After high-speed centrifugation, the supernatant was diluted with water (1:1 (V / V)) and injected for analysis.

[0233] 4. Test results:

[0234]

Table 33

[0235]

Table 34

[0236]

Table 35

[0237]

Table 36

[0238] From the results, the following were shown: (1) For Compound 11-P4, the exposure (AUC) in vivo increased significantly. The exposure by intravenous administration was approximately 3 times that of DHTBZ, and the exposure by forced oral administration was approximately 4 times that of DHTBZ; (2) By intravenous administration, Compound 11-P4 had a longer half-life and thus the dosing frequency could be reduced. The conversion rate from VBZ to DHTBZ was 15.9%, and the conversion rate from Compound 21-P3 to 11-P4 was 26.8%. Compared with VBZ, Compound 21-P3 had a higher conversion rate. Since the VMAT2 binding activity of VBZ and 21-P3 was much lower than that of DHTBZ and 11-P4, from the test results, it was shown that at equimolar doses, Compound 21-P3 had higher availability and could produce much stronger efficacy compared with VBZ. (3) By forced oral administration, Compound 21-P3 and Compound 11-P4 had higher bioavailability compared with VBZ and DHTBZ. (3) By forced oral administration, Compound 21-P3 and Compound 11-P4 had higher bioavailability compared with VBZ and DHTBZ. (3) By forced oral administration, Compound 21-P3 and Compound 11-P4 had higher bioavailability compared with VBZ and DHTBZ.

[0239] Experimental Example 4: Pharmacokinetic Evaluation of Compounds 21 and 21-P3 in SD Rats 1. Purpose In this experiment, the SD rat spontaneous activity model was used. VBZ xylenesulfonate was used as a control. Equimolar doses of Compound 21 and 21-P3 were administered by single-dose forced oral administration. The moving distance of mice in the open field was compared to investigate the pharmacodynamic differences between Compound 21, 21-P3 and the control drug VBZ xylenesulfonate.

[0240] 2. Experimental Materials 2.1 Test animals: 32 SD rats, SPF-grade, male, 5-7 weeks old, body weight: 200-220 g, acclimated for at least 1 week before the test. Source of animals: Ji’nan Pengyue Laboratory Animal Technique Co., Ltd.; Animal Certification Number: SCXK(LU)20140007

[0241] 2.2 Test drugs Compound 21: Prepared according to Example 21 Compound 21-P3: Prepared according to Example 31 VBZ xylenesulfonate: Jiangsu Vcare Pharmatech Co., Ltd., lot number 334-1-1517-15 Preparation method: Weighed an appropriate amount of the drug and dissolved it in a small amount of CMS (less than 1% of the total amount). Then, 20% sorbitol was added to obtain the desired drug concentration, and the final concentration of DMSO was <4%.

[0242] 3. Grouping and dosing of the test On the day before the test, the rats were randomly classified into the following 4 groups according to body weight: control group (NS, no test drug in the solvent), VBZ xylenesulfonate group, Compound group 21 21-P3 group (8 animals / group). The rats were placed in the detection box, acclimated for 10 minutes in advance, and then fasted. Information on animal grouping and dosing is detailed in Table 3 5 as detailed below.

[0243]

Table 37

[0244] 4. Test method On the test day, the animals were acclimated in the laboratory for at least 1 hour. Each group of rats was administered vehicle or the corresponding drug once by single-dose forced oral administration according to the dosage in Table 35, and then placed in the activity room. The total moving distance of the rats 2 - 3 hours after dosing was recorded and analyzed using the TopScan monitoring system. Rats in the same group should not be placed in the same room of one of the eight activity rooms, and at least one rat from the control group was present in each round of the test to prevent mutual interference. At the end of each round of the test, the excreta was swept out and the activity room was cleaned to avoid the influence of irrelevant interfering factors (such as odors) on the motor activity of the rats.

[0245] 5. Observation indicators The total moving distance of the rats 2 - 3 hours after dosing was recorded, analyzed using the TopScan monitoring system, and the reduction rate (RR) of the total moving distance was calculated. Here, RR = (control group moving distance - administered group moving distance) / control group moving distance × 100%.

[0246] 6. Statistical analysis The test data was represented as mean ± standard error of the mean (mean ± SEM). One-way analysis of variance (ANOVA) was used to compare the distances between various groups at each time point by using PASW Statistics 18.0 software. All tests were two-sided tests, and p < 0.05 indicated that the difference was statistically significant.

[0247] 7. Test results: Compared with the control group (moving distance = 16210 ± 3465 mm), the VBZ group showed a significantly decreased spontaneous activity distance in rats (moving distance = 4882 ± 1022 mm, P < 0.05); the compound 21 group showed a decreased spontaneous activity distance (moving distance = 11630 ± 2839 mm, P > 0.05); the compound 21-P3 group showed a significantly decreased spontaneous activity distance in rats (moving distance = 2956 ± 1101 mm, P < 0.01), with a significant difference compared to the control group. The reduction rates of total movement in the VBZ group, compound 21 group, and compound 21-P3 group were 69.9%, 28.3%, and 81.8% respectively. The compound 21-P3 group showed strong effectiveness compared to the VBZ group.

[0248] Experimental Example 5 Pharmacokinetic Evaluation of Compound 11-P4 in SD Rats The test method was the same as that in Experimental Example 4. The animal grouping and dosing information were detailed in Table 36.

[0249]

Table 38

[0250] The total moving distance of rats within 0 - 1 hour after drug administration was recorded and analyzed. The test results were found in Table 37. Compared with the control group (moving distance 14190 ± 2785 mm), all three VBZ groups at doses of 2.5 μmol / kg, 5.0 μmol / kg, and 10.0 μmol / kg showed a decrease in the spontaneous activity distance of rats. The 5.0 μmol / kg group and 10.0 μmol / kg group had significant differences compared with the control group (the moving distances were 8349 ± 2536 mm, P > 0.05; 6365 ± 2564 mm, P < 0.05; 6742 ± 892.6 mm, P < 0.05 respectively). All four 11 - P4 groups at doses of 1.25 μmol / kg, 2.5 μmol / kg, 5.0 μmol / kg, and 10.0 μmol / kg showed a decrease in the spontaneous activity distance of rats. The three dose groups other than the 1.25 μmol / kg group had significant differences compared with the control group (the moving distances were 9313 ± 1213 mm, P > 0.05; 5959 ± 1615 mm, P < 0.05; 1216 ± 429.9 mm, P < 0.01; 1355 ± 524.1 mm, P < 0.01 respectively).

[0251]

Table 39

[0252] The inhibition rates of various doses of the drug on the spontaneous activity of rats were calculated. Here, the inhibition rate = the reduction rate of the total moving distance (RR) and RR = (the moving distance of the control group - the moving distance of the administration group) / the moving distance of the control group × 100%; the dose - effect curves of VBZ and 11 - P4 were obtained and could be found in Figure 14; and the ED50 value was calculated using the "log(inhibitor) vs. response - Variable slope" method of the software Graph Pad Prism 5.

[0253] According to the test results, under the condition of equimolar drug administration, the ED 50 values of the VBZ group and 11 - P4 were 5.142 μmol / kg and 1.883 μmol / kg respectively. Therefore, it was shown that the effect of 11 - P4 was significantly better than that of the VBZ group.

[0254] Experimental Example 6 Incubation Test of Liver Microsomes from Five Species 1. Test Compounds Compounds 11 - 13, 15, and 16; the compound of Comparative Example 44: Prepared according to the corresponding above Examples.

[0255] 2. Test Process Incubation: The 100 μL incubation system contained the following: liver microsomes (human, rat, mouse, monkey, or dog) (0.5 mg / mL), sodium phosphate buffer (100 mM), and magnesium chloride (10 mM). Compounds 11 - 13, 15, and 16, and the compound of Comparative Example 44 were added to this incubation system to a final concentration of 1 μM. After pre - incubating this system at 37°C for 3 minutes, NADPH was added to a final concentration of 1 mM. The reaction was initiated. The system was incubated for 0 minutes, 5 minutes, 15 minutes, 30 minutes, and 60 minutes, and then 200 μL of ice - cold acetonitrile was added to terminate the reaction. The reaction system was stored at - 20°C for detection. Each sample at each time point was processed in duplicate in parallel, and a blank control group and a positive control group without coenzymes were prepared.

[0256] 3. Sample Analysis and Data Processing After termination with acetonitrile, a specific amount of internal standard was added to this sample. After centrifugation at 13000 rpm for 10 minutes, the supernatant was diluted 1:1 (V / V) with water, and the LC - MS / MS method was used to determine the concentrations of Compounds 11 - 13, 15, and 16, and the compound of Comparative Example 44. The relative remaining amount was taken on the vertical axis and time on the horizontal axis. The elimination rate constant k of each compound was calculated using a semi - logarithmic plot, and the equation t 1 / 2 = 0.693 / k was used to calculate the elimination half - life (t 1 / 2 ) of each compound in the liver microsome incubation system, and the results could be found in Table 38.

[0257] From the results, in the liver microsomes of mice and monkeys, the half-life of Compound 11 was longer than that of DHTBZ. In addition, Compounds 12 and 13 were also shown to have better liver microsome stability than the comparative examples.

[0258]

Table 40

[0259] Experimental Example 7 Excipient Compatibility Test of Compound 11-P4 and Crystal Form A of Compound 11-P4S 1. Test Drugs Compound 11-P4: Prepared according to Example 29 Crystal Form A of Compound 11-P4S: Prepared according to Example 30.

[0260] 2. Test Method Compound 11-P4 and Crystal Form A of Compound 11-P4S were each mixed with the excipient at a ratio of 1:20. Then, this mixture was left open at 60°C for 5 days. Samples of Compound 11-P4 / Crystal Form A of Compound 11-P4S were taken and the purity was detected.

[0261] Purity Detection Method: Approximately 35 mg of the sample was accurately weighed and placed in a 25-ml volumetric flask. 15 ml of acetonitrile was added and the sample was dissolved by ultrasound. Water was used to dilute to the predetermined mark, and this mixture was shaken uniformly and used as the sample solution to be tested. The determination was carried out based on high-performance liquid chromatography, using octadecylsilane-bonded silica gel as the filler (Inerstil ODS-3V, 250 mm × 4.6 mm, 5 μm); 10 mmol / L diammonium hydrogen phosphate solution (pH adjusted to 6.95 ± 0.05)-acetonitrile (80:20) was used as Mobile Phase A, and acetonitrile was used as Mobile Phase B, and gradient elution was carried out according to Table 39. The detection wavelength was 282 nm, the column temperature was 35°C, and the flow rate was 1.0 ml / min. 10 μl of the sample solution to be tested was accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded. The calculation was carried out by the peak area normalization method.

[0262]

Table 41

[0263] 3. The test results could be found in Table 40.

[0264]

Table 42

[0265] From the results, it was shown that after mixing 11-P4 with the excipient described above and placing it at a high temperature for 5 days, the purity clearly decreased, while there was no obvious change in the purity of crystalline form A of 11-P4S, indicating that crystalline form A of 11-P4S has good excipient compatibility and is easy to develop into a formulation.

[0266] Experimental Example 8 11P4S Crystalline Form A / D / E Suspension Competition Test 1. Test drug Crystalline forms A / D / E of compound 11-P4S: Prepared according to Example 30.

[0267] 2. Test method: To saturated solutions (2 mL) of IPA and IPAc of crystalline form A of 11P4S, crystalline forms A / D / E of 11-P4S (5 mg each) were respectively added and suspended, and stirred at room temperature / 50 °C for 17 hours. Subsequently, XRPD was performed on the solid.

[0268] 3. The test results could be found in Table 41 and Figure 15.

[0269]

Table 43

[0270] The results show that 11-P4S crystalline form A and crystalline form A can be obtained in all systems, indicating that 11-P4S crystalline form A is the most thermodynamically stable crystalline form at temperatures from room temperature to 50 °C.

Claims

1. The following formula (I) 【Chemical 1】 In formula (I), "---" is selected from a single bond and a double bond; When "---" is a single bond, R is OH and the following groups: [Chemical 2] selected from; When "---" is a double bond, R is O; R １ is methyl; R ２ is selected from unsubstituted C ２～１０ alkyl, C ３～６ cycloalkyl-C １～６ alkyl, and C ３ alkyl substituted with two or three R ２～１０ groups; and R ３ is selected from F, Cl, and Br a compound represented by, or a stereoisomer or pharmaceutically acceptable salt thereof.

2. R ２ is unsubstituted C ２～５ alkyl and two or three R ３ substituted C ２～５ alkyl selected from, the compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

3. R １ is methyl; R ２ is selected from ethyl, propyl, isobutyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl and cyclopropanemethylene; "---" is a single bond, and R is selected from OH and the following groups: 【Chemical Formula 3】 or "---" is a double bond and R is O, the compound according to claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof.

4. The following formula: 【Chemical Formula 4】 【Chemical Formula 5】 The compound according to claim 1, selected from the compounds represented by, or a stereoisomer or pharmaceutically acceptable salt thereof.

5. The following formula: 【Chemical Formula 6】 The compound according to any one of claims 1 to 4, which is a compound represented by, or a stereoisomer or pharmaceutically acceptable salt thereof.

6. A crystal of the compound represented by the following formula: 【Chemical Formula 7】 The crystal belongs to crystal form A of the orthorhombic P212121 space group, a = 27.14408(13) Å, b = 16.24056(7) Å, c = 6.13775(3) Å, α = 90°, β = 90°, γ = 90°, V = 2705.74(2) Å3, Z = 4.

7. The following formula: 【Chemical Formula 7】 A crystal of a compound represented by, wherein the crystal is crystal form A, and the X-ray powder diffraction pattern obtained by Cu-K α radiation contains characteristic peaks determined at the following 2θ reflection angles: 6.33 ± 0.2°, 10.87 ± 0.2°, and 18.89 ± 0.2°.

8. The crystalline form A is Cu-K α The crystal according to claim 7, comprising characteristic peaks at diffraction angles 2θ of 6.33 ± 0.2°, 10.87 ± 0.2°, 16.61 ± 0.2°, 18.89 ± 0.2°, 19.27 ± 0.2°, and 22.19 ± 0.2° measured by X-ray powder diffraction using Cu-K radiation.

9. The crystalline form A is Cu-K α The crystal according to claim 8, comprising characteristic peaks of 2θ diffraction angle at 6.33 ± 0.2°, 10.87 ± 0.2°, 13.77 ± 0.2°, 16.61 ± 0.2°, 18.20 ± 0.2°, 18.89 ± 0.2°, 19.27 ± 0.2°, 20.05 ± 0.2°, 22.19 ± 0.2°, 24.60 ± 0.2°, and 24.77 ± 0.2°, measured by X-ray powder diffraction using Cu-K radiation.

10. The following formula: 【Chemical Formula 7】 A crystal of a compound represented by, wherein the crystal is Cu-K α A crystal, which is crystal form B, containing characteristic peaks at diffraction angles 2θ of 6.32 ± 0.2°, 5.42 ± 0.2°, and 10.85 ± 0.2° measured by X-ray powder diffraction using radiation

11. The crystalline form B is Cu-K α The crystal according to claim 10, which contains characteristic peaks at diffraction angles 2θ of 6.32 ± 0.2°, 5.42 ± 0.2°, 10.85 ± 0.2°, 16.60 ± 0.2°, 18.88 ± 0.2°, and 22.02 ± 0.2° measured by X-ray powder diffraction using Cu-K radiation.

12. The following formula: 【Chemical Formula 7】 A crystal of a compound represented by, wherein the crystal is Cu-K α Crystal form C, which is a crystal containing characteristic peaks at diffraction angles of 2θ of 5.81 ± 0.2°, 6.33 ± 0.2°, and 12.86 ± 0.2° as measured by X-ray powder diffraction using radiation

13. The crystalline form C is Cu-K α The crystal according to claim 12, comprising characteristic peaks at diffraction angles 2θ of 5.81 ± 0.2°, 6.33 ± 0.2°, 7.99 ± 0.2°, 12.86 ± 0.2°, 19.09 ± 0.2°, and 23.17 ± 0.2°, measured by X-ray powder diffraction using Cu-K radiation.

14. The crystalline form C is Cu-K α The crystal according to claim 13, comprising characteristic peaks at diffraction angles 2θ of 5.81 ± 0.2°, 6.33 ± 0.2°, 7.99 ± 0.2°, 10.31 ± 0.2°, 11.63 ± 0.2°, 12.86 ± 0.2°, 18.16 ± 0.2°, 19.09 ± 0.2°, 23.17 ± 0.2°, 24.00 ± 0.2°, and 27.32 ± 0.2°, measured by X-ray powder diffraction using Cu-K radiation.

15. The following formula: [Chemical Formula 7] A crystal of a compound represented by, wherein the crystal is Cu-K α A crystal, which is crystal form D and includes characteristic peaks at diffraction angles 2θ of 6.02 ± 0.2° and 23.91 ± 0.2° measured by X-ray powder diffraction using radiation

16. The crystalline form D is Cu-K α The crystal according to claim 15, comprising characteristic peaks at diffraction angles 2θ of 5.31 ± 0.2°, 6.02 ± 0.2°, 18.88 ± 0.2°, 22.12 ± 0.2°, and 23.91 ± 0.2° measured by X-ray powder diffraction using Cu-K radiation.

17. The following formula: 【Chemical Formula 7】 A crystal of a compound represented by, wherein the crystal is Cu-K α A crystal, which is crystal form E containing characteristic peaks at diffraction angles of 2θ of 6.06 ± 0.2°, 18.32 ± 0.2°, and 30.79 ± 0.2° measured by X-ray powder diffraction using radiation.

18. The following formula: 【Chemical 8】 A crystal of crystalline form A of the compound represented by, wherein the crystalline form A has a P2 １ 2 １ 2 １ space group and unit cell parameters of a = 6.28880(10) Å, b = 15.7958(3) Å, c = 27.9234(6) Å, α = 90°, β = 90°, γ = 90°, V = 2773.82(9) Å3, Z = 4, belonging to the orthorhombic system, a crystal.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, a stereoisomer or pharmaceutically acceptable salt thereof, or the crystal according to any one of claims 6 to 18, and a pharmaceutically acceptable carrier.

20. A medicament for the treatment of hyperkinetic disorders, comprising the compound according to any one of claims 1 to 5, a stereoisomer or pharmaceutically acceptable salt thereof, or the crystal according to any one of claims 6 to 18, or the pharmaceutical composition according to claim 19.

21. The medicament according to claim 20, wherein the hyperkinetic disorder includes Huntington's chorea, tardive dyskinesia, Tourette syndrome, or spasm.

22. The following preparation steps: 【Chemical Formula 9】 (1) A step of reacting the fragment 1 compound of the above left formula with R2-X to produce a compound of formula (II); 【Chemical Formula 10】 (2) Reacting the reactant I compound of the left formula with R2-X to produce the intermediate compound of the central formula, and then reacting the intermediate compound with 3-dimethylaminomethyl-5-methyl-2-hexanone to produce the compound of formula (II); or 【Chemical 11】 (3) Reacting the reactant I compound of the left formula with 3-dimethylaminomethyl-5-methyl-2-hexanone to produce the fragment 1 compound of the central formula, and then reacting the fragment 1 compound with R2-X to produce the compound of formula (II) A method for preparing a compound of formula (II), comprising R ２ is unsubstituted C ２～１０ alkyl, C ３～６ cycloalkyl-C １～６ alkyl, and C ３ alkyl substituted with two or three R ２～１０ selected from alkyl, R ３ is selected from F, Cl and Br; X is a leaving group,[[]] Method.

23. R ２ is unsubstituted C ２～５ alkyl, and C ３ substituted with two or three Rs ２～５ alkyl, the method according to claim 22, wherein the R is selected from

24. R ２ is selected from ethyl, propyl, isobutyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl and cyclopropane methylene; The method according to claim 22 or 23, wherein X is selected from Cl, Br, and I.

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