Quinolinone double-ligand derivative and application thereof as D2R agonist

Abstract

The invention discloses a quinolinone double-ligand derivative and an application of the quinolinone double-ligand derivative as a dopamine D2R agonist. According to the invention, n-propyl indene-2-amine is used as a normal ligand fragment, quinolinone or indolone is used as an allosteric ligand fragment, and an intermediate LINKER part is connected by a methylene carbon chain and a cyclohexyl carbon chain with different lengths to obtain the dopamine D2R agonist as shown in a formula (1) and a formula (2). According to the invention, the functional activity of all compounds on D2R on a G protein dependent signaling pathway is tested through a GloSensor cAMP accumulation experiment. Pharmacological results show that all the synthesized target compounds have good agonistic activity on D2R, that is, the target compounds of the invention are D2R agonists. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically discloses a quinolinone dual-position ligand derivative and its application as a D2R agonist. Background Art

[0002] The dopamine D2 receptor (D2R) is a key member of the class A G protein-coupled receptors (GPCRs) and a promising drug target. Therefore, developing drugs targeting the D2R holds great research value.

[0003] Modern pharmacological research has shown that dopamine D2 receptors are associated with a variety of diseases, including Parkinson's disease, restless legs syndrome, hyperprolactinemia, and addiction. Hyperprolactinemia can lead to conditions such as amenorrhea and galactorrhea in women, sexual dysfunction in men, osteoporosis, and even pituitary adenomas and breast tumors. Currently, marketed dopamine D2R agonists (such as pramipexole, ropinirole, and cabergoline) are primarily used to treat Parkinson's disease, restless legs syndrome, and hyperprolactinemia. Cabergoline is also used to treat pituitary adenomas (such as prolactinomas) by reducing tumor size and lowering prolactin levels. A bi-stable ligand can be categorized as a chemical structure possessing both allosteric and orthosteric pharmacophores, connected by an optimal linker, allowing simultaneous binding to two distinct binding sites within a single receptor. These ligands have several advantages over traditional orthosteric targeting molecules, as they can improve receptor affinity; may enhance receptor selectivity; may have biased agonism; and, in contrast to allosteric targeting ligands, do not require endogenous ligand to induce biological effects.

[0004] A potent D2R agonist, 11b, was discovered in a structure-activity relationship study of dopamine D2R agonists (ChemMedChem 2022, 17, e202100681). Studies have shown that n-propylindan-2-amine is effective as the orthosteric ligand fragment of a bi-situate ligand. Marketed drugs such as ropinirole are D2R agonists, while aripiprazole and brepirazole are D2R partial agonists. This suggests that bi-situate ligands constructed with quinolinones / indolones are also effective for D2R agonism. Therefore, we selected n-propylindan-2-amine as the orthosteric ligand portion of the bi-situate ligand and quinolinones / indolones as the allosteric ligand fragments. We selected methylene carbon chains or cyclohexyl carbon chains of varying lengths to connect the linker fragments, hoping to obtain D2R agonists with enhanced activity as potential drug candidates.

[0005]

[0006]

[0007] Structures of some D2R ligands Summary of the Invention

[0008] The present invention aims to provide a quinolinone-based binarized ligand derivative and its use as a D2R agonist. This invention utilizes n-propylinden-2-amine as the orthosteric ligand fragment of the binarized ligand, quinolinone / indolone as the allosteric ligand portion of the binarized ligand, and connects the intermediate linker with methylene or cyclohexyl carbon chains of varying lengths. This yields a series of novel binarized ligand compounds, which are then tested for their D2R functional activity.

[0009] The quinolinone di-position ligand derivative provided by the present invention has a structure as shown in formula (1): , Wherein LINKER is one of the following structural formulas: ; R is one of the following structural formulas: ; X is one of NH, CH2, O and S.

[0010] Furthermore, the LINKER fragment is One of the following; R is One of the following; X is NH.

[0011] The present invention also provides a method for synthesizing the quinolinone binary ligand derivatives of formula (1) and formula (2). The specific synthetic routes of the quinolinone binary ligand derivatives of formula (1) and formula (2) are as follows: The synthetic route and specific synthetic method of quinolinone binary ligand derivative LINKER is a methylene carbon chain:

[0012]

[0013]

[0014] Synthesis route of Class A target compounds Synthesis method of Class A compounds: (1) Dissolve 2-indanone in DCE at room temperature under nitrogen protection, add n-propylamine dropwise, and stir for 15 min. Slowly add solid NaBH(OAc)3 in three small batches to the reaction flask and stir at room temperature for 3.5 h to obtain intermediate compound 2.

[0015] (2) 3,4-dihydro-7-hydroxy-2(1H)-quinolinone was dissolved in acetone, methyl bromoacetate and K2CO3 were added, and the mixture was heated to reflux for 5 h under nitrogen protection to obtain compound 4.

[0016] (3) Compound 4 was dissolved in anhydrous methanol, 15% NaOH was added, and the mixture was reacted at room temperature for 12 h to obtain compound 5.

[0017] (4) Compound 5 was dissolved in DMF, and the coupling agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was added at 0°C for 30 min. Compound 2 was then added, and triethylamine was slowly added dropwise. The reaction was continued at room temperature for 12 h to obtain the target compound A1.

[0018] (5) 3,4-Dihydro-7-hydroxy-2(1H)-quinolinone was dissolved in acetone, and 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane was added. Potassium carbonate was added, and the mixture was heated to reflux overnight to obtain compounds 6a / 6b / 6c.

[0019] (6) Compound 6a / 6b / 6c was dissolved in acetonitrile, compound 2 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain target compounds A2 / A3 / A4.

[0020] (7) 7-Hydroxy-2(1H)-quinolinone was dissolved in acetone, and 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane was added. Potassium carbonate was added, and the mixture was heated to reflux overnight to obtain compounds 8a / 8b / 8c.

[0021] (8) Compound 8a / 8b / 8c was dissolved in acetonitrile, compound 2 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain target compounds A5 / A6 / A7.

[0022] (9) Compound 2 was dissolved in acetonitrile, 2-chloroethoxy-2-ethoxydiethanol was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80 °C under nitrogen protection overnight to obtain 9.

[0023] (10) Compound 9 was dissolved in DCM, triethylamine was added, and methanesulfonyl chloride (MsCl) was slowly added dropwise in an ice bath. After 30 minutes, the mixture was stirred at room temperature for 2.2 hours to obtain compound 10.

[0024] (11) Compound 10 was dissolved in DMF, compound 3 was added, and potassium carbonate was added, and the mixture was heated to 100°C overnight to obtain the target compound A8.

[0025] (12) Compound 2 was dissolved in acetonitrile, tetraethylene glycol bromide was added, and then potassium carbonate and potassium iodide were added. The mixture was heated to 80 °C under nitrogen protection and reacted overnight to obtain 11.

[0026] (13) Compound 11 was dissolved in DCM, triethylamine was added, and MsCl was slowly added dropwise in an ice bath. After 30 min, the mixture was stirred at room temperature for 2.2 h to obtain compound 12.

[0027] (14) Compound 12 was dissolved in DMF, compound 3 was added, and potassium carbonate was added. The mixture was heated to 100 °C overnight to obtain the target compound A9.

[0028] (15) Compound 2 was dissolved in acetonitrile, and tetrabromobutyronitrile and potassium carbonate were added. The mixture was protected by nitrogen and heated to 80 °C overnight to obtain 13.

[0029] (16) Compound 13 was dissolved in dry tetrahydrofuran, and LiAlH4 was slowly added. The reaction was carried out at room temperature for 2 h to obtain compound 14.

[0030] (17) Compound 4-hydroxybenzoic acid was dissolved in DMF, and the coupling agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was added at 0°C for 30 min. Then, compound 14 was added, and triethylamine was slowly added dropwise. The reaction was continued at room temperature for 12 h to obtain compound 15.

[0031] (18) Compound 15 was dissolved in DMF, compound 6b was added, potassium carbonate was added, and the mixture was heated to 100 °C overnight under nitrogen protection to obtain the target compound A10.

[0032] (19) Compound 4-hydroxybiphenyl-4-carboxylic acid was dissolved in DMF, and the coupling agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was added at 0°C for 30 min. Then, 14 was added, and triethylamine was slowly added dropwise. The reaction was continued at room temperature for 12 h to obtain compound 16.

[0033] (20) Compound 16 was dissolved in DMF, compound 6b was added, potassium carbonate was added, and the mixture was heated to 100 °C overnight under nitrogen protection to obtain the target compound A11.

[0034] (21) 2-Indanone was dissolved in DCE at room temperature under nitrogen atmosphere. Methylamine was added dropwise and stirred for 15 min. Solid NaBH(OAc)3 was slowly added to the reaction flask in three small batches and stirred at room temperature for 3.5 h to obtain intermediate compound 17.

[0035] (22) Compound 17 was dissolved in acetonitrile, and compound 6b was added. Potassium carbonate and potassium iodide were added. Under nitrogen protection, the mixture was heated to 80°C and reacted overnight to obtain the target compound A12.

[0036] (23) 2-Indanone was dissolved in DCE at room temperature under nitrogen atmosphere. Ethylamine was added dropwise and stirred for 15 min. Solid NaBH(OAc)3 was slowly added to the reaction flask in three small batches and stirred at room temperature for 3.5 h to obtain intermediate compound 18.

[0037] (24) Compound 18 was dissolved in acetonitrile, and compound 6b was added. Potassium carbonate and potassium iodide were added. Under nitrogen protection, the mixture was heated to 80°C and reacted overnight to obtain the target compound A13.

[0038] (25) 2-Indanone was dissolved in DCE at room temperature under nitrogen atmosphere. Isopropylamine was added dropwise and stirred for 15 min. Solid NaBH(OAc)3 was slowly added to the reaction flask in three small batches and stirred at room temperature for 3.5 h to obtain intermediate compound 19.

[0039] (26) Compound 19 was dissolved in acetonitrile, and compound 6b was added. Potassium carbonate and potassium iodide were added. Under nitrogen protection, the mixture was heated to 80°C and reacted overnight to obtain the target compound A14.

[0040] (27) 2-Indanone was dissolved in DCE at room temperature under nitrogen atmosphere. Cyclopropylamine was added dropwise and stirred for 15 min. Solid NaBH(OAc)3 was slowly added to the reaction flask in three small batches and stirred at room temperature for 3.5 h to obtain intermediate compound 20.

[0041] (28) Compound 20 was dissolved in acetonitrile, and compound 6b was added. Potassium carbonate and potassium iodide were added. Under nitrogen protection, the mixture was heated to 80°C and reacted overnight to obtain the target compound A15.

[0042] (29) 2-Indanone was dissolved in DCE at room temperature under nitrogen atmosphere. Cyclohexylamine was added dropwise and stirred for 15 min. Solid NaBH(OAc)3 was slowly added to the reaction flask in three small batches and stirred at room temperature for 3.5 h to obtain intermediate compound 21.

[0043] (24) Compound 21 was dissolved in acetonitrile, and compound 6b was added. Potassium carbonate and potassium iodide were added. Under nitrogen protection, the mixture was heated to 80°C and reacted overnight to obtain the target compound A16.

[0044] 2. Synthesis route and specific synthesis method of quinolinone binary ligand compound LINKER with cyclohexyl carbon chain:

[0045]

[0046] Synthesis route of type B target compounds Synthesis method of Class B compounds: (1) tert-Butyl trans-(4-hydroxymethyl)cyclohexylcarbamate was dissolved in DCM at room temperature, TEA was added, and MsCl was slowly added dropwise in an ice bath. After 30 minutes, the mixture was stirred at room temperature for 2.2 hours to obtain compound 23.

[0047] (2) Add 23 to n-propylamine and heat to reflux for 16 h to obtain 24.

[0048] (3) 24 was dissolved in DCE, 2-indanone was added, acetic acid was slowly added dropwise under nitrogen protection, and the reaction was continued for 2 h. NaBH(OAc)3 was slowly added to the reaction solution and the reaction was continued at room temperature for 12 h to obtain 25.

[0049] (4) 25 was dissolved in DCM and 4 M HCl(g) in dioxane was added at room temperature and reacted for 2 h to obtain 26.

[0050] (5) Compound 5 was dissolved in DMF, and the coupling agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was added at 0°C for 30 min. Compound 26 was then added, and triethylamine was slowly added dropwise. The reaction was continued at room temperature for 12 h to obtain the target compound B1.

[0051] (6) Compound 6a / 6b / 6c was dissolved in acetonitrile, compound 26 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain the target compounds B2 / B3 / B4.

[0052] (7) Compound 8a / 8b / 8c was dissolved in acetonitrile, compound 26 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain the target compounds B5 / B6 / B7.

[0053] (8) Compound 4-hydroxybenzoic acid was dissolved in DMF, and the coupling agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was added at 0°C for 30 min. Then, 26 was added, and triethylamine was slowly added dropwise. The reaction was continued at room temperature for 12 h to obtain compound 27.

[0054] (9) Compound 27 was dissolved in DMF, compound 6b was added, potassium carbonate was added, and the mixture was heated to 100°C overnight under nitrogen protection to obtain the target compound B8.

[0055] (10) Tert-butyl trans-(4-hydroxyethyl)cyclohexylcarbamate was dissolved in DCM at room temperature, TEA was added, and MsCl was slowly added dropwise in an ice bath. After 30 minutes, the mixture was stirred at room temperature for 2.2 hours to obtain compound 29.

[0056] (11) 29 was added to n-propylamine and heated to reflux for 16 h to obtain 30.

[0057] (12) 30 was dissolved in DCE, 2-indanone was added, acetic acid was slowly added dropwise under nitrogen protection, and the reaction was carried out for 2 h. NaBH(OAc)3 was slowly added to the reaction solution and the reaction was carried out at room temperature for 12 h to obtain 31.

[0058] (13) 31 was dissolved in DCM and 4 M HCl(g) in dioxane was added at room temperature for 2 h to obtain 32.

[0059] (14) Compound 8a was dissolved in acetonitrile, compound 32 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain the target compound B9.

[0060] 3. Synthesis route and specific synthesis method of indole ketone binary ligand compounds:

[0061] Synthesis route of type C target compounds Synthesis method of Class C compounds: (1) 5-Hydroxyindolin-2-one was dissolved in acetone, 1,4-dibromobutane and potassium carbonate were added, and the mixture was heated to reflux overnight to obtain compound 34.

[0062] (2) Compound 34 was dissolved in acetonitrile, compound 2 was added, potassium carbonate and potassium iodide were added, and the mixture was heated to 80°C overnight to obtain the target compound C1.

[0063] The present invention tested the synthesized novel compounds' agonist activity against D2R via the G protein-dependent signaling pathway using a GloSensor cAMP accumulation assay. Pharmacological results showed that all synthesized target compounds exhibited strong D2R agonist activity, indicating that the target compounds of the present invention are D2R agonists.

[0064] The present invention provides the use of the above-mentioned quinolinone dual-position ligand derivative in the preparation of dopamine D2R agonists.

[0065] The present invention also provides the use of the above-mentioned quinolinone di-position ligand derivatives in the preparation of drugs for preventing and treating dopamine D2R-related diseases, including Parkinson's disease, restless legs syndrome, prolactinoma, acromegaly, central emesis, erectile dysfunction, etc.

[0066] The present invention also provides a pharmaceutical composition comprising the above-mentioned quinolinone binarized ligand derivative, or a pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or metabolite thereof, or a pharmaceutically acceptable carrier or excipient thereof.

[0067] The present invention has the following beneficial effects: This invention utilizes n-propylinden-2-amine as the orthosteric ligand fragment of the di-positional ligand, quinolinone / indolone as the allosteric ligand portion of the di-positional ligand, and connects the intermediate linker with methylene and cyclohexyl carbon chains of varying lengths, resulting in a series of novel di-positional ligand compounds. The functional activity of the target compounds against D2R was tested using a GloSensor cAMP accumulation assay. The results showed that the synthesized new compounds exhibited strong D2R agonist activity. The D2R agonists described in this invention will provide new potential drug candidates for the treatment of diseases such as Parkinson's disease and endocrine disorders. DETAILED DESCRIPTION

[0068] The present invention is described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0069] Example 1

[0070] Synthesis of 7-(3-((2,3-dihydro-1H-inden-2-yl(propyl)amino)propoxy)-3,4-dihydroquinolin-2(1H)-one (A1): Step 1: Dissolve 2-indanone (2 g, 15.15 mmol) in DCE (150 mL). Add n-propylamine (1.5 mL, 18.18 mmol) under nitrogen and react for 15 min. Add NaBH(OAc)3 (9.6 g, 45.45 mmol) and react for 3.5 h. After the reaction is complete, quench with saturated sodium bicarbonate and extract with DCM (50 mL x 3). Wash the organic phase with distilled water and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =50:1), and concentrated to obtain 1.66 g of compound 2, which was a dark green oily liquid, with a reaction yield of 63%.

[0071] Step 2: Dissolve compound 3 (200 mg, 1.23 mmol) in acetone (20 mL), add methyl bromoacetate (175 μl, 1.85 mmol), add K2CO3 (339 mg, 2.46 mmol), and heat to reflux under nitrogen for 5 h. After the reaction, extract with DCM (50 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =40:1), and concentrated to obtain 188 mg of compound 4 as a white solid with a reaction yield of 65%.

[0072] Step 3: Dissolve compound 4 (50 mg, 0.21 mmol) in methanol (10 mL) and add 15% NaOH (1 mL). React at room temperature for 2 h. After the reaction, slowly add 1 mol / L HCl dropwise to adjust the pH to 3-4. Dried methanol is then extracted with distilled water (20 mL x 3). The organic phase is washed with distilled water and the solvent removed to obtain the crude product. Concentration affords 38 mg of compound 5 as a white solid with a yield of 81%.

[0073] Step 4: Dissolve compound 5 (80 mg, 0.36 mmol) in DMF (15 mL) and add (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (179 mg, 0.47 mmol) under ice-cooling. React for 30 min, then add compound 2 (51 mg, 0.29 mmol) and triethylamine (100 μl, 0.72 mmol) dropwise. Move to room temperature and stir for 12 h. After the reaction, extract with EA (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =40:1), and concentrated to obtain 50 mg of the final product A1 as a white solid with a reaction yield of 36%. 1 H NMR (400 MHz, CDCl3) δ8.85 (d,J = 20.5 Hz, 1H), 7.18 (dq, J = 13.3, 5.0 Hz, 4H), 7.04 (d, J = 8.3 Hz,1H), 6.56 (td, J = 7.1, 6.1, 2.4 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 4.89 (dp, J =39.2, 8.2 Hz, 1H), 4.71 (d, J = 19.9 Hz, 2H), 3.32 – 3.11 (m, 5H), 3.05 (dd, J =16.0, 8.0 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.59 (dd, J = 8.6, 6.4 Hz, 2H), 1.62(dq, J = 15.4, 7.5 Hz, 2H), 0.84 (dt, J = 29.6, 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.01, 167.75, 157.66, 141.13, 140.35, 138.52, 128.81, 127.11,126.69, 124.61, 124.51, 116.76, 108.80, 102.48, 68.32, 57.67, 44.80, 37.30,36.46, 31.04, 24.67, 11.64, 1.11. Example 2

[0074] Synthesis of 7-(3-((2,3-dihydro-1H-inden-2-yl(propyl)amino)propoxy)-3,4-dihydroquinolin-2(1H)-one (A2): Step 1: Dissolve 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (500 mg, 3.07 mmol) in acetone (15 mL), add 1,3-dibromopropane (962 μL, 9.21 mmol), and potassium carbonate (847 mg, 6.14 mmol). Heat to reflux and react overnight. After the reaction, extract with DCM (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 420 mg of compound 6a as a white solid with a reaction yield of 48%.

[0075] Step 2: Dissolve compound 6a (157 mg, 0.55 mmol) in acetonitrile (3 mL), add compound 2 (80 mg, 0.46 mmol), potassium carbonate (190 mg, 1.38 mmol) and potassium iodide (23 mg, 0.14 mmol), evacuate the atmosphere and replace with nitrogen, then heat to 80°C and react overnight. After the reaction, extract with EA (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 64 mg of compound A2 as a brown-yellow solid with a reaction yield of 36%. 1 H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.20–7.11 (m, 4H), 7.02 (d, J = 8.3 Hz,1H), 6.50 (dd, J = 8.2, 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 4.01 (t, J = 5.9 Hz,2H), 3.82 (p, J = 8.1 Hz, 1H), 3.21–3.06 (m, 4H), 2.93 (t, J = 7.6 Hz, 2H), 2.87(dd, J = 8.6, 6.5 Hz, 2H), 2.76–2.67 (m, 2H), 2.60 (dd, J = 8.5, 6.5 Hz, 2H),2.08 (dq, J = 12.0, 6.1 Hz, 2H), 1.65 (dq, J = 12.6, 7.5 Hz, 2H), 0.93 (t, J= 7.3Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.31, 157.29, 139.65, 137.26, 127.57,125.73, 123.45, 114.86, 107.68, 101.30, 64.80, 62.21, 52.02, 46.91, 34.82,30.00, 24.76, 23.51, 17.85, 10.75. Example 3

[0076] Synthesis of 7-(4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A3): Other conditions were the same as those for the synthesis of A2, except that 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain 58 mg of a light yellow solid with a yield of 51%. 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.18 (s, 2H), 7.14 (s, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.40 (s, 1H), 3.95 (t, J = 6.4Hz, 2H), 3.69 (p, J = 7.9 Hz, 1H), 3.04 (dd, J = 15.6, 7.6 Hz, 2H), 2.89 (d, J =8.2 Hz, 4H), 2.62 (q, J = 8.3 Hz, 4H), 2.57–2.50 (m, 2H), 1.78 (t, J = 7.2 Hz,2H), 1.67 (d, J = 7.6 Hz, 2H), 1.52 (q, J = 7.6 Hz, 2H), 0.90 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.24, 158.70, 141.83, 141.29, 138.20, 128.61,126.58, 126.36, 124.70, 124.49, 115.66, 108.82, 102.31, 68.04, 63.14, 53.33,51.01, 39.33, 36.57, 31.10, 27.32, 24.58, 23.57, 20.15, 12.04. Example 4

[0077] Synthesis of 7-(5-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (A4): Other conditions were the same as those for the synthesis of A2, except that 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain 112 mg of a white solid with a yield of 59%. 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.20–7.10 (m, 4H), 7.00 (d, J = 8.3 Hz, 1H), 6.48 (dd, J = 8.3, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 3.94–3.83 (m, 3H), 3.31 (dd, J = 15.6, 8.5 Hz, 2H), 3.16 (dd, J = 15.5, 7.9 Hz, 2H),2.86 (q, J = 11.7, 9.9 Hz, 6H), 2.61–2.53 (m, 2H), 1.75 (dt, J = 24.2, 7.5 Hz,6H), 1.48 (p, J = 7.5 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ172.28, 158.55, 139.88, 138.35, 128.61, 127.13, 124.52, 115.77, 108.76,102.36, 67.73, 63.43, 52.69, 50.91, 50.61, 35.56, 31.11, 28.86, 24.58, 23.94,18.08, 11.67, 1.07. Example 5

[0078] Synthesis of 7-(3-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)propoxy)quinolin-2(1H)-one (A5): Step 1: Dissolve 7-hydroxy-2(1H)-quinolinone (500 mg, 3.11 mmol) in acetone (15 mL), add 1,3-dibromopropane (975 μL, 9.33 mmol), and potassium carbonate (858 mg, 6.22 mmol). Heat to reflux and react overnight. After the reaction, extract with DCM (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =50:1), and concentrated to afford 547 mg of compound 8a as a white solid with a reaction yield of 62%.

[0079] Step 2: Dissolve compound 8a (115 mg, 0.41 mmol) in acetonitrile (3 mL), add compound 2 (60 mg, 0.34 mmol), potassium carbonate (141 mg, 1.02 mmol), and potassium iodide (14 mg, 0.10 mmol), evacuate the atmosphere, replace with nitrogen, and heat to 50°C overnight. After the reaction, extract with EA (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =40:1), and concentrated to obtain 29 mg of compound A5 as a light yellow solid with a reaction yield of 23%. 1 H NMR (400 MHz, CDCl3) δ 12.04 (s, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.44 (d, J =8.7 Hz, 1H), 7.16 (dt, J = 9.0, 6.4, 3.0 Hz, 4H), 6.94 (d, J= 2.3 Hz, 1H), 6.79(dd, J = 8.7, 2.3 Hz, 1H), 6.51 (d, J = 9.4 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.87(p, J = 8.4 Hz, 1H), 3.37 (d, J = 7.7 Hz, 1H), 3.17 (q, J = 15.5, 11.7 Hz, 4H),3.00 (d, J = 15.3 Hz, 2H), 2.77 (d, J = 8.4 Hz, 2H), 2.18 (s, 2H), 0.95 (t, J = 7.3Hz, 3H). Example 6

[0080] Synthesis of 7-(4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)butoxy)quinolin-2(1H)-one (A6): Other conditions were the same as those for the synthesis of A6, except that 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain 32 mg of a light yellow oily liquid with a yield of 28%. 1 H NMR (400 MHz, CDCl3) δ 12.77 (s, 1H), 7.72 (d, J = 9.4 Hz,1H), 7.43 (d,J= 8.7 Hz, 1H), 7.21–7.09 (m, 4H), 6.88 (d, J = 2.4 Hz, 1H), 6.80(dd, J = 8.7, 2.3 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.68(p, J = 8.3 Hz, 1H), 3.04 (dd, J = 15.5, 7.7 Hz, 2H), 2.91 (dt, J = 15.4, 7.0 Hz,2H), 2.63 (t, J= 7.5 Hz, 2H), 2.58–2.47 (m, 2H), 1.83 (p, J = 6.5 Hz, 2H), 1.68(p, J = 7.5, 6.7 Hz, 2H), 1.52 (dq, J = 14.9, 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ 165.32, 161.52, 144.04, 141.99, 140.99, 140.54,129.04, 126.37, 124.55, 123.47, 117.85, 114.25, 112.90, 99.05, 84.45, 68.36,63.18, 53.39, 51.08, 36.70, 27.31, 23.70, 20.29, 12.13, 1.13. Example 7

[0081] Synthesis of 7-(5-((2,3-dihydro-1H-inden-2-yl(propyl)amino)pentyl)oxy)quinolin-2(1H)-one (A7): Other conditions were the same as those for the synthesis of A6, except that 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain 36 mg of a light yellow oily liquid with a yield of 26%. 1 H NMR (400 MHz, CDCl3) δ 12.43 (s, 1H), 7.80 (d, J = 9.4 Hz,1H), 7.51 (d, J = 8.7 Hz, 1H), 7.27 – 7.18 (m, 4H), 7.11 (d, J = 2.4 Hz, 1H),6.87 (dd, J = 8.6, 2.3 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.15 (t, J = 6.1 Hz, 2H), 3.62 – 3.41 (m, 3H), 3.31 (dd, J = 15.6, 7.9 Hz, 2H), 3.14 – 2.96 (m, 4H), 1.91(tt, J= 17.8, 7.1 Hz, 6H), 1.63 (p, J = 7.8 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 164.70, 161.27, 141.00, 140.49, 139.17, 129.04,127.32, 124.56, 117.85, 114.29, 112.75, 99.25, 67.92, 63.54, 53.55, 52.63,50.90, 36.33, 35.36, 28.69, 23.86, 11.60, 1.10. Example 8

[0082] Synthesis of 7-(2-(2-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)ethoxy)ethoxycarbonyl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (A8): Step 1: Dissolve compound 2 (200 mg, 1.14 mmol) in acetonitrile (3 mL), add 2-(2-chloroethoxy)ethoxyethane-1-ol (198 uL, 1.37 mmol), then add potassium carbonate (472 mg, 3.42 mmol) and potassium iodide (57 mg, 0.34 mmol). Evacuate the mixture and replace with nitrogen. Heat to 80°C and react overnight. After the reaction, extract with DCM (20 mL x 3). Wash the organic phase with distilled water and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 240 mg of compound 9 as a yellow oily liquid with a reaction yield of 68%.

[0083] Step 2: Compound 9 (230 mg, 0.75 mmol) was dissolved in DCM (20 mL), triethylamine (311 μL, 2.25 mmol) was added, and methanesulfonyl chloride (87 μL, 1.13 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to react for 3 h. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate, extracted with DCM (20 mL x 3), and the organic phase was washed with distilled water. The solvent was removed to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 250 mg of compound 10 as a yellow oily liquid with a reaction yield of 86%.

[0084] Step 3: Dissolve compound 10 (60 mg, 0.16 mmol) in DMF (3 mL), add 3,4-dihydro-7-hydroxyquinolinone (31 mg, 0.19 mmol), and then add potassium carbonate (66 mg, 0.48 mmol). Evacuate the mixture and replace with nitrogen. Heat to 100°C and react overnight. After the reaction, extract with EA (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 53 mg of compound A8, which was a light yellow oily liquid, with a reaction yield of 73%. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.19–7.08 (m, 4H), 7.01 (d, J = 8.3 Hz, 1H),6.50 (dd, J = 8.3, 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 4.10–4.03 (m, 2H), 3.87–3.75 (m, 3H), 3.74–3.61 (m, 6H), 3.13–2.97 (m, 4H), 2.93–2.82 (m, 4H), 2.71–2.54 (m, 4H), 1.59 (q, J = 8.6, 7.5 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 172.04, 158.43, 141.31, 138.32, 128.66, 126.64, 124.55,116.08, 108.81, 102.57, 70.90, 70.62, 69.80, 67.71, 63.78, 54.35, 53.55,50.71, 36.32, 31.14, 24.66, 11.88, 1.12. Example 9

[0085] Synthesis of 7-((12-(2,3-dihydro-1H-inden-2-yl)-3,6,9-trioxa-12-azapentadecyl)oxy)-3,4-dihydroquinolin-2(1H)-one (A9): Other conditions were the same as those for the synthesis of A8, except that 2-(2-chloroethoxy)ethoxyethane-1-ol was replaced with 2-(2-(2-bromoethoxy)ethoxyethyl)ethan-1-ol to give 44 mg of a light yellow oily liquid with a yield of 63%. 1 H NMR (400 MHz, CDCl3)δ 8.22 (s, 1H), 7.18 – 7.09 (m, 4H), 7.02 (d, J = 8.3 Hz, 1H), 6.52 (dd, J = 8.3,2.5 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.12 – 4.04 (m, 2H), 3.86 – 3.75 (m,3H), 3.70 – 3.60 (m, 9H), 3.08 (dd, J = 15.5, 7.8 Hz, 3H), 2.95 (s, 1H), 2.92 –2.80 (m, 5H), 2.60 (q, J = 11.0, 7.0 Hz, 4H), 1.66 – 1.51 (m, 2H), 0.89 (t, J =7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.96, 158.46, 138.32, 128.68, 126.62,124.55, 116.09, 108.88, 102.59, 70.90, 70.74, 70.71, 70.60, 69.79, 67.75,63.79, 54.37, 50.69, 36.35, 31.16, 24.68, 11.90, 1.13. Example 10

[0086] Synthesis of N-(4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)butyl)-4-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butoxy)benzamide (A10): Step 1: Dissolve compound 2 (300 mg, 1.71 mmol) in acetonitrile (3 mL), add tetrabromobutyronitrile (207 uL, 2.05 mmol), then add potassium carbonate (472 mg, 3.42 mmol) and potassium iodide (85 mg, 0.51 mmol). Evacuate the mixture and replace with nitrogen. Heat to 80°C and react overnight. After the reaction, extract with DCM (20 mL x 3). Wash the organic phase with distilled water and remove the solvent to obtain the crude product. Column chromatography (V PE :V EA =9:1), and concentrated to obtain 394 mg of compound 13, which was a light yellow oily liquid, with a reaction yield of 95%.

[0087] Step 2: Dissolve compound 13 (394 mg, 1.63 mmol) in anhydrous tetrahydrofuran (20 mL). Slowly add LiAlH4 in an ice bath and stir at room temperature for 50 min. After the reaction, add saturated sodium bicarbonate and adjust the pH to 8-10. Extract with EA (20 mL x 3). Wash the organic phase with distilled water and remove the solvent to obtain the crude product. Column chromatography (V PE :V EA =30:1), and concentrated to obtain 208 mg of compound 14, which was a light yellow oily liquid, with a reaction yield of 51%.

[0088] Step 3: Dissolve p-hydroxybenzoic acid (68 mg, 0.49 mmol) in DMF (15 mL). Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (203 mg, 0.53 mmol) under ice-cooling and react for 30 min. Then add compound 14 (100 mg, 0.41 mmol) and slowly add triethylamine (170 uL, 1.23 mmol) dropwise. React at room temperature for 12 h. After the reaction, extract with EA (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =20:1), and concentrated to obtain 62 mg of compound 15 as a white solid with a reaction yield of 41%.

[0089] Step 4: Compound 15 (62 mg, 0.17 mmol) was dissolved in DMF (3 mL), compound 6b (76 mg, 0.255 mmol) was added, and potassium carbonate (70 mg, 0.51 mmol) was added. The mixture was heated to 80°C and reacted for 5 h. After the reaction, the mixture was extracted with EA (20 mL × 3), and the organic phase was washed with distilled water to remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =20:1), and concentrated to obtain 58 mg of compound A10 as a white solid. The reaction yield was 58%.1 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.85 (d, J J = 8.5 Hz, 2H), 7.33 (s, 1H), 7.13 (s, 4H), 7.00 (d, J J = 8.2 Hz, 1H), 6.85 (d, J J = 8.5 Hz, 2H), 6.48 (dd, J J = 8.2, 2.4 Hz, 1H), 6.43 (d, J J = 2.4 Hz, 1H), 4.06 – 3.83 (m, 5H), 3.47 (q, J J = 6.2 Hz, 2H), 3.25 (dd, J J = 15.7, 8.1 Hz, 2H), 3.14 (dd, J J = 15.7, 8.0 Hz, 2H), 2.92 (d, J J = 7.7 Hz, 2H), 2.88 – 2.75 (m, 4H), 2.56 (t, J J = 7.5 Hz, 2H), 1.98 – 1.87 (m, 4H), 1.82 (t, J J = 7.5 Hz, 2H), 1.69 (t, J J = 6.8 Hz, 4H), 0.90 (t, J J = 7.3 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 172.02, 167.46, 161.50, 158.56, 1 39.79, 138.41, 135.24, 129.15, 128.61, 127.17, 126.71, 124.53, 115.79, 114.18, 108.68, 102.42, 67.57, 63.36, 53.57, 52.58, 50.90, 39.01, 35.42, 31.18, 26.96, 25.87, 25.83, 24.63, 22.64, 17.83, 11.62, 1.09. Example 11

[0090] Synthesis of N-(4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)butyl)-4'-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butoxy)-[1,1'-biphenyl]-4-carboxamide (A11): Other conditions were the same as those for the synthesis of A10, except that p-hydroxybenzoic acid was replaced with 4'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid to obtain 37 mg of a white solid with a yield of 49%. 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.85 (d, J = 6.4Hz, 2H), 7.54 (dd, J = 22.0, 8.5 Hz, 4H), 7.13 (p, J = 4.5 Hz, 4H), 7.03 (d, J =8.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 3H), 6.52 (dd, J = 8.3, 2.5 Hz, 1H), 6.40 (d, J =2.4 Hz, 1H), 4.11 – 3.95 (m, 4H), 3.76 (p, J = 8.2 Hz, 1H), 3.50 (q, J = 6.0 Hz,2H), 3.12 – 2.96 (m, 4H), 2.87 (dd, J = 8.6, 6.4 Hz, 2H), 2.72 (d, J = 6.7 Hz,2H), 2.62 (dd, J = 15.3, 8.7, 6.3 Hz, 4H), 1.98 (dd, J = 7.9, 4.8, 4.0 Hz, 4H),1.76 – 1.64 (m, 4H), 1.57 (dd, J = 15.8, 7.6 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13CNMR (101 MHz, CDCl3) δ 172.09, 167.58, 159.12, 158.67, 143.71, 140.99,138.33, 132.78, 132.47, 128.72, 128.32, 127.64, 126.75, 126.62, 124.55,115.82, 114.95, 108.79, 102.31, 67.69, 67.61, 63.23, 53.07, 51.03, 39.76,36.13, 31.18, 27.53, 26.04, 24.66, 24.10, 19.01, 11.92, 1.12. Example 12

[0091] Synthesis of 7-(4-((2,3-dihydro-1H-inden-2-yl)(methyl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A12): Other conditions were the same as those for the synthesis of A3, except that n-propylamine was replaced with methylamine to obtain 74 mg of a green oily liquid with a yield of 59%. 1 HNMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.21 – 7.10 (m, 4H), 7.02 (d, J = 8.3 Hz,1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 3.96 (t, J = 5.9 Hz,2H), 3.45 (p, J = 8.1 Hz, 1H), 3.09 (dd, J = 15.5, 7.6 Hz, 2H), 2.98 (dd, J = 15.5,8.5 Hz, 2H), 2.91 – 2.84 (m, 2H), 2.65 – 2.56 (m, 4H), 2.35 (s, 3H), 1.78(dt, J = 17.9, 9.9 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 172.32, 158.69, 141.44,138.35, 128.65, 126.61, 124.49, 115.78, 108.82, 102.40, 67.92, 66.14, 55.05,39.20, 36.72, 31.16, 27.30, 24.64, 23.25, 1.10. Example 13

[0092] Synthesis of 7-(4-((2,3-dihydro-1H-inden-2-yl)(ethyl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A13): Other conditions were the same as those for the synthesis of A3, except that n-propylamine was replaced with ethylamine to obtain 91 mg of a brown oily liquid with a yield of 77%. 1 HNMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.24 – 7.09 (m, 4H), 7.03 (d, J = 8.4 Hz,1H), 6.51 (d, J = 8.6 Hz, 1H), 6.40 (d, J = 9.1 Hz, 1H), 3.95 (t, J = 6.2 Hz, 2H),3.68 (p, J = 8.1 Hz, 1H), 3.19 – 2.84 (m, 6H), 2.82 – 2.52 (m, 6H), 1.74 (dt, J =30.0, 6.5 Hz, 4H), 1.10 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.30,158.71, 141.64, 138.30, 128.69, 126.52, 124.54, 115.78, 108.82, 102.38,68.00, 62.92, 50.10, 44.84, 36.82, 31.17, 27.38, 24.65, 23.26, 11.35, 1.13. Example 14

[0093] Synthesis of 7-(4-((2,3-dihydro-1H-inden-2-yl)(isopropyl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A14): Other conditions were the same as those for the synthesis of A3, except that n-propylamine was replaced with isopropylamine to obtain 31 mg of a brown oily liquid with a yield of 27%. 1 HNMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.23 – 7.08 (m, 4H), 7.03 (d, J = 8.3 Hz,1H), 6.51 (dd, J = 8.3, 2.5 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 3.94 (t, J = 6.3 Hz,2H), 3.75 (p, J = 8.8 Hz, 1H), 3.16 (s, 1H), 3.04 – 2.83 (m, 6H), 2.60 (dd, J =16.6, 9.6 Hz, 4H), 1.76 (q, J = 6.8 Hz, 2H), 1.66 (s, 2H), 1.08 (d, J = 6.5 Hz,6H). 13 C NMR (101 MHz, CDCl3) δ 171.07, 157.64, 141.07, 137.13, 127.55, 125.23,123.37, 114.59, 107.68, 101.23, 67.08, 45.44, 36.74, 30.05, 26.16, 23.53,18.33. Example 15

[0094] Synthesis of 7-(4-(cyclopropyl(2,3-dihydro-1H-inden-2-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A15): Other conditions were the same as those for the synthesis of A3, except that n-propylamine was replaced with cyclopropylamine to obtain 46 mg of a brown oily liquid with a yield of 40%. 1 HNMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.23 – 7.10 (m, 4H), 7.03 (d, J = 8.3 Hz,1H), 6.51 (dd,J = 8.2, 2.5 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 3.95 (d, J = 5.8 Hz,2H), 3.76 (p, J = 8.2 Hz, 1H), 3.06 (p, J = 7.8 Hz, 4H), 2.88 (t, J = 7.5 Hz, 2H),2.79 (d, J = 7.4 Hz, 2H), 2.66 – 2.56 (m, 2H), 1.90 (t, J = 5.5 Hz, 1H), 1.83 –1.68 (m, 4H), 0.70 – 0.50 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 172.47, 158.72,141.84, 138.31, 128.61, 126.69, 126.39, 124.71, 124.44, 115.69, 108.84,102.38, 68.01, 64.98, 53.17, 36.56, 34.95, 31.13, 27.49, 24.61, 22.55, 7.16,5.70, 1.10. Example 16

[0095] Synthesis of 7-(4-(cyclohexyl(2,3-dihydro-1H-inden-2-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (A16): Other conditions were the same as those for the synthesis of A3, except that n-propylamine was replaced with cyclohexylamine to obtain 27 mg of a white solid with a yield of 27%. 1 HNMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.15 (t, J = 3.8 Hz, 4H), 7.01 (d, J = 8.3Hz, 1H), 6.47 (dd, J = 8.3, 2.5 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 3.94 (q, J =7.1, 5.8 Hz, 3H), 3.17 (d, J= 82.2 Hz, 4H), 2.86 (dd, J = 8.6, 6.4 Hz, 4H), 2.62– 2.54 (m, 2H), 2.14 – 1.95 (m, 2H), 1.94 – 1.72 (m, 6H), 1.66 (d, J = 12.9 Hz,1H), 1.38 (s, 2H), 1.31 (d, J = 12.8 Hz, 2H), 1.12 (dd, J = 16.3, 12.8, 6.2 Hz,1H), 0.84 (dt, J = 13.8, 6.9, 3.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 172.23,158.47, 138.38, 128.64, 126.81, 124.49, 115.84, 108.74, 102.35, 67.73, 53.55,31.12, 29.77, 27.07, 25.98, 24.62, 1.09. Example 17

[0096] Synthesis of N-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)acetamide (B1): Step 1: Add tert-butyl trans-(4-hydroxymethyl)cyclohexylcarbamate (5 g, 21.8 mmol) to dichloromethane (50 mL). Add triethylamine (9.1 mL, 65.5 mmol) as an acid-binding agent. Slowly add methanesulfonyl chloride (2.5 mL, 32.7 mmol) dropwise in an ice bath. Allow to react for 3 h. After completion of the reaction, quench with saturated sodium bicarbonate. Extract with DCM (50 mL x 3). Wash the organic phase with distilled water, and remove the solvent to yield 6.5 g of a crude white solid.

[0097] Step 2: Compound 23 (6.5 g, 21.2 mmol) was added to n-propylamine (30 mL), acetonitrile was added to dissolve the mixture, the mixture was evacuated and replaced with nitrogen, and the mixture was heated to 80°C for overnight reaction. After the reaction, the mixture was extracted with DCM (50 mL × 3), the organic phase was washed with distilled water, and the solvent was removed to obtain the crude product. Column chromatography (V DCM :V MeOH=30:1), and concentrated to obtain 4.1 g of compound 24 as a white solid with a reaction yield of 68%.

[0098] Step 3: Dissolve compound 24 (500 mg, 1.76 mmol) in DCM, add 2-indanone (279 mg, 2.11 mmol), and slowly add acetic acid (151 uL, 2.64 mmol) under nitrogen. React for 2 h, then add NaBH(OAc)3 (1.12 g, 5.28 mmol) and continue the reaction for 12 h. After completion of the reaction, quench with saturated sodium bicarbonate, extract with DCM (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V PE :V EA =10:1), and concentrated to obtain 343 mg of compound 25 as a yellow oily liquid with a reaction yield of 50%.

[0099] Step 4: Dissolve compound 25 (330 mg, 0.85 mmol) in DCM and slowly add 4M hydrogen chloride gas (638 μL, 2.55 mol) for 2 h. After the reaction, adjust the pH to 8-10 with sodium hydroxide solution, extract with DCM (20 mL x 3), wash the organic phase with distilled water, and remove the solvent to obtain the crude product. Column chromatography (V DCM :V MeOH =20:1), and concentrated to obtain 215 mg of compound 26, which was a brown oily liquid, with a reaction yield of 88%.

[0100] Step 5: Compound 5 (50 mg, 0.23 mmol) was dissolved in DMF (15 mL). (2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (114 mg, 0.30 mmol) was added under ice-cooling. The mixture was reacted for 30 min. Compound 26 (51 mg, 0.18 mmol) was then added dropwise. Triethylamine (64 uL, 0.46 mmol) was then added dropwise. The mixture was stirred at room temperature for 12 h. After the reaction, the mixture was extracted with EA (20 mL × 3). The organic phase was washed with distilled water and the solvent was removed to obtain the crude product. Column chromatography (V DCM :V MeOH =30:1), and concentrated to obtain 21 mg of the final product B1 as a white solid with a reaction yield of 27%. 1 H NMR (400 MHz, CDCl3) δ 9.15(s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.14 – 7.10 (m, 2H), 7.06 (d, J= 8.3 Hz, 1H), 6.56 – 6.47 (m, 2H), 6.43 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 3.86 – 3.75 (m,1H), 3.70 (p, J = 8.4 Hz, 1H), 2.97 (t, J = 4.9 Hz, 4H), 2.88 (dt, J = 16.7, 8.0Hz, 4H), 2.62 (dd, J = 8.5, 6.5 Hz, 2H), 2.52 – 2.43 (m, 2H), 2.30 (d, J = 6.9Hz, 2H), 2.00 (dd, J = 12.2, 3.4 Hz, 2H), 1.95 – 1.87 (m, 2H), 1.52 – 1.41 (m,3H), 0.97 (dt, J = 13.1, 10.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.36, 167.29, 156.83, 149.75, 141.94, 141.35, 138.62, 128.97,126.39, 124.57, 118.41, 117.30, 108.61, 102.87, 67.55, 63.23, 58.08, 54.50,48.70, 36.06, 35.86, 32.96, 32.85, 30.96, 30.44, 30.08, 24.61, 20.25, 11.99,1.11. Example 18

[0101] Synthesis of 7-(3-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)propoxy)-3,4-dihydroquinolin-2(1H)-one (B2): Other conditions were the same as those for the synthesis of A2, except that compound 2 was replaced by compound 26 to obtain 28.8 mg of a light yellow oily liquid with a yield of 28%. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.19 – 7.09 (m, 4H), 7.00 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 8.2, 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.67 (p, J = 8.2 Hz, 1H), 3.00 – 2.91 (m, 4H), 2.84 (dd, J =14.1, 7.2 Hz, 4H), 2.66 – 2.57 (m, 1H), 2.57 – 2.51 (m, 2H), 2.46 – 2.39 (m,2H), 2.24 (d, J = 6.9 Hz, 2H), 2.13 – 2.04 (m, 4H), 1.91 (d, J = 12.4 Hz, 2H),1.44 (h, J = 7.3 Hz, 3H), 1.34 – 1.21 (m, 3H), 0.86 (t, J = 7.3 Hz, 5H). 13 C NMR(101 MHz, CDCl3) δ 172.13, 158.41, 142.19, 138.36, 128.60, 126.28, 124.55,115.86, 108.95, 102.34, 66.00, 62.93, 57.95, 57.83, 54.36, 43.33, 36.26,35.90, 31.51, 31.11, 30.30, 29.79, 28.44, 24.59, 20.42, 12.03, 1.12. Example 19

[0102] Synthesis of 7-(4-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (B3): Other conditions were the same as those for the synthesis of A3, except that compound 2 was replaced by compound 26 to obtain 51 mg of a light yellow oily liquid with a yield of 58%.1 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.13 (d, J J = 10.9 Hz, 4H), 6.97(d, J J = 8.4 Hz, 1H), 6.46 (d, J J = 9.8 Hz, 2H), 3.89 (d, J J = 6.0 Hz, 2H), 3.66 (p, J J=8.3, 7.7 Hz, 1H), 3.47 (s, 2H), 2.94 (dt, J J = 19.7, 9.7 Hz, 3H), 2.83 (d, J J=12.2 Hz, 4H), 2.73 (d, J J = 10.6 Hz, 1H), 2.55 (t, J J = 7.6 Hz, 2H), 2.41 (t, J J = 7.7Hz, 2H), 2.22 (d, J J = 6.9 Hz, 2H), 2.12 (d, J J = 10.9 Hz, 2H), 1.91 (t, J J = 11.6 Hz,3H), 1.79 (d, J J = 14.5 Hz, 2H), 1.50 – 1.34 (m, 5H), 0.86 (q, J J = 8.4 Hz, 5H). 13 13C NMR (101 MHz, CDCl3) δ 171.96, 158.37, 142.06, 128.56, 126.24, 124.48,115.80, 109.05, 102.41, 67.61, 62.81, 57.74, 54.23, 50.68, 45.46, 35.94,35.82, 31.05, 30.55, 30.03, 29.72, 26.71, 24.50, 20.31, 11.94. Example 20

[0103] Synthesis of 7-(5-(((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (B4): Other conditions were the same as those for the synthesis of A4, except that compound 2 was replaced by compound 26 to obtain 50 mg of a light yellow oily liquid with a yield of 46%. 1 H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.20 – 7.06 (m, 4H), 6.96 (d, J =8.3 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 3.90 (t, J =6.3 Hz, 2H), 3.76 (dd, J = 16.6, 8.6 Hz, 1H), 3.10 – 2.89 (m, 7H), 2.86 – 2.76(m, 2H), 2.64 – 2.49 (m, 4H), 2.39 (s, 2H), 2.27 (d, J = 11.2 Hz, 2H), 2.02 (d, J = 15.5 Hz, 5H), 1.75 (q, J = 7.0 Hz, 2H), 1.68 (d, J = 12.4 Hz, 3H), 1.55 – 1.47 (m, 4H), 0.96 – 0.83 (m, 5H). 13 C NMR (101 MHz, CDCl3) δ 171.96, 158.44,138.42, 128.52, 126.65, 124.54, 115.64, 109.24, 102.41, 67.67, 57.56, 57.41,54.09, 44.76, 35.55, 31.15, 29.70, 28.61, 28.50, 25.87, 24.55, 23.43, 11.79,1.08. Example 21

[0104] Synthesis of 7-(3-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)propoxy)quinolin-2(1H)-one (B5): Other conditions were the same as those for the synthesis of A5, except that compound 2 was replaced by compound 26 to obtain 40 mg of a light yellow oily liquid with a yield of 39%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 9.4 Hz, 1H), 7.42 (d, J = 8.7 Hz,1H), 7.20 – 7.08 (m, 4H), 6.85 (d, J = 2.3 Hz, 1H), 6.79 (dd, J = 8.7, 2.3 Hz,1H), 6.53 (d, J = 9.3 Hz, 1H), 4.14 (t, J = 6.1 Hz, 2H), 3.68 (p, J = 8.2 Hz, 1H),2.97 (dd, J = 15.7, 7.8 Hz, 2H), 2.91 – 2.78 (m, 4H), 2.50 – 2.39 (m, 3H), 2.25(d, J = 6.9 Hz, 2H), 2.00 (q, J = 9.6, 8.1 Hz, 4H), 1.89 (d, J = 10.9 Hz, 2H), 1.45(h, J = 6.9, 6.5 Hz, 3H), 1.17 – 1.05 (m, 2H), 0.86 (t, J = 7.2 Hz, 5H). 13 C NMR(101 MHz, CDCl3) δ 165.13, 161.38, 142.25, 140.95, 140.50, 129.03, 126.26,124.56, 117.91, 114.30, 112.81, 99.12, 66.82, 63.05, 58.22, 57.69, 54.42,43.95, 36.71, 35.91, 33.17, 30.63, 29.86, 20.43, 12.05, 1.12. Example 22

[0105] Synthesis of 7-(4-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)butoxy)quinolin-2(1H)-one (B6): Other conditions were the same as those for the synthesis of A6, except that compound 2 was replaced by compound 26 to obtain 53 mg of a light yellow oily liquid with a yield of 50%. 1 H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 25.1, 9.4 Hz, 1H), 7.38 (dd, J =27.4, 8.7 Hz, 1H), 7.20 – 7.08 (m, 4H), 6.83 (d, J = 2.3 Hz, 1H), 6.80 – 6.72(m, 1H), 6.51 (dd, J = 19.4, 9.4 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.68 (p, J =8.2 Hz, 1H), 2.97 (dd, J = 15.7, 7.8 Hz, 2H), 2.85 (dd, J = 15.6, 8.6 Hz, 2H),2.73 (t, J = 7.3 Hz, 1H), 2.52 (t, J = 7.1 Hz, 1H), 2.48 – 2.38 (m, 3H), 2.25 (d, J = 6.9 Hz, 2H), 1.96 (d, J = 13.2 Hz, 2H), 1.91 – 1.78 (m, 4H), 1.69 (p, J = 7.3Hz, 2H), 1.60 (t, J = 7.3 Hz, 1H), 1.45 (dq, J = 14.5, 7.3 Hz, 3H), 1.10 (q, J =11.7, 10.9 Hz, 2H), 0.86 (d, J = 6.0 Hz, 5H). 13C NMR (101 MHz, CDCl3) δ 165.20,165.13, 161.52, 161.41, 142.20, 140.97, 140.47, 128.98, 126.24, 124.53,117.75, 114.22, 114.14, 112.92, 99.00, 68.43, 68.18, 63.02, 58.19, 57.54,54.37, 46.65, 36.66, 35.89, 33.14, 30.60, 27.04, 26.80, 25.54, 20.34, 12.03,1.09. Example 23

[0106] Synthesis of 7-(5-((((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)amino)pentyl)oxy)quinolin-2(1H)-one (B7): Other conditions were the same as those for the synthesis of A7, except that compound 2 was replaced by compound 26 to obtain 48 mg of a light yellow oily liquid with a yield of 44%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 9.4 Hz, 1H), 7.42 (d, J = 8.6 Hz,1H), 7.21 – 7.06 (m, 4H), 6.81 (dd, J = 13.7, 4.3 Hz, 2H), 6.53 (d, J = 9.3 Hz,1H), 4.05 (t, J = 6.4 Hz, 2H), 3.68 (p, J = 8.2 Hz, 1H), 2.97 (dd, J = 15.7, 7.8Hz, 2H), 2.85 (dd, J = 15.7, 8.6 Hz, 2H), 2.68 (t, J = 7.0 Hz, 2H), 2.50 – 2.36(m, 3H), 2.25 (d, J = 6.8 Hz, 2H), 1.96 (d, J = 13.4 Hz, 2H), 1.86 (dd, J= 15.6,9.9 Hz, 4H), 1.64 – 1.51 (m, 3H), 1.44 (dt, J = 14.7, 7.3 Hz, 4H), 1.10 (q, J =11.2, 10.1 Hz, 2H), 0.86 (t, J = 7.2 Hz, 5H). 13 C NMR (101 MHz, CDCl3) δ 165.16,161.51, 142.22, 141.00, 140.50, 129.00, 126.25, 124.55, 117.78, 114.22,112.90, 99.03, 68.25, 63.02, 58.20, 57.63, 54.39, 46.88, 36.66, 35.90, 33.07,30.61, 29.90, 29.03, 23.95, 20.36, 12.04, 1.11. Example 24

[0107] Synthesis of N-((1r,4r)-4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclohexyl)-4-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butoxy)benzamide (B8): Other conditions were the same as those for the synthesis of A10, except that compound 14 was replaced by compound 26 to obtain 33 mg of a white solid with a yield of 43%. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.76 – 7.65 (m, 2H), 7.23 – 7.10 (m, 4H), 7.03 (d, J = 8.3 Hz, 1H), 6.94 – 6.85 (m, 2H), 6.51 (dd, J = 8.3, 2.4Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.01 (d, J = 7.8 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.99 (q, J = 4.5, 3.6 Hz, 2H), 3.89 (dt, J= 11.6, 5.8 Hz, 1H), 3.84 – 3.69 (m,1H), 3.01 (ddd, J = 34.6, 14.4, 8.0 Hz, 4H), 2.88 (t, J = 7.5 Hz, 2H), 2.60 (dd, J = 8.5, 6.5 Hz, 4H), 2.10 (d, J = 9.6 Hz, 2H), 2.02 – 1.89 (m, 6H), 1.52 (s, 2H), 1.35 – 1.17 (m, 5H), 1.04 (q, J = 12.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 172.21, 166.47, 161.49, 158.61, 138.31, 128.79,128.69, 127.21, 126.59, 124.58, 115.82, 114.23, 108.85, 102.32, 67.63, 63.44,58.18, 54.43, 49.22, 35.69, 32.93, 31.16, 30.51, 29.78, 25.93, 24.63, 11.87,1.11. Example 25

[0108] Synthesis of 7-(3-((1r,4r)-4-(2-(2,3-dihydro-1H-inden-2-yl)(propyl)amino)ethyl)cyclohexyl)amino)propoxy)quinolin-2(1H)-one: Other conditions were the same as those for the synthesis of B5, except that compound 26 was replaced by compound 32 to obtain 30 mg of a white solid with a yield of 36%. 1 HNMR (400 MHz, CDCl3) δ 7.70 (d, J = 9.4 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.21 –7.06 (m, 4H), 6.91 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.7, 2.3 Hz, 1H), 6.51 (d, J= 9.4 Hz, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.61 (p, J = 8.3 Hz, 1H), 3.00 (dd, J =15.4, 7.6 Hz, 2H), 2.93 – 2.79 (m, 4H), 2.62 – 2.52 (m, 2H), 2.52 – 2.40 (m,3H), 2.08 – 1.91 (m, 4H), 1.84 – 1.70 (m, 2H), 1.55 – 1.42 (m, 2H), 1.42 –1.32 (m, 2H), 1.30 – 1.18 (m, 2H), 1.18 – 1.07 (m, 2H), 0.97 (qd, J = 13.1, 3.1Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.05, 161.33,142.01, 140.93, 140.49, 129.01, 126.34, 124.52, 117.89, 114.28, 112.79,99.12, 66.72, 63.36, 57.39, 53.40, 49.25, 43.85, 36.84, 35.97, 33.94, 33.05,32.09, 29.69, 20.20, 12.14, 1.11. Example 26

[0109] Synthesis of 5-(4-((2,3-dihydro-1H-inden-2-yl)(propyl)amino)butoxy)indol-2-one: Other conditions were the same as those for the synthesis of A3, except that compound 6b was replaced by compound 34 to obtain 45 mg of a yellow oily liquid with a yield of 42%. 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.15 (dt, J = 9.5, 7.1, 3.6 Hz, 4H), 6.87 – 6.76 (m, 2H), 6.73 (dd, J = 8.5, 2.4 Hz, 1H), 3.99 – 3.86 (m, 2H), 3.71(p, J= 8.3 Hz, 1H), 3.50 (s, 2H), 3.05 (dd, J = 15.5, 7.7 Hz, 2H), 2.95 (dd, J =15.5, 8.8 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.61 – 2.51 (m, 2H), 1.78 (p, J =6.5 Hz, 2H), 1.69 (t, J = 9.2, 5.6 Hz, 2H), 1.58 – 1.46 (m, 2H), 0.90 (t, J = 7.3Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 177.93, 155.09, 141.68, 136.20, 126.70,126.48, 124.53, 113.43, 112.50, 110.16, 68.54, 63.21, 53.32, 50.99, 36.84,36.50, 27.39, 23.43, 20.00, 12.05, 1.11. Biological activity test New compounds were tested for their functional activity at D2R and D4R using the GloSensor cAMP accumulation assay to determine if they are targeted D2R agonists.

[0110] Results of the target compound's agonist activity test on D2R and D4R:

[0111] Table 1. ECs of target compounds of formula (1) and formula (2) for activation of D2R and D4R 50 value

[0112] Note: Fold Shift is the ratio of the activity of lead compound 2 on D2R to the activity of the target compound on D2R.

[0113] The 26 new compounds synthesized were tested for their agonist activity on D2R and D4R using the Glosensor cAMP accumulation assay. The experimental results are shown in Table 1 above. The target compounds of the present invention all have agonist activity on D2R. Among them, the agonist activity of A3, A8, A12, B2, B3, B6, B9 and C1 on D2R is more than 10 times higher than that of the lead compound 2, and the agonist activity of A12 and B3 is 16 times that of the lead compound 2; A3, A6, A7, A8, A9, A12, A13, B2, B3, B4, B5, B6 and B7 have strong agonist activity on D2R and D4R, but poor selectivity; A11, A14, A15, A16, B9 and C1 have significantly stronger agonist activity on D2R than on D4R. Therefore, it can be seen that these compounds have better selectivity for D2R and poor selectivity for D4R, among which A15 The D4R / D2R ratios of A16, C1 and A5 are as high as 180 times, 142 times and 101 times respectively; while the agonist activity of A5 and A10 on D4R is better than that on D2R, and thus their selectivity for D4R is better than that for D2R.

Claims

1. A quinolinone di-position ligand derivative, characterized in that: The structure of the quinolinone binary ligand derivative is shown in formula (1) or formula (2): ， Formula (1) ， Formula (2) The LINKER fragment is one of the following structural formulas: ， m is 1 or 2, n is an integer from 1 to 4; R is one of the following structural formulas: ； X is one of NH, CH2, O and S.

2. The quinolinone dual-position ligand derivative according to claim 1, characterized in that: LINKER is one of the following structural formulas: ； The R group is One of the following; X is NH.

3. The quinolinone dual-position ligand derivative according to claim 1 or 2, characterized in that: The structure of the quinolinone binary ligand derivative is one of the following structural formulas: 。 4. The use of the quinolinone dual-position ligand derivative according to any one of claims 1 to 3, characterized in that: The invention relates to an application of the quinolinone dual-position ligand derivative in the preparation of dopamine D2R agonist drugs.

5. The use of the quinolinone dual-position ligand derivative according to any one of claims 1 to 3, characterized in that: The invention relates to an application of the quinolinone dual-position ligand derivative in the preparation of a drug for treating dopamine D2R-related diseases.

6. The use of the quinolinone dual-position ligand derivative according to claim 5, characterized in that: The dopamine D2R-related diseases include Parkinson's disease, restless legs syndrome, hyperprolactinemia, prolactinoma, acromegaly, central emesis, and erectile dysfunction.

7. A pharmaceutical composition, characterized in that: The invention comprises the quinolinone dual-position ligand derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form or metabolite thereof, or a pharmaceutically acceptable carrier or excipient thereof.

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