Peptidyl nitrile compound, preparation method therefor and use thereof

Abstract

Provided in the present application are a peptidyl nitrile compound, a preparation method therefor and the use thereof. The peptidyl nitrile compound of the present application has a structure represented by formula (I): wherein the definitions of Cy, R1, m, X and R are as described in the description. The peptidyl nitrile compound of the present application has a strong activity inhibitory effect on DPP1, and can be used as a DPP1 inhibitor.

Description

Peptide nitrile compounds, their preparation methods and uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a peptide-based nitrile compound, its preparation method, and its uses. Background Technology

[0002] Neutrophils play a crucial role in the progression of metastatic cancers and inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), emphysema, asthma, multiple sclerosis, and cystic fibrosis. Their excessive infiltration and uncontrolled activation can lead to the destruction of normal tissue structures and uncontrolled inflammation.

[0003] When activated, neutrophils release neutrophil serine proteases (NSPs), including neutrophil elastase (NE), cathepsin G (Cat-G), and protease 3 (PR3), which endow neutrophils with a potent immune-killing effect. In the extracellular environment, NSPs can degrade bacterial virulence factors. NE in NSPs is also responsible for activating other inflammatory effectors.

[0004] While non-spirin proteases (NSPs) such as norepinephrine (NE) generally play physiological and beneficial roles in the lungs, high levels of these proteases can lead to undesirable problems. NE-dependent structural damage can result in irreversible airway dilation, leading to bronchiectasis. NSPs are produced as zymogens during neutrophil differentiation and are activated before or during the transport of cathepsin C (CTSC, also known as dipeptidyl peptidase 1, DPP1) to granules. Therefore, targeting DPP1 is an important strategy for maintaining NSP functional homeostasis.

[0005] The most advanced DPP1 inhibitor in research is Brensocatib (INS1007), which has met its primary endpoint in a phase III clinical trial for the treatment of bronchiectasis and has been approved for marketing. However, clinical data show that Brensocatib requires a relatively high dosage, increasing the risk of adverse reactions such as periodontal disease and hyperkeratosis. Therefore, there is still significant room for molecular modification and optimization of DPP1 inhibitors to obtain those with better activity and higher bioavailability, thereby reducing dosage and mitigating drug toxicity. Summary of the Invention

[0006] To overcome this deficiency in the prior art, this application provides a peptide-based nitrile compound, its preparation method, and its uses. The peptide-based nitrile compound of this application has an inhibitory effect on DPP1 and can be used as a DPP1-targeting inhibitor. The compound of this application has a strong inhibitory effect on DPP1 and is well absorbed.

[0007] One object of the present invention is to provide a peptide-based nitrile compound.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned peptide nitrile compounds.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described peptide nitrile compounds.

[0010] Another object of the present invention is to provide pharmaceutical uses for the above-mentioned peptide nitrile compounds.

[0011] Another object of the present invention is to provide a method for treating diseases using the above-mentioned peptide-based nitrile compounds.

[0012] The technical solution adopted in this invention is as follows:

[0013] On the one hand, the present invention provides compounds of general formula (I), namely peptide nitrile compounds, or their stereoisomers, tautomers, deuterated derivatives, prodrugs, or pharmaceutically acceptable salts thereof:

[0014] In equation (I) above, the ring Cy is selected from

[0015] X is O, S, CH2 or CD2;

[0016] R is selected from H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl-halogenated C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 epoxy alkyl, 3-8 member heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, phenyl, 3-8 member heteroaryl containing 1-3 heteroatoms selected from N, O, S, hydroxyl, acyl, wherein the C1- C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl-halogenated C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 epoxy alkyl, 3-8 heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S, phenyl, 3-8 heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, hydroxyl, acyl groups can each be independently surrounded by 0, 1, 2, 3, or 4 R groups. a replace;

[0017] Each R aThe same or different, and each independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -O(C3-C8 epoxyalkyl), 3-8 member heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, bridged cycloalkyl containing 1-3 heteroatoms selected from N, O, S, 3-8 member spirocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, 5-6 member heteroaryl, phenyl, cyano, hydroxyl, mercapto, -NR'R”, And halogens (e.g., F, Cl, Br, I);

[0018] R' and R" are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to.

[0019] Each R 1 The same or different, and each independently selected from H, deuterium, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxyl, cyano, amino, and mercapto, wherein the C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -O(C1-C6 alkyl), and -O(C3-C6 cycloalkyl) are optionally substituted by 0, 1, 2, or 3 deuterium, halogen (e.g., F, Cl, Br, I), hydroxyl, cyano, amino, or mercapto groups;

[0020] m can be 0, 1, 2, or 3.

[0021] Preferably, R is selected from H, C1-C4 alkyl, C1-C4 alkyl halo-C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkoxy, C1-C4 alkyl-C3-C6 cycloalkyl, phenyl, 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, and hydroxyl, wherein the C1-C4 alkyl, C1-C4 alkyl halo-C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkoxy, C1-C4 alkyl-C3-C6 cycloalkyl, and phenyl can each be independently separated by 0 or 1 R. a replace;

[0022] Preferably, R is selected from H, C2-C3 alkyl, C2-C3 alkyl halo-C2-C3 alkyl, C2-C3 alkyl-C2-C3 alkoxy, C2-C3 alkyl-C3-C6 cycloalkyl, phenyl, thiazolyl, oxazolyl, hydroxyl, and acyl, wherein the C2-C3 alkyl, C2-C3 alkyl halo-C2-C3 alkyl, C2-C3 alkyl-C2-C3 alkoxy, C2-C3 alkyl-C3-C6 cycloalkyl, and phenyl can each be independently separated by 0 or 1 R. a replace;

[0023] Preferably, R is selected from H,

[0024] Preferably, R a Each is independently selected from H, deuterium, -NR'R", C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C4 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). 5-6 nucleotides containing 1-3 heteroaryl, phenyl, cyano, or hydroxyl groups selected from N, O, or S heteroatoms. And halogens (e.g., F, Cl, Br, I);

[0025] Preferably, R a Each is independently selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C3 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I).

[0026] Preferably, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to.

[0027] Preferably, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to.

[0028] Preferably, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-5 membered heterocycle with the N atom they are attached to.

[0029] Preferably, each R 1They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups;

[0030] Preferably, each R 1 They may be the same or different, and each is independently selected from H, deuterium, and halogens (e.g., F, Cl, Br, I);

[0031] Preferably, m is 1, 2, or 3;

[0032] In one specific implementation, the Cy ring is selected from...

[0033] X is O, S, CH2 or CD2;

[0034] R is selected from H,

[0035] R a Selected from H, deuterium, -NR'R", C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C4 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). 5-6 nucleotides containing 1-3 heteroaryl, phenyl, cyano, or hydroxyl groups selected from N, O, or S heteroatoms. And halogens (e.g., F, Cl, Br, I);

[0036] R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to;

[0037] Each R 1 They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups;

[0038] m can be 1, 2, or 3.

[0039] In another preferred embodiment, the cyclone Cy is selected from...

[0040] X is O, S, CH2 or CD2;

[0041] R is selected from H,

[0042] R a Selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O(C1-C3 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I);

[0043] R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to;

[0044] Each R 1 They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups;

[0045] m can be 1, 2, or 3.

[0046] In yet another preferred technical solution, the cyclone Cy is selected from...

[0047] X is O, S, CH2 or CD2;

[0048] R is selected from H,

[0049] R a Each is independently selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O(C1-C3 alkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I);

[0050] R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to;

[0051] Each R 1 They may be the same or different, and each is independently selected from H, deuterium, and halogens (e.g., F, Cl, Br, I);

[0052] m can be 1, 2, or 3.

[0053] In a particularly preferred embodiment, R is selected from H, -CH3, -CH2CH2-O-CH2CH3, ...

[0054] Each R 1 They may be the same or different, and each is independently selected from H, halogens (e.g., F, Cl, Br, I);

[0055] m can be 1, 2, or 3.

[0056] In a specific technical solution, the compound represented by general formula (I) is selected from:

[0057] On the other hand, the compounds of the present invention, as shown in general formula (I), can be prepared using commercially available chemical raw materials and chemical synthesis methods known in the art. In one specific embodiment, the preparation method of compound 1 of the present invention is shown in the following figure:

[0058] For the preparation methods of other specific compounds of the present invention, please refer to the Examples section.

[0059] In another aspect, the present invention provides a pharmaceutical composition comprising at least a therapeutically effective amount of the above-described compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0060] In another aspect, the present invention provides the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of cathepsin C-related conditions.

[0061] Preferably, the cathepsin C-related conditions are selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, lower respiratory tract infection, chronic sinusitis, eosinophilic sinusitis, nasal polyps, hidradenitis suppurativa, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis), psoriasis, antitrypsin A deficiency, lupus nephritis, diabetes, inflammatory bowel disease, and rheumatoid arthritis.

[0062] In another aspect, the present invention provides a method for preventing and / or treating conditions related to cathepsin C, the method comprising administering to a patient in need a therapeutically effective amount of the above-mentioned compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0063] Preferably, the cathepsin C-related conditions are selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, lower respiratory tract infection, chronic sinusitis, eosinophilic sinusitis, nasal polyps, hidradenitis suppurativa, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis), psoriasis, antitrypsin A deficiency, lupus nephritis, diabetes, inflammatory bowel disease, and rheumatoid arthritis.

[0064] Compared with the prior art, the compound provided by the present invention has better inhibitory effect on cathepsin C (DPP1) activity, better inhibitory effect on neutrophil elastase (NE) activity in cells, and has the advantage of higher bioavailability. Detailed Implementation

[0065] The present invention will be further described below with reference to embodiments. These embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention.

[0066] Example 1: Synthesis of Compound 1

[0067] The synthetic route of compound 1 is shown in the figure below.

[0068] The specific synthesis method is as follows:

[0069] Synthesis of intermediates 1-2

[0070] Ingredient 1-1 (1.00 g, 5.39 mmol) and cesium carbonate (7.03 g, 21.58 mmol) were added to DMF (30 mL), and iodomethane (1.15 g, 8.10 mmol) was added dropwise while stirring. The reaction system was stirred at 50 °C for 3 hours. After the reaction was completed, purified water (200 mL) was added, and the mixture was extracted three times (50 mL * 3) with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 30:1) to obtain intermediate 1-2 (0.90 g, 4.51 mmol), yield: 83.6%.

[0071] MS m / z(ESI): 200.0 [M+H] + .

[0072] Synthesis of intermediates 1-3

[0073] Intermediate 1-2 (0.30 g, 1.50 mmol), B2Pin2 (0.77 g, 3.02 mmol), potassium acetate (0.44 g, 4.48 mmol), Xphos (71 mg, 0.15 mmol), and palladium acetate (17 mg, 0.075 mmol) were added to 1,4-dioxane (10 mL). The reaction system was stirred at 90 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, purified water (20 mL) was added, and the mixture was extracted three times with EA (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 4:1) to obtain intermediate 1-3 (50 mg, 0.17 mmol), yield: 11.3%.

[0074] MS m / z(ESI): 292.2 [M+H] + .

[0075] Synthesis of intermediates 1-5

[0076] Raw materials 1-4 (5.00 g, 14.57 mmol) were dissolved in anhydrous acetonitrile (50 mL), and TsOH (5.03 g, 29.2 mmol) was added. The mixture was stirred at 20-25 °C for 2 hours. After the reaction was complete, DCM (50 mL) and purified water (50 mL) were added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with DCM (100 mL * 2). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain crude intermediate 1-5 (4.35 g, 17.90 mmol), yield: 122.9%.

[0077] MS m / z(ESI): 243.0 [M+H] + .

[0078] Synthesis of intermediates 1-7

[0079] Crude intermediates 1-5 (4.35 g, 17.90 mmol) were dissolved in DCM (75 mL). Starting materials 1-6 (4.53 g, 18.47 mmol), HATU (10.57 g, 27.80 mmol), and DIPEA (7.21 g, 55.7 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, purified water (75 mL) was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with DCM (20 mL * 2). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography (DCM:MeOH = 99:1) to obtain intermediates 1-7 (3.34 g, 7.10 mmol), yield: 39.7%.

[0080] MS m / z (ESI): 414.1 [M+H-56] + .

[0081] Synthesis of intermediates 1-8

[0082] Intermediate 1-3 (50 mg, 0.17 mmol), intermediate 1-7 (80 mg, 0.17 mmol), potassium acetate (50 mg, 0.51 mmol), and Pd(OAc)₂(PPh₃)₂ (13 mg, 0.017 mmol) were added to 1,4-dioxane (5 mL). The reaction system was stirred at 90 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, purified water (20 mL) was added, and the mixture was extracted three times with EA (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain intermediate 1-8 (50 mg, 0.09 mmol), yield: 52.9%.

[0083] MS m / z(ESI): 499.2 [M+H-56] + .

[0084] Synthesis of Compound 1

[0085] Intermediate 1-8 (50 mg, 0.09 mmol) was dissolved in anhydrous acetonitrile (5 mL), and TsOH (46 mg, 0.27 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified to give compound 1 (4 mg, 0.009 mmol), yield: 9.8%.

[0086] MS m / z (ESI): 455.2 [M+H] + .

[0087] 1 H NMR (400MHz, DMSO-d6) δ8.82–8.72(m,1H),8.21(s,1H),7.75(d,J=8.1Hz,1H),7.70–7.54(m,4H),7.48(d,J=8.0Hz,1H ),5.06(d,J=8.1Hz,1H),4.12–3.67(m,4H),3.50(s,3H),3.34–3.06(m,4H),2.84(dd,J=12.8,6.1Hz,1H),1.79(s,2H).

[0088] Example 2: Synthesis of Compound 2

[0089] The synthetic route of compound 2 is shown in the figure below.

[0090] The specific synthesis method is as follows:

[0091] Synthesis of intermediates 2-3

[0092] Add raw material 2-1 (300 mg, 1.40 mmol) and potassium carbonate (390 mg, 2.82 mmol) to DMF (3 mL), cool to 0-5 °C, and add 2-2 (490 mg, 2.11 mmol). Stir the reaction system at room temperature for 1 hour. After the reaction is complete, add purified water (20 mL), extract three times with DCM (10 mL * 3), combine the organic phases, wash with saturated brine and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain crude product, and purify by column chromatography (PE:EA = 10:1) to obtain intermediate 2-3 (370 mg, 1.25 mmol), yield: 89.3%.

[0093] 1 H NMR (500MHz, CDCl3) δ7.35 (dd, J=8.5, 1.9Hz, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 4.41 (q, J=8.4Hz, 2H).

[0094] Synthesis of intermediates 2-4

[0095] Intermediate 2-3 (370 mg, 1.25 mmol), B2Pin2 (381 mg, 1.50 mmol), potassium acetate (369 mg, 3.76 mmol), and Pd(dppf)Cl2 (91 mg, 0.125 mmol) were added to 1,4-dioxane (10 mL). The reaction system was stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was completed, purified water (30 mL) was added, and the mixture was extracted three times with EA (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain intermediate 2-4 (329 mg, 0.96 mmol), yield: 76.8%.

[0096] 1 H NMR (500MHz, CDCl3) δ7.67(dd,J=8.0,0.8Hz,1H),7.46(s,1H),7.24(d,J=8.0Hz,1H),4.46–4.39(m,2H),1.26(s,12H).

[0097] Synthesis of intermediates 2-5

[0098] Intermediate 2-4 (100 mg, 0.29 mmol), intermediate 1-7 (137 mg, 0.29 mmol), potassium carbonate (80 mg, 0.58 mmol), and Pd(dppf)Cl2 (21 mg, 0.029 mmol) were added to 1,4-dioxane (5 mL). The reaction system was stirred at 90 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, purified water (20 mL) was added, and the mixture was extracted three times with EA (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain intermediate 2-5 (85 mg, 0.14 mmol), yield: 48.3%.

[0099] 1 H NMR (500MHz, CDCl3) δ7.41 (dd, J=14.6, 7.2Hz, 2H), 7.35 (t, J=6.0Hz, 2H), 7.3 1(s,1H),7.23(s,1H),7.17(s,1H),5.26–5.11(m,1H),4.49(q,J=8.4Hz,2H), 4.14(dt,J=30.2,18.4Hz,3H),3.82–3.64(m,1H),3.56(t,J=12.3Hz,1H),3.5 0–3.38(m,1H),3.26(dd,J=20.6,10.3Hz,3H),2.03–1.88(m,2H),1.48(s,9H).

[0100] Synthesis of Compound 2

[0101] The synthesis method of compound 2 is the same as that of compound 1, with a yield of 51.2%.

[0102] MS m / z (ESI): 507.2 [M+H] + .

[0103] 1H NMR (500MHz, CDCl3) δ7.43(t,J=7.8Hz,1H),7.39(dd,J=8.4,1.5Hz,1H),7.34(d,J=8.3Hz,2H),7.31 –7.29(m,1H),7.28–7.27(m,1H),7.23(s,1H),5.25–5.15(m,1H),4.49(q,J=8.4Hz,2H),4.12(dd,J=7 .0,3.8Hz,1H),4.04(dt,J=12.4,5.0Hz,1H),3.83–3.78(m,1H),3.77–3.66(m,2H),3.33(dd,J=14.4, 3.8Hz, 1H), 3.30–3.21 (m, 2H), 3.00–2.95 (m, 1H), 2.94 (d, J = 5.0Hz, 1H), 1.87 (dd, J = 6.5, 3.4Hz, 2H).

[0104] Example 3: Synthesis of Compound 3

[0105] The synthetic route of compound 3 is shown in the figure below.

[0106] The specific synthesis method is as follows:

[0107] Synthesis of intermediate 3-2

[0108] Starting material 2-1 (500 mg, 2.34 mmol), starting material 3-1 (390 mg, 2.81 mmol), and potassium carbonate (969 mg, 7.01 mmol) were added to acetonitrile (10 mL). The reaction system was stirred at 60 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed three times with water (30 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE:EA = 5:1) to obtain intermediate 3-2 (397 mg, 1.46 mmol), yield: 62.4%.

[0109] 1 H NMR (500MHz, CDCl3) δ7.32–7.20 (m, 2H), 7.07 (d, J = 8.4Hz, 1H), 3.99 (t, J = 5.1Hz, 2H), 3.71 (t, J = 5.1Hz, 2H), 3.37 (d, J = 1.2Hz, 3H).

[0110] Synthesis of intermediate 3-3

[0111] The synthesis method of intermediate 3-3 is the same as that of intermediate 2-4, with a yield of 65.5%.

[0112] 1 H NMR(500MHz, CDCl3)δ7.63(dd,J=8.0,1.1Hz,1H),7.49(s,1H),7.22(d,J=8.0H z, 1H), 4.04 (t, J = 5.6Hz, 2H), 3.74 (t, J = 5.5Hz, 2H), 3.37 (s, 3H), 1.38 (s, 12H).

[0113] Synthesis of intermediates 3-4

[0114] The synthesis method of intermediates 3-4 is the same as that of intermediates 2-5, with a yield of 72.5%.

[0115] MS m / z (ESI): 605.3 [M+Na] + .

[0116] Synthesis of Compound 3

[0117] The synthesis method of compound 3 is the same as that of compound 1, with a yield of 68.8%.

[0118] MS m / z (ESI): 483.2 [M+H] + .

[0119] 1 H NMR(500MHz,DMSO-d6)δ8.81(d,J=8.5Hz,1H),7.70(d,J=1.8Hz,1H),7.62–7 .51(m,2H),7.51–7.43(m,2H),7.42(d,J=8.3Hz,1H),5.10–5.01(m,1H),4.1 0(dt,J=22.3,5.1Hz,3H),3.88(m,1H),3.75(m,1H),3.69(t,J=5.3Hz,2H),3 .26(s,3H),3.24–3.13(m,2H),2.91(m,1H),2.79–2.64(m,2H),1.80(m,2H).

[0120] Example 4: Synthesis of Compound 4

[0121] The synthetic route of compound 4 is shown in the figure below.

[0122] The specific synthesis method is as follows:

[0123] Synthesis of intermediate 4-1

[0124] The synthesis method of intermediate 4-1 is the same as that of intermediate 1-2, with a yield of 88.4%.

[0125] 1 H NMR (500MHz, CDCl3) δ7.30–7.10 (m, 3H), 3.90 (d, J = 7.3Hz, 2H), 1.41 (t, J = 7.3Hz, 3H).

[0126] Synthesis of intermediate 4-2

[0127] The synthesis method of intermediate 4-2 is the same as that of intermediate 2-4, with a yield of 55.8%.

[0128] MS m / z(ESI): 290.1 ​​[M+H] + .

[0129] Synthesis of intermediate 4-3

[0130] The synthesis method of intermediate 4-3 is the same as that of intermediate 2-5, with a yield of 87.5%.

[0131] 1 H NMR (500MHz, CDCl3) δ7.44–7.33(m,2H),7.33–7.28(m,3H),7.25–7.10(m,2H),5.20(dd,J=15.0,7.8Hz,1H),4.23–4.06(m,3H),3.96(q,J=7.2Hz,2 H),3.77(d,J=11.9Hz,1H),3.55(dd,J=24.3,15.5Hz,2H),3.25(dd,J=20. 9, 10.8Hz, 3H), 1.96 (s, 2H), 1.48 (d, J = 6.3Hz, 9H), 1.44 (t, J = 7.2Hz, 3H).

[0132] Synthesis of Compound 4

[0133] The synthesis method of compound 4 is the same as that of compound 1, with a yield of 43.9%.

[0134] MS m / z (ESI): 453.2 [M+H] + .

[0135] 1H NMR(500MHz, CDCl3)δ7.42(t,J=7.8Hz,1H),7.36(dd,J=8.0,1.4Hz,1H),7.33–7.28(m,4H),7.15(s,1H), 5.21(dd,J=15.8,7.1Hz,1H),4.11(dd,J=7.0,3.8Hz,1H),4.04(dt,J=12.3,5.0Hz,1H),3.97(q,J=7.2Hz ,2H),3.79(ddd,J=12.4,8.6,3.8Hz,1H),3.67(d,J=6.2Hz,1H),3.35(ddd,J=30.3,14.4,3.8Hz,1H),3.3 0–3.20(m,2H),3.01–2.92(m,2H),2.90(dd,J=7.9,5.3Hz,1H),1.96–1.80(m,2H),1.44(t,J=7.2Hz,3H).

[0136] Example 5: Synthesis of Compound 5

[0137] The synthetic route of compound 5 is shown in the figure below.

[0138] The specific synthesis method is as follows:

[0139] Synthesis of intermediate 5-1

[0140] The synthesis method of intermediate 5-1 is the same as that of intermediate 1-2, with a yield of 93.1%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.23(d,J=1.7Hz,1H),7.17(d,J=1.6Hz,1H),7.08(d,J=8.4Hz,1H),3.68 (d,J=7.1Hz,2H),1.23(ddd,J=12.6,7.5,4.8Hz,1H),0.65–0.59(m,2H),0.44(q,J=5.1Hz,2H).

[0142] Synthesis of intermediate 5-2

[0143] The synthesis method of intermediate 5-2 is the same as that of intermediate 2-4, with a yield of 76.6%.

[0144] MS m / z (ESI): 316.2 [M+H] + .

[0145] Synthesis of intermediate 5-3

[0146] The synthesis method of intermediate 5-3 is the same as that of intermediate 2-5, with a yield of 63.7%.

[0147] 1 H NMR (500MHz, CDCl3) δ7.41–7.33(m,2H),7.31–7.27(m,3H),7.18(s,1H),5.17(s,1H),4.12(dd,J=14.3,7.2Hz,2H),3.76(d,J=7.1Hz,2H),3.5 4(s,2H),3.21(d,J=6.8Hz,2H),2.85(s,2H),1.99(d,J=5.4Hz,2H),1. 46(s,9H),1.35–1.23(m,3H),0.65–0.61(m,2H),0.48(t,J=5.1Hz,2H).

[0148] Synthesis of Compound 5

[0149] The synthesis method of compound 5 is the same as that of compound 1, with a yield of 45.3%.

[0150] MS m / z (ESI): 479.2 [M+H] + .

[0151] 1 H NMR(500MHz, CDCl3)δ7.42(t,J=7.8Hz,1H),7.38–7.35(m,1H),7.31(dd,J=6.1,4. 7Hz,4H),7.20(s,1H),5.21(dd,J=15.7,7.1Hz,1H),4.17–4.10(m,1H),4.09–4.01 (m,1H),3.67(d,J=6.6Hz,3H),3.31–3.21(m,3H),3.02–2.96(m,3H),2.95–2.91(m ,1H),1.97–1.87(m,2H),1.29(s,1H),0.65(q,J=5.7Hz,2H),0.50(q,J=5.1Hz,2H).

[0152] Example 6: Synthesis of Compound 6

[0153] The synthetic route for compound 6 is shown in the figure below.

[0154] The specific synthesis method is as follows:

[0155] Synthesis of intermediate 6-1

[0156] The synthesis method of intermediate 6-1 is the same as that of intermediate 1-2, with a yield of 67.4%.

[0157] MS m / z(ESI): 272.0 [M+H] + .

[0158] Synthesis of intermediate 6-2

[0159] The synthesis method of intermediate 6-2 is the same as that of intermediate 2-4, with a yield of 73.9%.

[0160] MS m / z (ESI): 320.2 [M+H] + .

[0161] 1 H NMR (500MHz, CDCl3) δ7.63 (dd, J=8.0, 1.1Hz, 1H), 7.48 (d, J=1.2Hz, 1H), 7.22 (d, J= 8.0Hz, 1H), 4.04 (t, J = 5.6Hz, 2H), 3.73 (t, J = 5.6Hz, 2H), 3.37 (s, 3H), 1.38 (s, 12H).

[0162] Synthesis of intermediate 6-4

[0163] The synthesis method of intermediate 6-4 is the same as that of intermediate 1-7, with a yield of 46.5%.

[0164] MS m / z (ESI): 466.1 [M+H] + .

[0165] Synthesis of intermediate 6-5

[0166] The synthesis method of intermediate 6-5 is the same as that of intermediate 2-5, with a yield of 60.7%.

[0167] MS m / z (ESI): 601.3 [M+Na] + .

[0168] Synthesis of Compound 6

[0169] The synthesis method of compound 6 is the same as that of compound 1, with a yield of 63.8%.

[0170] MS m / z (ESI): 479.2 [M+H] + .

[0171] 1H NMR(500MHz, CDCl3)δ8.83(s,1H),7.41(t,J=7.7Hz,1H),7.38–7.33(m,1H),7.30(d,J=3.6Hz,2H),7.28–7.24(m,2H),5.09(q,J=7.5Hz,1H), 4.07(t,J=5.2Hz,2H),3.75(t,J=5.2Hz,3H),3.37(d,J=1.1Hz,3H),3.28(d,J=7.6Hz,2H),2.79(s,1H),1.81–1.65(m,4H),1.50–1.13(m,3H).

[0172] Example 7: Synthesis of Compound 7

[0173] The synthetic route of compound 7 is shown in the figure below.

[0174] The specific synthesis method is as follows:

[0175] Synthesis of intermediate 7-2

[0176] The synthesis method of intermediate 7-2 is the same as that of intermediate 3-2, with a yield of 73.9%.

[0177] 1 H NMR (500MHz, CDCl3) δ7.38 (d, J = 1.4 Hz, 1H), 7.29 (dd, J = 4.5, 2.7 Hz, 2H), 4.12 (dd, J = 6.1, 5.0 Hz, 2H), 3.70 (m, 2H), 3.36 (d, J = 1.0 Hz, 3H).

[0178] Synthesis of intermediate 7-3

[0179] The synthesis method of intermediate 7-3 is the same as that of intermediate 2-4, with a yield of 67.4%.

[0180] 1 H NMR(500MHz, CDCl3)δ7.62(dd,J=7.8,1.1Hz,1H),7.55(s,1H),7.45(d,J=7.7H z, 1H), 4.20 (t, J = 5.9Hz, 2H), 3.72 (t, J = 5.9Hz, 2H), 3.38 (s, 3H), 1.38 (s, 12H).

[0181] Synthesis of intermediate 7-4

[0182] The synthesis method of intermediate 7-4 is the same as that of intermediate 2-5, with a yield of 56.1%.

[0183] MS m / z (ESI): 621.3 [M+Na] + .

[0184] Synthesis of Compound 7

[0185] The synthesis method of compound 7 is the same as that of compound 1, with a yield of 69.6%.

[0186] MS m / z (ESI): 499.2 [M+H] + .

[0187] 1 H NMR(500MHz, CDCl3)δ7.50(d,J=8.1Hz,1H),7.47–7.30(m,5H),5.22(q,J=7.3Hz,1H),4.21(t,J=5.4Hz,2H) ,4.12(dd,J=7.0,3.9Hz,1H),4.04(m,1H),3.83–3.72(m,3H),3.39–3.20(m,6H),2.94(m,3H),1.88(m,2H).

[0188] Example 8: Synthesis of Compound 8

[0189] The synthetic route of compound 8 is shown in the figure below.

[0190] The specific synthesis method is as follows:

[0191] Synthesis of intermediate 8-3

[0192] The synthesis method of intermediate 8-3 is the same as that of intermediate 2-3, with a yield of 90.0%.

[0193] MS m / z(ESI): 234.0 [M+H] + .

[0194] Synthesis of intermediate 8-4

[0195] The synthesis method of intermediate 8-4 is the same as that of intermediate 1-3, with a yield of 54.8%.

[0196] MS m / z(ESI): 326.2 [M+H] + .

[0197] Synthesis of intermediate 8-5

[0198] The synthesis method of intermediate 8-5 is the same as that of intermediate 2-5, with a yield of 56.1%.

[0199] MS m / z (ESI): 533.2 [M+H-56] +.

[0200] Synthesis of Compound 8

[0201] The synthesis method of compound 8 is the same as that of compound 1, with a yield of 16.0%.

[0202] MS m / z (ESI): 489.2 [M+H] + .

[0203] 1 H NMR (400MHz, DMSO-d6) δ8.80–8.78(m,1H),7.77(s,1H),7.59–7.44(m,6H),5.09–5.02(m,1H),4.44–4.36(m,2H),4.11–4 .08(m,1H),3.90–3.84(m,1H),3.77–3.71(m,1H),3.22–3.12(m,4H),2.91–2.85(m,1H),2.75–2.63(m,2H),1.78(s,2H).

[0204] Example 9: Synthesis of Compound 9

[0205] The synthetic route of compound 9 is shown in the figure below.

[0206] The specific synthesis method is as follows:

[0207] Synthesis of intermediate 9-1

[0208] The synthesis method of intermediate 9-1 is the same as that of intermediate 1-2, with a yield of 76.0%.

[0209] MS m / z(ESI): 223.0 [M+H] + .

[0210] Synthesis of intermediate 9-2

[0211] The synthesis method of intermediate 9-2 is the same as that of intermediate 1-3, with a yield of 47.4%.

[0212] MS m / z (ESI): 315.1 [M+H] + .

[0213] Synthesis of intermediate 9-3

[0214] The synthesis method of intermediate 9-3 is the same as that of intermediates 1-8, with a yield of 66.1%.

[0215] MS m / z(ESI): 522.2 [M+H-56] + .

[0216] Synthesis of Compound 9

[0217] The synthesis method of compound 9 is the same as that of compound 1, with a yield of 6.7%.

[0218] MS m / z (ESI): 478.2 [M+H] + .

[0219] 1 H NMR(400MHz,DMSO-d6)δppm 8.79(d,J=8.5Hz,1H),8.19(s,1H),7.84(d,J=1.5Hz,1H),7.67–7.42(m,5H),5.06(dd,J=16.3,8.2Hz,1H),4.21(t,J=6.6Hz,2H),4.10(dd,J=8 .4,3.5Hz,1H),3.94–3.82(m,2H),3.79–3.68(m,2H),3.31(dd,J=13.7, 7.6Hz, 2H), 3.24–3.15 (m, 2H), 3.09 (t, J = 6.6Hz, 2H), 1.84–1.74 (m, 2H).

[0220] Example 10: Synthesis of Compound 10

[0221] The synthetic route of compound 10 is shown in the figure below.

[0222] The specific synthesis method is as follows:

[0223] Synthesis of intermediate 10-2

[0224] Starting materials 8-1 (1.71 g, 10.08 mmol) and 10-1 (3.69 g, 30.11 mmol) were dissolved in tetrahydrofuran (45 mL), and potassium tert-butoxide (2.28 g, 20.32 mmol) was added. The reaction system was stirred at 80 °C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and saturated brine (80 mL) was added. The mixture was extracted three times with EA (40 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then slurried with EA (10 mL), filtered, and the filter cake was dried at 40 °C to obtain intermediate 10-2 (1.22 g, 4.77 mmol), yield: 47.3%.

[0225] MS m / z(ESI): 256.1 [M+H] + .

[0226] Synthesis of intermediate 10-3

[0227] The synthesis method of intermediate 10-3 is the same as that of intermediate 1-3, with a yield of 40.5%.

[0228] MS m / z (ESI): 348.2 [M+H] + .

[0229] Synthesis of intermediate 10-4

[0230] The synthesis method of intermediate 10-4 is the same as that of intermediate 2-5, with a yield of 52.3%.

[0231] MS m / z (ESI): 611.3 [M+H] + .

[0232] Synthesis of Compound 10

[0233] The synthesis method of compound 10 is the same as that of compound 1, with a yield of 10.3%.

[0234] MS m / z (ESI): 511.2 [M+H] + .

[0235] 1 H NMR(400MHz,DMSO-d6)δ9.11–9.05(m,1H),7.60–7.53(m,2H),7.49–7.39(m,5 H),7.11(d,J=8.0Hz,2H),6.18–6.14(m,1H),5.53–5.50(m,1H),5.09–4.99(m, 1H),4.45–4.40(m,1H),3.96–3.88(m,2H),3.82–3.74(m,1H),3.52–3.48(m,1H ),3.24–3.11(m,3H),3.01–2.94(m,1H),2.33–2.29(m,3H),2.01–1.98(m,2H).

[0236] Example 11: Synthesis of Compound 11

[0237] The synthetic route of compound 11 is shown in the figure below.

[0238] The specific synthesis method is as follows:

[0239] Synthesis of intermediate 11-2

[0240] The synthesis method of intermediate 11-2 is the same as that of intermediate 1-2, with a yield of 25.8%.

[0241] MS m / z(ESI): 283.0 [M+H] + .

[0242] Synthesis of intermediate 11-3

[0243] The synthesis method of intermediate 11-3 is the same as that of intermediate 2-4, with a yield of 55.8%.

[0244] MS m / z(ESI): 331.2 [M+H] + .

[0245] Synthesis of intermediate 11-4

[0246] The synthesis method of intermediate 11-4 is the same as that of intermediate 2-5, with a yield of 46.9%.

[0247] MS m / z (ESI): 538.3 [M+H-56] + .

[0248] Synthesis of Compound 11

[0249] The synthesis method of compound 11 is the same as that of compound 1, with a yield of 31.1%.

[0250] MS m / z (ESI): 494.3 [M+H] + .

[0251] 1 H NMR (500MHz, CDCl3) δ7.50–7.37 (m, 4H), 7.28 (d, J = 9.6Hz, 2H), 7.20 (s, 1H), 5. 20(dd,J=15.4,7.2Hz,1H),4.14–4.03(m,2H),4.01–3.93(m,2H),3.78(d,J=7. 4Hz,1H),3.72(s,1H),3.66(s,2H),3.33–3.20(m,3H),2.95(dd,J=14.0,7.1Hz ,2H),2.93–2.90(m,1H),2.38(s,6H),2.27(t,J=6.4Hz,2H),2.07–1.88(m,2H).

[0252] Example 12: Synthesis of Compound 12

[0253] The synthetic route of compound 12 is shown in the figure below.

[0254] The specific synthesis method is as follows:

[0255] Synthesis of intermediate 12-1

[0256] Starting material 11-1 (1.06 g, 5.00 mmol) and silver trifluoromethanesulfonate (64 mg, 0.25 mmol) were added to heavy water (50 mL). The reaction system was stirred at 90 °C for 18 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with EA (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 12-1 (0.90 g, 4.20 mmol), yield: 84.0%.

[0257] MS m / z(ESI): 214.0 [M+H] + .

[0258] Synthesis of intermediate 12-2

[0259] The synthesis method of intermediate 12-2 is the same as that of intermediate 1-2, with a yield of 22.7%.

[0260] MS m / z(ESI): 285.0 [M+H] + .

[0261] Synthesis of intermediate 12-3

[0262] The synthesis method of intermediate 12-3 is the same as that of intermediate 2-4, with a yield of 46.6%.

[0263] MS m / z(ESI): 333.2 [M+H] + .

[0264] Synthesis of intermediate 12-4

[0265] The synthesis method of intermediate 12-4 is the same as that of intermediate 2-5, with a yield of 36.6%.

[0266] MS m / z (ESI): 540.3 [M+H-56] + .

[0267] Synthesis of Compound 12

[0268] The synthesis method of compound 12 is the same as that of compound 1, with a yield of 42.6%.

[0269] MS m / z (ESI): 496.3 [M+H] + .

[0270] 1H NMR (500MHz, CDCl3) δ7.51–7.37 (m, 4H), 7.28 (d, J = 9.6Hz, 2H), 7.21 (s, 1H) ,5.21(dd,J=15.0,7.1Hz,1H),4.14–4.04(m,2H),4.00–3.93(m,2H),3.77(d ,J=7.3Hz,1H),3.71(s,1H),3.33–3.21(m,3H),2.95(dd,J=14.0,7.0Hz,2H ),2.94–2.89(m,1H),2.39(s,6H),2.25(t,J=6.5Hz,2H),2.07–1.88(m,2H).

[0271] Example 13: Synthesis of Compound 13

[0272] The synthetic route of compound 13 is shown in the figure below.

[0273] The specific synthesis method is as follows:

[0274] Synthesis of intermediate 13-2

[0275] Starting material 13-1 (1.03 g, 5.00 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL), and CDI (0.89 g, 5.49 mmol) was added. The reaction system was stirred at 60 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and washed successively with 2M HCl (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 13-2 (0.65 g, 2.80 mmol), yield: 56.0%.

[0276] MS m / z(ESI): 232.0 [M+H] + .

[0277] Synthesis of intermediate 13-3

[0278] The synthesis method of intermediate 13-3 is the same as that of intermediate 1-2, with a yield of 42.6%.

[0279] MS m / z(ESI): 303.0 [M+H] + .

[0280] Synthesis of intermediate 13-4

[0281] The synthesis method of intermediate 13-4 is the same as that of intermediate 2-4, with a yield of 66.5%.

[0282] MS m / z (ESI): 351.2 [M+H] + .

[0283] Synthesis of intermediate 13-5

[0284] The synthesis method of intermediate 13-5 is the same as that of intermediate 2-5, with a yield of 62.7%.

[0285] MS m / z (ESI): 636.3 [M+Na] + .

[0286] Synthesis of Compound 13

[0287] The synthesis method of compound 13 is the same as that of compound 1, with a yield of 18.8%.

[0288] MS m / z (ESI): 514.2 [M+H] + .

[0289] 1 H NMR (500MHz, CDCl3) δ7.44(t,J=7.5Hz,1H),7.37(d,J=8.0Hz,1H),7.34(s, 3H),7.30–7.28(m,1H),5.23(dd,J=15.2,8.0Hz,1H),4.18–4.11(m,1H),4.0 5(dt,J=12.3,5.3Hz,3H),3.85–3.76(m,1H),3.62(s,1H),3.38–3.21(m,3H ),3.06–2.87(m,3H),2.75(t,J=6.2Hz,2H),2.37(s,6H),1.94–1.86(m,2H).

[0290] Example 14: Synthesis of Compound 14

[0291] The synthetic route of compound 14 is shown in the figure below.

[0292] The specific synthesis method is as follows:

[0293] Synthesis of intermediate 14-2

[0294] The synthesis method of intermediate 14-2 is the same as that of intermediate 1-2, with a yield of 42.8%.

[0295] MS m / z(ESI): 301.0 [M+H] + .

[0296] Synthesis of intermediate 14-3

[0297] The synthesis method of intermediate 14-3 is the same as that of intermediate 2-4, with a yield of 47.6%.

[0298] MS m / z (ESI): 349.2 [M+H] + .

[0299] Synthesis of intermediate 14-4

[0300] The synthesis method of intermediate 14-4 is the same as that of intermediate 2-5, with a yield of 39.3%.

[0301] MS m / z(ESI): 512.3 [M+H-100] + .

[0302] Synthesis of Compound 14

[0303] The synthesis method of compound 14 is the same as that of compound 1, with a yield of 17.7%.

[0304] MS m / z (ESI): 512.3 [M+H] + .

[0305] 1 H NMR(500MHz, CDCl3)δ7.48(d,J=7.5Hz,1H),7.37–7.34(m,3H),7.30–7.28(m,2H),5.22(dd,J=15.2,7.6Hz,1H),4.14–4.00(m,4H), 3.80–3.75(m,1H),3.66–3.64(m,3H),3.34–3.20(m,3H),3.03–2.87(m,3H),2.75(t,J=6.4Hz,2H),2.35(s,6H),1.94–1.86(m,2H).

[0306] Example 15: Synthesis of Compound 15

[0307] The synthetic route of compound 15 is shown in the figure below.

[0308] The specific synthesis method is as follows:

[0309] Synthesis of intermediate 15-1

[0310] Intermediate 2-1 (8.94 g, 41.77 mmol) was dissolved in DMF (55 mL), cooled to 10 °C, and 1,2-dibromoethane (10.00 g, 53.23 mmol) and potassium carbonate (41.05 g, 297.03 mmol) were added. The reaction mixture was stirred at 20-25 °C for 16 hours. After the reaction was complete, 275 mL of purified water was added, and the mixture was extracted three times (75 mL * 3) with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain intermediate 15-1 (7.78 g, 24.24 mmol), yield: 58.0%.

[0311] MS m / z (ESI): 319.9 [M+H] + .

[0312] Synthesis of intermediate 15-2

[0313] The starting material 15-1 (7.78 g, 24.24 mmol) was dissolved in DMF (20 mL), cooled to 10 °C, and then aziridine (18.36 g, 321.54 mmol) and potassium carbonate (13.51 g, 97.76 mmol) were added. The reaction system was stirred at 20-25 °C for 3 hours. After the reaction was completed, 100 mL of purified water was added, and the mixture was extracted twice with DCM (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 8:1) to obtain intermediate 15-2 (6.43 g, 21.64 mmol), yield: 89.3%.

[0314] MS m / z(ESI): 297.0 [M+H] + .

[0315] Synthesis of intermediate 15-3

[0316] The synthesis method of intermediate 15-3 is the same as that of intermediate 1-3, with a yield of 84.8%.

[0317] MS m / z (ESI): 345.2 [M+H] + .

[0318] Synthesis of intermediate 15-4

[0319] The synthesis method of intermediate 15-4 is the same as that of intermediate 2-5, with a yield of 64.3%.

[0320] MS m / z (ESI): 552.3 [M+H-56] + .

[0321] Synthesis of Compound 15

[0322] The synthesis method of compound 15 is the same as that of compound 1, with a yield of 7.5%.

[0323] MS m / z (ESI): 508.2 [M+H] + .

[0324] 1 H NMR(400MHz, DMSO-d6)δ8.80(d,J=8.6Hz,1H),8.26(s,1H),7.70(d,J=2.3Hz,1H),7.45–7.34(m,3 H),7.24(dd,J=8.5,2.3Hz,1H),6.92(d,J=8.4Hz,1H),5.05(t,J=8.2Hz,1H),4.24(dd,J=5.2,3.7 Hz,3H),4.11(dd,J=8.4,3.6Hz,2H),3.94(s,3H),3.77–3.72(m,1H),3.70(s,2H),3.27(d,J=7.5H z,1H),3.17(dd,J=17.9,9.0,4.8Hz,2H),2.97–2.61(m,3H),2.23–2.13(m,2H),1.86–1.73(m,2H).

[0325] Example 16: Synthesis of Compound 16

[0326] The synthetic route of compound 16 is shown in the figure below.

[0327] The specific synthesis method is as follows:

[0328] Synthesis of intermediate 16-1

[0329] The synthesis method of intermediate 16-1 is the same as that of intermediate 1-2, with a yield of 30.0%.

[0330] 1 H NMR (500MHz, CDCl3) δ7.25 (s, 1H), 7.22 (d, J = 6.1Hz, 1H), 7.07 (d, J = 8.4Hz, 1H), 3.96 (t, J = 6.3Hz, 2H), 2.73 (t, J = 6.0Hz, 2H), 2.37 (s, 6H).

[0331] Synthesis of intermediate 16-2

[0332] The synthesis method of intermediate 16-2 is the same as that of intermediate 2-4, with a yield of 73.7%.

[0333] MS m / z(ESI): 333.2 [M+H] + .

[0334] Synthesis of intermediate 16-3

[0335] The synthesis method of intermediate 16-3 is the same as that of intermediate 2-5, with a yield of 56.2%.

[0336] MS m / z (ESI): 592.3 [M+H] + .

[0337] Synthesis of Compound 16

[0338] The synthesis of compound 16 was performed using the same method as that of compound 1, with a yield of 17.1%.

[0339] MS m / z(ESI): 492.2 [M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),7.78(s,1H),7.60–7.54(m,2H),7.50–7.46(m,3H),7.17–7.14(m,1H),5.05(q,J=7.2Hz,1H),4.17( t,J=5.4Hz,2H),3.75(s,1H),3.32–3.27(m,2H),3.04(t,J=6.4Hz,2H),2.37(s,6H),2.19(s,1H),1.63–1.47(m,3H),1.31–1.20(m,4H).

[0341] Example 17: Synthesis of Compound 17

[0342] The synthetic route of compound 17 is shown in the figure below.

[0343] The specific synthesis method is as follows:

[0344] Synthesis of intermediate 17-1

[0345] The synthesis method of intermediate 17-1 is the same as that of intermediate 2-5, with a yield of 36.7%.

[0346] MS m / z (ESI): 518.2 [M+H-56] + .

[0347] Synthesis of Compound 17

[0348] The synthesis method of compound 17 is the same as that of compound 1, with a yield of 39.2%.

[0349] MS m / z(ESI): 474.2 [M+H] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=6.7Hz,1H),7.84(s,1H),7.64–7.57(m,2H),7.53–7.44(m,3H),7.12(d,J=7.8Hz,1H),5.07(dd,J=15.5,7 .8Hz,1H),4.22(t,J=6.4Hz,2H),3.63(s,1H),3.28–3.26(m,2H),3.09(t,J=6.51Hz,2H),2.29(s,1H),1.59–1.53(m,3H),1.24–1.16(m,4H).

[0351] Example 18: Synthesis of Compound 18

[0352] The synthetic route of compound 18 is shown in the figure below.

[0353] The specific synthesis method is as follows:

[0354] Synthesis of intermediate 18-1

[0355] The synthesis method of intermediate 18-1 is the same as that of intermediate 1-2, with a yield of 47.9%.

[0356] MS m / z(ESI): 286.0 [M+H] + .

[0357] Synthesis of intermediate 18-2

[0358] The synthesis method of intermediate 18-2 is the same as that of intermediate 2-4, with a yield of 78.0%.

[0359] MS m / z(ESI): 334.2 [M+H] + .

[0360] 1H NMR (500MHz, CDCl3) δ7.61(dd,J=7.9,1.1Hz,1H),7.57(s,1H),7.21(d,J=8.0Hz,1H),4.04(t,J =5.5Hz, 2H), 3.76 (t, J = 5.6Hz, 2H), 3.51 (q, J = 6.9Hz, 2H), 1.37 (s, 12H), 1.17 (t, J = 7.0Hz, 3H).

[0361] Synthesis of intermediate 18-3

[0362] The synthesis method of intermediate 18-3 is the same as that of intermediate 2-5, with a yield of 50.0%.

[0363] MS m / z (ESI): 615.3 [M+Na] + .

[0364] Synthesis of Compound 18

[0365] The synthesis method of compound 18 is the same as that of compound 1, with a yield of 60.0%.

[0366] MS m / z(ESI): 493.3 [M+H] + .

[0367] 1 H NMR (500MHz, CDCl3) δ8.74 (s, 1H), 7.40 (t, J = 7.7Hz, 1H), 7.35 (d, J = 6.7Hz, 2H), 7. 31(s,2H),7.26(d,J=8.4Hz,1H),5.10(q,J=7.8Hz,1H),4.07(t,J=5.2Hz,2H),3.79 (t,J=5.2Hz,2H),3.69(d,J=21.2Hz,1H),3.52(q,J=6.9Hz,2H),3.28(d,J=7.5Hz, 2H), 2.77 (s, 1H), 1.71 (q, J = 12.0Hz, 4H), 1.44–1.19 (m, 3H), 1.17 (t, J = 7.0Hz, 3H).

[0368] Example 19: Synthesis of Compound 19

[0369] The synthetic route of compound 19 is shown in the figure below.

[0370] The specific synthesis method is as follows:

[0371] Synthesis of intermediate 19-1

[0372] The starting material 8-1 (3.39 g, 20.00 mmol) was dissolved in tetrahydrofuran (20 mL), and 37% formaldehyde aqueous solution (10 mL) and 40% dimethylamine aqueous solution (10 mL) were added. The reaction system was stirred at 50 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, purified water (50 mL) was added and the mixture was extracted twice with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 4:1) to obtain intermediate 19-1 (2.83 g, 12.49 mmol), yield: 62.5%.

[0373] MS m / z(ESI): 227.0 [M+H] + .

[0374] Synthesis of intermediate 19-2

[0375] The synthesis method of intermediate 19-2 is the same as that of intermediate 1-3, with a yield of 57.5%.

[0376] MS m / z(ESI): 319.2 [M+H] + .

[0377] Synthesis of intermediate 19-3

[0378] The synthesis method of intermediate 19-3 is the same as that of intermediate 2-5, with a yield of 56.1%.

[0379] MS m / z (ESI): 600.3 [M+Na] + .

[0380] Synthesis of Compound 19

[0381] The synthesis method of compound 19 is the same as that of compound 1, with a yield of 9.9%.

[0382] MS m / z (ESI): 478.2 [M+H] + .

[0383] 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=6.5Hz,1H),7.80(s,1H),7.64–7.50(m,5H),7.12(d,J=7.5Hz,1H),5.03(dd,J= 15.4,7.7Hz,1H),4.70(s,2H),3.65(s,2H),3.29–3.26(m,2H),2.29(s,6H),1.55–1.49(m,3H),1.26–1.17(m,4H).

[0384] Example 20: Synthesis of Compound 20

[0385] The synthetic route of compound 20 is shown in the figure below.

[0386] The specific synthesis method is as follows:

[0387] Synthesis of intermediate 20-1

[0388] The synthesis method of intermediate 20-1 is the same as that of intermediate 2-5, with a yield of 54.7%.

[0389] MS m / z (ESI): 604.1 [M+H] + .

[0390] Synthesis of Compound 20

[0391] The synthesis method of compound 20 is the same as that of compound 1, with a yield of 28.5%.

[0392] MS m / z (ESI): 504.1 [M+H] + .

[0393] 1 H NMR(400MHz,DMSO-d6)δ8.67(d,J=8.4Hz,1H),7.69(d,J=2.2Hz,1H),7.46–7.32(m,3H) ,7.23(dd,J=8.5,2.2Hz,1H),6.92(d,J=8.5Hz,1H),5.02(dd,J=15.6,8.3Hz,1H),4.32– 4.15(m,2H),3.93(t,J=7.7Hz,4H),3.70–3.62(m,2H),3.41–3.34(m,1H),3.29–3.22(m, 2H),3.11(s,1H),2.36(s,1H),2.25–2.12(m,2H),1.68–1.26(m,5H),1.03–0.94(m,2H).

[0394] Example 21: Synthesis of Compound 21

[0395] The synthetic route of compound 21 is shown in the figure below.

[0396] The specific synthesis method is as follows:

[0397] Synthesis of intermediate 21-1

[0398] The synthesis method of intermediate 21-1 is the same as that of intermediate 1-2, with a yield of 93.9%.

[0399] MS m / z(ESI): 184.0 [M+H] + .

[0400] Synthesis of intermediate 21-2

[0401] The synthesis method of intermediate 21-2 is the same as that of intermediate 1-3, with a yield of 82.8%.

[0402] MS m / z(ESI): 276.1 [M+H] + .

[0403] Synthesis of intermediate 21-3

[0404] Intermediate 21-2 (5.36 g, 19.48 mmol) and starting material 1-4 (6.69 g, 19.49 mmol) were dissolved in 1,4-dioxane (55 mL). An aqueous solution of Pd(dppf)Cl2 (1.43 g, 1.95 mmol) and potassium carbonate (5.40 g, 39.07 mmol) (13 mL) was added. The reaction mixture was stirred at 85 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, purified water (100 mL) and ethyl acetate (100 mL) were added. The mixture was stirred for 0.5 hours and allowed to stand for separation. The aqueous phase was extracted twice with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 4:1 to 1:4) to obtain intermediate 21-3 (6.54 g, 15.90 mmol), yield: 81.6%.

[0405] MS m / z (ESI): 434.2 [M+Na] + .

[0406] Synthesis of intermediate 21-4

[0407] Intermediate 21-3 (5.72 g, 13.90 mmol) was dissolved in anhydrous acetonitrile (175 mL), and TsOH (7.18 g, 41.70 mmol) was added. The mixture was stirred at 20-25 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the filter cake was diluted with 100 mL of ethyl acetate. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with ethyl acetate (50 mL, 25 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give intermediate 21-4 (3.30 g, 10.60 mmol), yield: 76.3%.

[0408] MS m / z(ESI): 312.1 [M+H] + .

[0409] Synthesis of intermediate 21-6

[0410] Intermediate 21-4 (202 mg, 0.65 mmol), starting material 21-5 (173 mg, 0.71 mmol), HATU (376 mg, 0.99 mmol), and DIPEA (260 mg, 2.01 mmol) were dissolved in dichloromethane (12 mL) and reacted at room temperature for 2 hours. After the reaction was complete, 18 mL of purified water was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted three times with dichloromethane (10 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 5:1) to obtain intermediate 21-6 (290 mg, 0.54 mmol), yield: 83.1%.

[0411] MS m / z (ESI): 537.2 [M+H] + .

[0412] Synthesis of Compound 21

[0413] The synthesis method of compound 21 is the same as that of compound 1, with a yield of 18.3%.

[0414] MS m / z (ESI): 437.1 [M+H] + .

[0415] 1 H NMR(400MHz, DMSO-d6)δ8.83(d,J=7.8Hz,1H),7.75(s,1H),7.60–7.48(m,3H),7.40–7.35(m, 3H),5.07–5.01(m,1H),3.63–3.52(m,3H),3.40(s,3H),3.32–3.18(m,4H),2.49–2.24(m,2H).

[0416] Example 22: Synthesis of Compound 22

[0417] The synthetic route of compound 22 is shown in the figure below.

[0418] The specific synthesis method is as follows:

[0419] Synthesis of intermediate 22-1

[0420] The synthesis method of intermediate 22-1 is the same as that of intermediate 1-2, with a yield of 45.6%.

[0421] MS m / z (ESI): 325.1 [M+H] + .

[0422] Synthesis of intermediate 22-2

[0423] The synthesis method of intermediate 22-2 is the same as that of intermediate 2-4, with a yield of 57.2%.

[0424] MS m / z(ESI): 373.3 [M+H] + .

[0425] Synthesis of intermediate 22-3

[0426] The synthesis method of intermediate 22-3 is the same as that of intermediate 2-5, with a yield of 46.3%.

[0427] MS m / z (ESI): 632.4 [M+H] + .

[0428] Synthesis of Compound 22

[0429] The synthesis method of compound 22 is the same as that of compound 1, with a yield of 7.3%.

[0430] MS m / z(ESI): 532.3 [M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=8.4Hz,1H),7.71(d,J=1.5Hz,1H),7.65–7.41(m,5H),5.06(td,J=15.0,7.6Hz,1H),4.01(t,J=6.2Hz,1H),3 .32–3.19(m,3H),3.10(s,1H),2.63(t,J=6.22Hz,2H),2.48–2.32(m,6 H), 2.01 (td, J=13.5, 6.8Hz, 1H), 1.54–1.50 (m, 3H), 1.41–1.32 (m, 9H).

[0432] Example 23: Synthesis of Compound 23

[0433] The synthetic route of compound 23 is shown in the figure below.

[0434] The specific synthesis method is as follows:

[0435] Synthesis of intermediate 23-1

[0436] The synthesis method of intermediate 23-1 is the same as that of intermediate 1-2, with a yield of 78.5%.

[0437] MS m / z (ESI): 327.1 [M+H] + .

[0438] Synthesis of intermediate 23-2

[0439] The synthesis method of intermediate 23-2 is the same as that of intermediate 2-4, with a yield of 74.2%.

[0440] MS m / z (ESI): 375.3 [M+H] + .

[0441] Synthesis of intermediate 23-3

[0442] The synthesis method of intermediate 23-3 is the same as that of intermediate 2-5, with a yield of 55.3%.

[0443] MS m / z (ESI): 634.4 [M+H] + .

[0444] Synthesis of Compound 23

[0445] The synthesis method of compound 23 is the same as that of compound 1, with a yield of 5.3%.

[0446] MS m / z (ESI): 534.3 [M+H] + .

[0447] 1 H NMR(400MHz, DMSO-d6)δ8.64(d,J=7.0Hz,1H),7.75–7.28(m,6H),5.02(dd, J=18.1,8.3Hz,1H),4.01(s,1H),3.49(dd,J=10.1,5.6Hz,4H),3.28(d,J=7. 2Hz,3H),3.26–3.16(m,3H),3.06(d,J=8.4Hz,1H),2.66(s,1H),2.45(s,2H ),2.33(d,J=8.0Hz,1H),2.11–1.95(m,1H),1.51(s,2H),1.40–1.30(m,5H).

[0448] Experimental Example 1: Inhibitory effect of representative compounds on cathepsin C (DPP1)

[0449] I. Reagents and Materials:

[0450] 1. OptiPlate 384-well plate, black and opaque (Cat#6007270, Revvity)

[0451] 2. Human cathepsin L / CTSL1 protein (His-tagged, active enzyme) (Cat#CAL-H52H3, ACRO)

[0452] 3. Human cathepsin C protein (His tag, active enzyme, MALS verified) (Cat#CAC-H52H3, ACRO)

[0453] 4. Substrate: Gly-Arg-AMC (Cat#GC45668, GLPBIO)

[0454] 5. MES(Cat#M3671,Sigma-Aldrich)

[0455] 6. NaCl(Cat#S7653,Sigma-Aldrich)

[0456] II. Instruments:

[0457] Microplate reader: SpectraMax M5(MD)

[0458] III. Experimental Methods:

[0459] Buffer solution preparation:

[0460] 1. Activation buffer: 25mM MES, 5mM DTT, pH 6.0

[0461] 2. Experimental buffer solution: 25mM MES, 50mM NaCl, 5mM DTT, pH 6.0

[0462] Test method:

[0463] 1. Dilute human cathepsin C to 80 μg / mL in activation buffer.

[0464] 2. Add human cathepsin L and activation buffer to human cathepsin C to a final concentration of 20 μg / mL human cathepsin L and 40 μg / mL human cathepsin C, and incubate at room temperature for 1 hour.

[0465] 3. Dilute activated human cathepsin C in experimental buffer, 10 μL / well.

[0466] 4. Start by diluting the compound at 10 μM, then dilute 4 times, to obtain 10 concentration points, 10 μL / well.

[0467] 5. Incubate the serially diluted compound with activated human cathepsin C at room temperature for 30 minutes.

[0468] 6. Dilute the substrate to 60 μM in experimental buffer, 10 μL / well.

[0469] 7. Add the diluted substrate to the above co-incubation system and incubate again at room temperature for 1 hour.

[0470] 8. Microplate reader test, with excitation and emission wavelengths of 380nm and 460nm respectively.

[0471] 9. Data Calculation

[0472] % Inhibition rate = (FP) B -FP S ) / (FP B -FP V )×100%

[0473] FP S =Sample fluorescence polarization value

[0474] FP B = Blank control fluorescence polarization value

[0475] FP V =Carrier control fluorescence polarization value.

[0476] Fit the inhibition rate-concentration curve and calculate IC50. 50 Numerical value.

[0477] IV. Experimental Results

[0478] Experimental conclusion: This series of compounds all have good inhibitory effects on cathepsin C (DPP1) and are superior to the positive reference INS1007.

[0479] Experimental Example 2: Inhibitory effect of representative compounds on intracellular neutrophil elastase (NE)

[0480] I. Reagents and Materials:

[0481] (1) RPMI 1640 (Invitrogen, part number: A1049101)

[0482] (2)PBS (ThermoFisher, catalog number: 10010023)

[0483] (3) MeOSuc-AAPV-AMC (Sigma, part number: M9771)

[0484] (4) NP-40 lysis buffer (Beyotime, catalog number: P0013F)

[0485] (5) 96-hole transparent flat plate (Corning, part number: 3599)

[0486] (6) 96-hole V-shaped base plate (Corning, part number: 651201)

[0487] (7) 96-well culture plate (Corning, part number: 3610)

[0488] II. Instruments and Equipment:

[0489] (1) Automated Cell Counter (Countstar, catalog number: IC-1000)

[0490] (2) Carbon dioxide cell incubator (ThermoFisher, catalog number: MCO-15AC)

[0491] (3) EnVision-2104 multichannel microplate reader (PerkinElmer)

[0492] III. Experimental Procedure:

[0493] Cell line: U937, 50,000 cells / well (100 μl / well)

[0494] 1. Compound preparation and cell treatment

[0495] (1) The compound stock solution was diluted to a concentration of 10 μM with DMSO, and then the solution was continuously diluted 5 times to obtain 8 different concentration points.

[0496] (2) Add 50 μL (3×) of the compound to the corresponding wells to achieve a final DMSO concentration of 0.5%. Then incubate the culture plate at 37°C and 5% carbon dioxide for 48 hours.

[0497] 2. CTG detection

[0498] (1) Add 50 μL of cell counting spectrophotometric reagent to each well according to the CTG assay kit instructions. Shake at 300 rpm for 30 minutes at room temperature, avoiding light exposure. Detect the entire sample using a microplate reader.

[0499] 3. NE activity test

[0500] (1) Remove the supernatant, add 60 μL of NP-40 lysis buffer to each well, and then incubate on ice for 10 minutes to collect the cell lysis buffer.

[0501] (2) Mix the cell lysate and blank control solution in a 384-well plate (Corning #4514) in the following proportions: Blank control: 7.5 μl Tris buffer + 7.5 μl NE substrate (0.5 mM); Sample: 7.5 μl cell lysate + 7.5 μl NE substrate (0.5 mM)

[0502] (3) A kinetic measurement was performed for 30 minutes using a Spark 10M instrument (excitation wavelength 380nm, emission wavelength 500nm).

[0503] 4. Calculation and Analysis

[0504] (1) Calculate the inhibition rate of NE at the compound concentration.

[0505] (2) Fit the inhibition rate-concentration curve and calculate IC50. 50 Numerical value.

[0506] IV. Test Results

[0507] V. Experimental Conclusions:

[0508] The compounds in this series all showed good inhibitory effects on intracellular neutrophil elastase (NE), and were superior to the positive reference INS1007.

[0509] Example 3: Animal PK test of representative compounds

[0510] I. Experimental Methods

[0511] 1. Experimental animals: SD rats, male, weight: 180-220 grams.

[0512] 2. Experimental Design (Single Compound)

[0513] 3. Drug preparation

[0514] 10% DMSO + 40% PEG400 + 5% Tween 80 + 45% physiological saline

[0515] Example: First, prepare a 10X DMSO stock solution; taking 1 ml of working solution as an example, add 100 μL of 10X DMSO stock solution to 400 μL of PEG400, then add 50 μL of Tween 80, and finally add 450 μL of physiological saline to bring the volume to 1 ml. Vortex for 30 seconds to mix.

[0516] II. Experimental Procedure

[0517] 1. Sample collection

[0518] Sampling time points: 5 min (venous group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h;

[0519] Plasma collection and processing: At the above-mentioned time points, 0.15 ml of blood was collected through the posterior venous plexus of the eye or a suitable site, placed in an EDTA-K2 test tube, centrifuged at 11000 rpm for 5 min, the plasma was separated, and frozen and stored in a freezer at -80℃.

[0520] 2. Sample Testing

[0521] The concentration of the original drug in plasma / whole blood was determined by LC-MS / MS.

[0522] 3. Data Analysis

[0523] Pharmacokinetic parameters after drug administration were calculated using a non-compartmental model in Phoenix WinNonlin software.

[0524] Peak concentration C max Peak Time T max These are measured values;

[0525] Area under the curve (AUC) during drug administration 0-t Value: Calculated using the trapezoidal rule; AUC 0-∞ =AUC 0-t +C t / k e C t k represents the blood drug concentration at the last measurable time point. e To eliminate the rate constant;

[0526] Absolute bioavailability F = (AUC gavage × D intravenous) / (AUC intravenous × D gavage) × 100%

[0527] IV. Test Results

[0528] The results of some of the head-to-head comparisons are shown in the table below:

[0529] V. Experimental Conclusions:

[0530] This series of compounds exhibits good absolute bioavailability, which is superior to that of the positive reference INS1007.

Claims

1. A compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts thereof: In equation (I) above, the ring Cy is selected from X is O, S, CH2 or CD2; R is selected from H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl-halogenated C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 epoxy alkyl, 3-8 member heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, phenyl, 3-8 member heteroaryl containing 1-3 heteroatoms selected from N, O, S, hydroxyl, acyl, wherein the C1- C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl-halogenated C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 epoxy alkyl, 3-8 heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S, phenyl, 3-8 heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, hydroxyl, acyl groups can each be independently surrounded by 0, 1, 2, 3, or 4 R groups. a replace; Each R a The same or different, and each independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C8 cycloalkyl), -O(C3-C8 epoxyalkyl), 3-8 member heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, bridged cycloalkyl containing 1-3 heteroatoms selected from N, O, S, 3-8 member spirocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, 5-6 member heteroaryl, phenyl, cyano, hydroxyl, mercapto, -NR'R”, And halogens (e.g., F, Cl, Br, I); R' and R" are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to; Each R 1 The same or different, and each independently selected from H, deuterium, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxyl, cyano, amino, and mercapto, wherein the C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -O(C1-C6 alkyl), and -O(C3-C6 cycloalkyl) are optionally substituted by 0, 1, 2, or 3 deuterium, halogen (e.g., F, Cl, Br, I), hydroxyl, cyano, amino, or mercapto groups; m can be 0, 1, 2, or 3.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or pharmaceutically acceptable salts thereof, wherein, R is selected from H, C1-C4 alkyl, C1-C4 alkyl-halogenated C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkoxy, C1-C4 alkyl-C3-C6 cycloalkyl, phenyl, 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, and hydroxyl group, wherein the C1-C4 alkyl, C1-C4 alkyl-halogenated C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkoxy, C1-C4 alkyl-C3-C6 cycloalkyl, and phenyl groups can each be independently separated by 0 or 1 R. a replace; Preferably, R is selected from H, C2-C3 alkyl, C2-C3 alkyl halo-C2-C3 alkyl, C2-C3 alkyl-C2-C3 alkoxy, C2-C3 alkyl-C3-C6 cycloalkyl, phenyl, thiazolyl, oxazolyl, hydroxyl, and acyl, wherein the C2-C3 alkyl, C2-C3 alkyl halo-C2-C3 alkyl, C2-C3 alkyl-C2-C3 alkoxy, C2-C3 alkyl-C3-C6 cycloalkyl, and phenyl can each be independently separated by 0 or 1 R. a replace; Preferably, R is selected from H, 3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or pharmaceutically acceptable salts thereof, wherein, R a Each is independently selected from H, deuterium, -NR'R", C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C4 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). 5-6 nucleotides containing 1-3 heteroaryl, phenyl, cyano, or hydroxyl groups selected from N, O, or S heteroatoms. And halogens (e.g., F, Cl, Br, I); Preferably, R a Each is independently selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C3 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I).

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, deuterated product, prodrug, or pharmaceutically acceptable salt thereof, wherein, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to; Preferably, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to; More preferably, R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-5 membered heterocycle with the N atom they are attached to.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, deuterated product, prodrug, or pharmaceutically acceptable salt thereof, wherein, Each R 1 They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups; Preferably, each R 1 They may be the same or different, and each is independently selected from H, deuterium, and halogens (e.g., F, Cl, Br, I); Preferably, m is 1, 2, or 3.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated product, prodrug, or pharmaceutically acceptable salt thereof, wherein, Cy selected from X is O, S, CH2 or CD2; R is selected from H, R a Selected from H, deuterium, -NR'R", C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O (C1-C4 alkyl), -O (C3-C6 cycloalkyl), -O (C3-C6 epoxyalkyl). 5-6 nucleotides containing 1-3 heteroaryl, phenyl, cyano, or hydroxyl groups selected from N, O, or S heteroatoms. And halogens (e.g., F, Cl, Br, I); R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-7 membered heterocycle with the N atom they are attached to; Each R 1 They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups; m is 1, 2, or 3; Preferably, the cyclic Cy is selected from X is O, S, CH2 or CD2; R is selected from H, R a Selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O(C1-C3 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I); R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to; Each R 1 They may be the same or different, and each is independently selected from H, deuterium, halogens (e.g., F, Cl, Br, I), and C1-C6 alkyl groups; m is 1, 2, or 3; Preferably, the cyclic Cy is selected from X is O, S, CH2 or CD2; R is selected from H, R a Each is independently selected from H, -NR'R", C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, O(C1-C3 alkyl). phenyl, cyano, hydroxy And halogens (e.g., F, Cl, Br, I); R' and R" are independently selected from H, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, or R' and R" form a 4-6 membered heterocycle with the N atom they are attached to; Each R 1 They may be the same or different, and each is independently selected from H, deuterium, and halogens (e.g., F, Cl, Br, I); m can be 1, 2, or 3.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, deuterated product, prodrug, or pharmaceutically acceptable salt thereof, wherein, R is selected from H, -CH3, -CH2CH2-O-CH2CH3, Each R 1 They may be the same or different, and each is independently selected from H, halogens (e.g., F, Cl, Br, I); m is 1, 2, or 3; Preferably, the compound represented by general formula (I) is selected from:

8. A pharmaceutical composition comprising at least a therapeutically effective amount of the compound of any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated compound, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Use of the compound of any one of claims 1 to 7, or a stereoisomer, tautomer, deuterated product, prodrug, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for the prevention and / or treatment of cathepsin C-related conditions; Preferably, the cathepsin C-related conditions are selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, lower respiratory tract infection, chronic sinusitis, eosinophilic sinusitis, nasal polyps, hidradenitis suppurativa, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis), psoriasis, antitrypsin A deficiency, lupus nephritis, diabetes, inflammatory bowel disease, and rheumatoid arthritis.

10. A method for preventing and / or treating a condition related to cathepsin C, the method comprising administering to a patient in need a therapeutically effective amount of the compound of any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, prodrug or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 8; Preferably, the cathepsin C-related conditions are selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, lower respiratory tract infection, chronic sinusitis, eosinophilic sinusitis, nasal polyps, hidradenitis suppurativa, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis), psoriasis, antitrypsin A deficiency, lupus nephritis, diabetes, inflammatory bowel disease, and rheumatoid arthritis.

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