Novel deuterated cyano compounds, methods of making, compositions, and uses thereof

Abstract

This invention discloses a novel deuterated cyano compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, or prodrug thereof. The preparation method, composition, and application of the above-mentioned deuterated compound are also disclosed. This type of compound, as a 3CL protease inhibitor, achieves superior pharmacokinetic properties and therapeutic effects while maintaining comparable viral inhibitory activity, exhibiting better drug-like properties. Formula I is shown below:

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to novel deuterated cyano compounds, their preparation methods, compositions, and applications. The aforementioned pharmaceutical compositions are used to prepare drugs for treating and preventing viral infections. Background Technology

[0002] The first coronaviruses in humans were isolated in the UK in the 1960s. They are named for the crown-like protrusions on their surface. They are likely associated with respiratory infections in humans, pigs, cats, dogs, rats, and chickens. The SARS virus belongs to the order Nidovirales, family Coronaviridae, and genus Coronavirus, specifically the β-B subgroup of coronaviruses. The virus particles are mostly spherical, enveloped, with crown-like spikes on the periphery, distributed in the cytoplasm, and are spherical in shape, with a diameter between 80 and 120 nm. SARS is an infectious disease with a rapid onset, rapid spread, and high mortality rate. Most infected patients had direct or indirect contact with infected individuals or lived in endemic areas. The MERS virus is a β-C subgroup of coronavirus, officially named Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which causes Middle East Respiratory Syndrome (MERS) after infection. MERS-CoV was first discovered in Saudi Arabia in September 2012. It was initially named "SARS-like virus" because of its similar clinical symptoms to SARS. It is the sixth known human coronavirus and the third to be isolated in the past 10 years.

[0003] Common signs of coronavirus infection include respiratory symptoms, fever, cough, shortness of breath, and difficulty breathing. In more severe cases, infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death. There is no specific treatment for the disease caused by the novel coronavirus.

[0004] In 2021, Dafydd R. Owen published a paper titled "An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19," describing the pharmacological effects of the 3CL protease inhibitor PF-07321332 as a virus inhibitor. By inhibiting the main protease, PF-07321332 prevents the virus from cleaving its long protein chains into the parts required for self-replication. This compound is currently undergoing Phase III clinical trials to evaluate its efficacy in treating COVID-19. Typically, this peptide compound, PF-07321332, is easily metabolized and degraded in vivo due to the first-pass effect, often requiring combination with other drugs (protease protectants) to improve its pharmacokinetic properties. The pharmacokinetic and metabolic properties of PF-07321332 require further improvement.

[0005] Therefore, there is still a need in the field to develop novel 3CL protease inhibitor compounds with better inhibitory activity or pharmacokinetic properties. This invention designs and discloses a novel deuterated cyano compound that, while possessing comparable viral inhibitory activity, achieves superior pharmacokinetic properties and therapeutic efficacy compared to PF-07321332, with better drug-like properties. The invention also discloses its preparation method, pharmaceutical composition, and applications, enabling scale-up production of this drug and demonstrating good clinical value.

[0006] Public content

[0007] This invention relates to novel deuterated cyano compounds, their preparation methods, compositions, and applications.

[0008] This invention discloses a deuterated cyano compound of formula I, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:

[0009] I

[0010] Where R1~R 17 It is a combination of hydrogen isotopes (including the isotopes protium and deuterium);

[0011] In the above compounds, at least one of R1 to R2 is deuterium, at least one of R6 to R7 is deuterium, and R9 to R... 17 All are deuterium.

[0012] This invention discloses a method for preparing deuterated cyano compounds, which includes the following steps:

[0013]

[0014] (1) In an organic solvent, under the action of a condensing agent, compound I-1 and compound I-2 undergo a condensation reaction to obtain intermediate I-3;

[0015] (2) In an organic solvent, under the action of alkali, intermediate I-3 undergoes a hydrolysis reaction to obtain intermediate I-4;

[0016] (3) In an organic solvent, under the action of a condensing agent, intermediate I-4 and compound I-5 undergo a condensation reaction to obtain compound I;

[0017] This invention discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0018] This invention discloses a pharmaceutical composition saturated with another therapeutic agent, said other therapeutic agent being an antiviral drug.

[0019] This invention discloses the use of the above-mentioned pharmaceutical composition for preparing a pharmaceutical composition that inhibits 3CL protease.

[0020] This invention discloses the use of the above-mentioned pharmaceutical composition, wherein the viral infectious human coronavirus, SARS-CoV-2, SARS coronavirus and MERS coronavirus are mentioned.

[0021] In various embodiments, the compound has one of the structures shown in Table 1 below.

[0022] Table 1 Representative Compounds

[0023]

[0024] In some embodiments, the present invention contemplates pharmaceutical compositions comprising pharmaceutically acceptable excipients and compounds disclosed herein. In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, or aqueous buffers, such as saline or phosphate buffers.

[0025] In some embodiments, the present invention relates to the use of the compounds described herein in the preparation of medicaments for treating or preventing viral infections, such as human coronaviruses, SARS-CoV-2, SARS coronaviruses, and MERS coronaviruses.

[0026] In some embodiments, the present invention relates to a method for preparing compounds by mixing the starting materials and reagents disclosed herein under conditions that form the compounds disclosed herein.

[0027] This invention designs and discloses a novel deuterated cyano compound that, while possessing comparable viral inhibitory activity, achieves superior pharmacokinetic properties and therapeutic efficacy compared to PF-07321332, with better drug-like properties. The invention also discloses its preparation method, pharmaceutical composition, and applications, enabling large-scale production of this drug and demonstrating significant clinical value.

[0028] The following detailed descriptions are illustrative and explanatory only, and not restrictive.

[0029] In the following examples, unless otherwise indicated, all solvents and reagents used were commercially available and used as is.

[0030] The procedures described below can be used to synthesize compounds 1–63.

[0031] The following abbreviations are used in this article:

[0032] BOP: Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate

[0033] (Boc)₂O: Ditert-butyl dicarbonate

[0034] DCM: Dichloromethane

[0035] D2O: Heavy water

[0036] EA: Ethyl acetate

[0037] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0038] HCl / EA: Ethyl hydrochloride solution

[0039] HOBt: 1-Hydroxybenzotriazole

[0040] LiHMDS: Bis(trimethylsilyl)aminolithium

[0041] MeOH: Methanol

[0042] MTBE: Methyl tert-butyl ether

[0043] NaOH: Sodium hydroxide

[0044] NH3 / MeOH: Ammonia-methanol solution

[0045] Ni: Raney nickel

[0046] NMM: N-methylmorpholine

[0047] SM1: L-glutamic acid

[0048] SOCl2: sulfoxide

[0049] TEA: Triethylamine

[0050] THF: Tetrahydrofuran

[0051] Ru / C: Ruthenium carbon. Detailed Implementation Example 1:

[0052] Synthesis of (S)-2-amino-3-((S)-2-carbonylpyrrolidone-3-yl)propionitrile hydrochloride (compound H)

[0053] Representative routes

[0054]

[0055] Preparation of intermediate compound A

[0056] A solution of L-glutamic acid (SM1: 100 g, 0.68 mol) in MeOH (500 ml) was adjusted to -5 to -5 °C, and SOCl2 (202 g, 1.70 mol) was added dropwise. After the addition was complete, the mixture was heated to reflux and stirred. After the reaction was basically complete as determined by TCL, the mixture was concentrated to dryness, and MeOH (1 L) was added. TEA (172 g, 1.70 mol) was added dropwise, and (Boc)2O (148.4 g, 1 eq) was added dropwise at -5 to -5 °C. The mixture was stirred at 50 to 60 °C for 3 to 5 hours. After the reaction was basically complete as determined by TCL, the mixture was concentrated to dryness, and saturated sodium bicarbonate (500 ml) was added. The mixture was extracted three times with MTBE (1 L, 0.5 L, 0.5 L). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness to obtain 178 g of a pale yellow oily product A, with a yield of 95%.

[0057] LC-MS (ESI, m / z, C) 12 H 21 NO6, 276, M+H)

[0058] 1 H NMR (400 MHz, CDCl3)δ: 5.40-5.37(m,1H), 4.35-4.30(m,1H), 3.74(s,3H), 3.68(s,3H), 2.47-2.40(m,2H), 2.17-2.16(m,2H), 1.99-1.94(m,1H), 1.44(s,9H).

[0059] Preparation of intermediate compound B

[0060] A solution of compound A (150 g, 0.545 mol) in THF (450 ml) was cooled to -78 °C, and LiHMDS (1 M, 1.2 L, 1.2 mol) was added dropwise under controlled temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 2 hours. Then, bromoacetonitrile (98 g, 0.817 mol) was added dropwise under controlled temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 4 hours. After TCL analysis showed that the reaction of the starting material was basically complete, the reaction was quenched by adding tetrahydrofuran acetate solution. The mixture was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain crude compound B. This crude compound B was purified by column chromatography (PE:EA = 1:1) to obtain 142 g of a pale yellow oily compound B, with a yield of 95%.

[0061] LC-MS (ESI, m / z, C) 14 H 22 N2O6, 315, M+H)

[0062] 1H NMR (400 MHz, CDCl3)δ: 5.19-5.17(m,1H), 4.38-4.33(m,1H), 3.77(s,6H), 2.88-2.79(m,3H), 2.19-2.14(m,2H), 1.45(s, 9H).

[0063] Preparation of intermediate compound D

[0064] Compound B (50 g, 0.159 mol), MeOH (150 ml), glacial acetic acid (150 ml), and Raney nickel (10 g) were added to a hydrogenation flask, and hydrogen gas was introduced to maintain a pressure of 50-60 psi. The reaction was maintained at this temperature and pressure with stirring for 4 hours. After the reaction was basically complete (as determined by TCL), nitrogen was introduced to replace the hydrogen gas, and the mixture was filtered. The filtrate was concentrated and replaced with a THF (500 ml) solution. TEA (100 ml) was added, and the temperature was adjusted to 50-60 °C with stirring for 16 hours. After the reaction was basically complete (as determined by TCL), water (150 ml) was added to dissolve the reaction solution, and the layers were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined, dried, and concentrated to obtain an oily crude product D. Column chromatography purification yielded a white solid powder D: 27.8 g, yield 61%.

[0065] LC-MS (ESI, m / z, C) 13 H 22 N2O5, 287, M+H)

[0066] 1 H NMR (400 MHz, CDCl3)δ: 6.35(s,1H), 5.54-5.52(m,1H), 4.32-4.30(m,1H), 3.74(s,3H), 3.37-3.33(m,2H), 2.50-2.46(m,2H), 2.17-2.13(m,1H), 1.87-1.81(m,2H), 1.44(s, 9H).

[0067] Preparation of intermediate compound E

[0068] Compound D (27 g, 0.094 mol), MeOH (270 ml), and NaOH (10 g, 0.25 mol) were added to a reaction flask. The mixture was stirred for 4 hours. After the starting materials were basically completely reacted as determined by TCL, the solution was concentrated and replaced with EA (270 ml), and water (100 ml) was added. The pH of the reaction solution was adjusted to 5-6 using 1N hydrochloric acid solution at 0-10℃, and the layers were separated. The aqueous phase was extracted twice with EA, and the organic phases were combined and concentrated to dryness to obtain a white solid powder E: 25 g, yield 97%.

[0069] LC-MS (ESI, m / z, C) 13 H 20 N2O5, 273, M+H)

[0070] 1 H NMR (400 MHz, CDCl3)δ: 6.37(s,1H), 5.58-5.53(m,1H), 4.52-4.50(m,1H), 3.38-3.35(m,2H), 2.53-2.48(m,2H), 2.19-2.16(m,1H), 1.88-1.84(m,2H), 1.45(s,9H).

[0071] Preparation of intermediate compound F

[0072] TEA (10.2 g, 0.1 mol) was added dropwise to a THF (250 ml) solution of compound E (25 g, 0.092 mol) and stirred for 30 minutes. Ethyl chloroformate (13.0 g, 0.12 mol) was added dropwise at -5-5℃, and the mixture was stirred for 1 hour after the addition was complete. Then, NH3 / MeOH (10 M, 100 ml) was added dropwise at -5-5℃, and the mixture was stirred for 2 hours after the addition was complete and the mixture was brought to room temperature. After the reaction was confirmed by TCL to be essentially complete, the solution was concentrated and replaced with EA (250 ml) solution. The solution was washed with water, then with saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness to obtain a white solid powder F: 23 g, yield 92%.

[0073] LC-MS (ESI, m / z, C) 12 H 21 N3O4, 272, M+H)

[0074] Preparation of intermediate compound G

[0075] At -5 to -5℃, TFAA (10.2 g, 0.1 mol) was added dropwise to a DCM (230 ml) solution of compound F (23 g, 0.085 mol) and TEA (38.6 g, 0.382 mol). After the addition was complete, the reaction mixture was brought to room temperature and stirred for 12 hours. After the reaction was confirmed by TCL to be essentially complete, the reaction solution was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a white solid powder G: 18.2 g, yield 85%.

[0076] LC-MS (ESI, m / z, C) 13 H 20 N2O3, 253, M+H)

[0077] Preparation of intermediate compound H

[0078] Compound G (18.2 g, 0.072 mol) was added to 150 ml of 4 mol / L ethyl acetate hydrochloride solution at 0-10 °C. After stirring at 0-10 °C for 1 hour, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was basically complete as determined by TCL, the solution was concentrated to dryness to obtain a white solid product H: 13.0 g, with a yield of 95%.

[0079] LC-MS (ESI, m / z, C7H) 12 ClN3O, 154, M (free base) + H)

[0080] 1 H NMR (400 MHz, DMSO)δ: 8.42 (s,2H), 8.25(s,1H), 7.83(s,1H) 3.51-3.40(m,3H), 2.15-1.84(m,5H). Example 2:

[0081] Synthesis of (S)-2-amino-3-((S)-2-carbonylpyrrolidone-3-yl-5,5-dideuterated)propionitrile hydrochloride (compound H-2D1)

[0082] Representative routes

[0083]

[0084] For the preparation of compound B, please refer to Example 1.

[0085] Sodium borodeuteride (6.7 g, 0.16 mol) was added in portions to a THF (50 g, 0.159 mol) solution of compound B (50 g, 0.159 mol) and cobalt chloride (20.6 g). After the addition was complete, the mixture was allowed to react at room temperature for 4 hours. After the reaction was confirmed to be largely complete by TCL, the mixture was quenched with water and dilute hydrochloric acid at -5 to -5°C, resulting in phase separation. The aqueous phase was extracted with EA, and the organic phases were combined and concentrated to replace the THF (500 ml) solution. TEA (100 ml) was added, and the mixture was heated to 50-60°C and stirred for 16 hours. After the reaction was confirmed to be largely complete by TCL, water (150 ml) was added to dissolve the reaction solution, resulting in phase separation. The aqueous phase was extracted twice with DCM, and the organic phases were combined, dried, and concentrated to obtain an oily crude product, D-2D1. Purification by column chromatography yielded a white solid powder, D-2D1: 32.1 g, with a yield of 70%.

[0086] LC-MS (ESI, m / z, C) 13 H 20 D2N2O5, 289, M+H)

[0087] The preparation of subsequent intermediates is as described in Example 1.

[0088] Compound H-2D1 was obtained: 15.3 g.

[0089] LC-MS (ESI, m / z, C7H) 10 D2ClN3O, 156, M (free base) + H)

[0090] 1 H NMR (400 MHz, DMSO)δ: 8.42(s,2H), 8.26(s,1H), 7.82(s,1H), 3.56(m,1H), 2.19-1.92(m,5H). Example 3:

[0091] Synthesis of (s)-2-amino-3-((s)-2-carbonylpyrrolidone-3-yl)propionitrile-2-deuterated hydrochloride (compound H-1D)

[0092] Representative routes

[0093]

[0094] For the preparation of intermediate compound E, please refer to Example 1.

[0095] Preparation of intermediate compound E-1D

[0096] Compound E (10 g, 36.7 mmol), Ru / C (0.5 g, 5 wt%), NaOH (4.4 g, 0.11 mol), and heavy water (100 ml) were added to a hydrogenation flask. The mixture was purged with hydrogen three times and reacted at 0.1–0.12 MPa and 70–75 °C with stirring for 52 hours. The reaction was monitored by ¹H NMR until complete conversion. The mixture was then cooled, filtered, and the pH of the filtrate was adjusted to 5–6. The filtrate was extracted three times with EA (extractant extract), and the combined organic phases were concentrated to dryness to obtain compound E-1D: 9.2 g, yield 92%.

[0097] LC-MS (ESI, m / z, C) 12 H 19 DN2O5, 274, M+H)

[0098] The preparation of subsequent intermediates is as described in Example 1.

[0099] Compound H-1D was obtained: 4.8 g.

[0100] LC-MS (ESI, m / z, C7H) 11 DClN3O, 155.2, M (free base) + H)

[0101] 1H NMR (400 MHz, DMSO)δ: 8.43 (s,2H), 8.27(s,1H), 7.82(s,1H), 3.53-3.44(m,2H), 2.20-1.92(m,5H). Example 4:

[0102] Synthesis of (s)-2-amino-3-((s)-2-carbonylpyrrolidone-3-yl-3-deuterated)propionitrile-2-deuterated hydrochloride (compound H-2D2)

[0103] Representative routes

[0104]

[0105] For the preparation of intermediate compound F-1D, please refer to Example 1.

[0106] Preparation of intermediate compound F-2D2

[0107] Compound F-1D (13.6 g, 0.05 mol), potassium carbonate (20.7 g, 0.15 mol), and heavy water (150 ml) were added to a reaction flask and stirred at 80 °C for 48 hours. The mixture was extracted with EA, dried over anhydrous sodium sulfate, separated by SFC, and concentrated to dryness to give a white solid product F-2D2: 6.3 g, yield 46%.

[0108] LC-MS (ESI, m / z, C) 12 H 19 D2N3O4, 274, M+H)

[0109] The preparation of subsequent intermediates is as described in Example 1.

[0110] Compound H-2D2 was obtained: 3.6 g.

[0111] LC-MS (ESI, m / z, C7H) 10 D2ClN3O, 156, M (free base) + H)

[0112] 1H NMR (400 MHz, DMSO)δ: 8.42(s,2H), 8.26(s,1H), 7.82(s,1H), 3.53-3.40(m,2H), 2.20-1.95(m,4H). Example 5:

[0113] Synthesis of (s)-2-amino-3-((s)-2-carbonylpyrrolidone-3-yl-3-deuterated-5,5-dideuterated)propionitrile-2-deuterated hydrochloride (compound H-4D)

[0114]

[0115] Chemical formula: C7H8D 24 FClN3O

[0116] Molecular weight: 193.67

[0117] Compound H-4D can be synthesized according to the representative routes described in Examples 2 and 4.

[0118] LC-MS (ESI, m / z, C7H8D2ClN3O, 158, M (free base) + H)

[0119] 1 H NMR (400 MHz, DMSO)δ: 8.43 (s,2H), 8.24(s,1H), 7.81(s,1H), 2.20-1.94(m,4H). Example 6:

[0120] Synthesis of (s)-3,3-dimethyl-2-(2,2,2-trifluoroacetamide)butyric acid (K)

[0121] Representative routes

[0122]

[0123] At -5 to -5°C, methyl trifluoroacetate (10.2 g, 80 mmol) and anhydrous tetrahydrofuran were added to a reaction flask. After stirring at this temperature for 15 minutes, L-tert-leucine (10 g, 76.2 mmol) was added, and the mixture was stirred at this temperature for 1 hour after the addition was complete. TLC analysis showed that the reaction was almost complete. After concentration, crude compound K was obtained, and column chromatography purification yielded a white solid powder K: 15.6 g, yield 90%.

[0124] LC-MS (ESI, m / z, C8H) 12 F3NO3, 228, M+H)

[0125] 1H NMR (400 MHz, DMSO)δ: 12.22 (s,1H), 8.30 (s,1H), 4.09 (s,1H), 0.92 (s,9H). Example 7:

[0126] Synthesis of (s)-3,3-dimethyl-2-(2,2,2-trifluoroacetamide)-2-deuterated-butyric acid (K-1D)

[0127] Representative routes

[0128]

[0129] Preparation of intermediate compound SM2-1D

[0130] L-tert-leucine (10 g, 76.2 mmol), Ru / C (0.5 g, 5 wt%), NaOH (4.4 g, 0.11 mol), and heavy water (100 ml) were added to a hydrogenation flask. The mixture was purged with hydrogen three times and reacted at 0.1–0.12 MPa and 70–75 °C with stirring for 52 hours. The reaction was monitored by ¹H NMR until complete conversion. The mixture was then cooled, filtered, and the pH of the filtrate was adjusted to 5–6. The filtrate was extracted three times with EA, and the combined organic phases were concentrated to dryness to give a white solid product SM₂-1D: 9.5 g, yield 94%.

[0131] LC-MS (ESI, m / z, C6H) 12 DNO2, 133, M+H)

[0132] Preparation of intermediate compound K-1D

[0133] At -5 to -5°C, methyl trifluoroacetate (9.6 g, 75.4 mmol) and anhydrous tetrahydrofuran were added to a reaction flask. After stirring at this temperature for 15 minutes, SM2-1D (9.5 g, 71.8 mmol) was added, and the mixture was stirred at this temperature for 1 hour after the addition was complete. TLC analysis showed that the reaction was almost complete. A certain amount of dilute hydrochloric acid was added to release the free product, and the product was concentrated to obtain crude compound K-1D. Column chromatography purification yielded 15.1 g of white solid powder K-1D, with a yield of 92%.

[0134] LC-MS (ESI, m / z, C8H) 11 DF3NO3, 229, M+H)

[0135] 1H NMR (400 MHz, DMSO)δ: 12.18 (s,1H), 8.14 (s,1H), 0.91 (s,9H). Example 8:

[0136] Synthesis of (s)-3,3-dideuterated methyl-2-(2,2,2-trifluoroacetamide)-4,4,4-deuterated butyric acid (K-9D)

[0137] Representative routes

[0138]

[0139] Chemical formula: C8H3D9F3NO3

[0140] Molecular weight: 236.24

[0141] Compound K-9D can be synthesized according to the representative route described in Example 6.

[0142] LC-MS (ESI, m / z, C8H3D9F3NO3, 237, M+H)

[0143] 1H NMR (400 MHz, DMSO)δ: 12.23 (s,1H), 8.30 (s,1H), 4.19 (s,1H). Example 9:

[0144] Synthesis of (s)-3,3-dideuterated methyl-2-(2,2,2-trifluoroacetamide)-2-4,4,4-deuterated butyric acid (K-10D)

[0145]

[0146] Chemical formula: C8H2D 10 F3NO3

[0147] Molecular weight: 237.24

[0148] Compound K-10D can be synthesized according to the representative route described in Example 7.

[0149] LC-MS (ESI, m / z, C8H2D) 10 F3NO3, 238.1, M+H)

[0150] 1H NMR (400 MHz, DMSO)δ: 12.22 (s,1H), 8.18 (s,1H). Example 10:

[0151] Synthesis of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-deuterium-carboxylate methyl ester (SM3-1D)

[0152] Representative routes

[0153]

[0154] Compound (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-methyl formate (SM3: 10 g, 48.6 mmol), Ru / C (0.5 g, 5 wt%), NaOH (9.7 g, 0.24 mol), and heavy water (100 ml) were added to a hydrogenation flask. The mixture was purged with hydrogen three times and reacted at 0.1–0.12 MPa and 70–75 °C with stirring for 52 hours. The reaction was monitored by ¹H NMR until complete conversion. The mixture was then cooled, filtered, and the pH of the filtrate was adjusted to 5–6. The filtrate was extracted three times with EA, and the combined organic phases were concentrated to dryness to obtain a white solid product M: 7 g, yield 92%.

[0155] Compound M and MeOH (100 ml) were added to a reaction flask, and the mixture was refluxed for 1 hour under saturated hydrogen chloride gas at 0-10 °C. After cooling to room temperature, the reaction was monitored by TLC to ensure complete conversion. The product was filtered and dried to obtain a white solid product SM3-1D: 8.9 g, yield 96%.

[0156] LC-MS (ESI, m / z, C9H) 15 DClNO2, 171, M (free base) + H)

[0157] 1H NMR (400 MHz, DMSO)δ: 8.22(s,1H), 3.70(s,3H), 2.87-2.63(m,2H), 2.07(m,1H), 1.68(d,1H), 1.06-0.98(m,1H), 0.87(s,6H). Example 11:

[0158] Synthesis of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4,4-deuterium-carboxylate methyl ester (SM3-3D)

[0159] Representative routes

[0160]

[0161] Compound SM3-1D (10 g, 48.4 mmol), potassium carbonate (31.6 g, 0.23 mol), and heavy water (150 ml) were added to a reaction flask and stirred at 60 °C for 48 hours. The mixture was extracted with EA, dried over anhydrous sodium sulfate, and then ethyl hydrogen chloride solution (4 mol / L, 150 ml) was added. After stirring for 4 hours, the mixture was concentrated to dryness to give a white solid product SM3-3D: 9.3 g, yield 92%.

[0162] LC-MS (ESI, m / z, C9H) 13 D3ClNO2, 173, M (free base) + H)

[0163] 1H NMR (400 MHz, DMSO)δ: 8.22(s,1H), 3.69(s,3H), 2.08(s,1H), 1.65(d,1H), 1.0(d,1H), 0.87(s,6H). Example 12:

[0164] Synthesis of Compound 1

[0165] Representative routes

[0166]

[0167] Preparation of intermediate compound M

[0168] Compound K (5 g, 22 mmol), SM3 (4.9 g, 22 mmol), and acetonitrile (100 mL) were added to a reaction flask and stirred. BOP (9.7 g, 22 mmol) and TEA (4.4 g, 44 mmol) were then added sequentially. The mixture was stirred at room temperature for 2 hours. TLC analysis showed that the reaction was essentially complete. After adding water (50 mL), the mixture was extracted three times with EA. The combined organic phases were washed successively with 2 mol / L HCl, 5% NaHCO3, and water. The mixture was dried over anhydrous magnesium sulfate and concentrated to dryness to give an off-white solid product M: 8.0 g, yield 96.1%.

[0169] LC-MS (ESI, m / z, C) 17 H 25 F3N2O4, 379, M+H)

[0170] Preparation of Compound 1

[0171] At room temperature, M (8 g, 21.1 mmol) was dissolved in THF (80 ml) and MeOH (80 ml). An aqueous solution of lithium hydroxide (1.5 g, 62.8 mmol) (15 ml) was added, and the mixture was stirred at room temperature for 2 hours. The temperature was adjusted to 0-10 °C, ethyl acetate was added, and the reaction solution was adjusted to acidity with 1 N HCl. The layers were separated, and the aqueous phase was extracted twice with EA. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness to obtain the crude product. Column chromatography was used to purify the hydrolysate of M.

[0172] Add the hydrolyzed compound obtained in the previous step and DMF (100 ml) to a reaction flask and adjust the temperature to 0-10°C. At this temperature, add EDCI (4.9 g, 25.6 mmol), HOBt (3.4 g, 25.2 mmol), and NMM (4.3 g, 42.5 mmol) sequentially, and stir for 30 minutes at this temperature. Then, add in portions at this temperature.

[0173] H-2D1 (4.0 g, 21 mmol) was added and stirred overnight at room temperature. TLC showed that the reaction was almost complete. After adding water (80 ml), the mixture was extracted three times with EA. The organic phases were combined and washed successively with 0.5 mol / L HCl, 5% NaHCO3, and water. The mixture was dried over anhydrous magnesium sulfate and concentrated to dryness to give crude product 1. Column chromatography gave product 1 (8.4 g) as an off-white solid, yield 79.7%.

[0174] LC-MS (ESI, m / z, C) 23 H 30 D2F3N5O4, 5O2, M+H)

[0175] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H).

[0176] Examples 13-74 were prepared using a preparation method similar to that described in Example 12. Example 13:

[0177] Synthesis of Compound 2

[0178]

[0179] Chemical formula: C 23 H 31 DF3N5O4

[0180] Molecular weight: 500.54

[0181] LC-MS (ESI, m / z, C) 23 H 31 DF3N5O4, 501, M+H)

[0182] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.67(s,1H), 4.43-4.41(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 14:

[0183] Synthesis of Compound 3

[0184]

[0185] Chemical formula: C 23 H 30 D2F3N5O4

[0186] Molecular weight: 501.55

[0187] LC-MS (ESI, m / z, C) 23 H 30 D2F3N5O4, 5O2, M+H)

[0188] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.06-9.02(m,1H), 7.69(s,1H), 4.44-4.40(m,1H), 4.16(s,1H), 3.93-3.90(m,1H), 3.71-3.68(m,1H), 3.14(m,1H), 3.05(m,1H), 2.18(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.30(m,1H), 1.03(s,3H) , 0.98(s,9H), 0.85(s,3H). Example 15:

[0189] Synthesis of Compound 4

[0190]

[0191] Chemical formula: C 23 H 29 D3F3N5O4

[0192] Molecular weight: 502.55

[0193] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0194] 1H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.44-4.41(m,1H), 4.15(s,1H), 3.94-3.91(m,1H), 3.71-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 16:

[0195] Synthesis of Compound 5

[0196]

[0197] Chemical formula: C 23 H 28 D4F3N5O4

[0198] Molecular weight: 503.56

[0199] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0200] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 4.44-4.40(m,1H), 4.15(s,1H), 3.94-3.90(m,1H), 3.72-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 17:

[0201] Synthesis of Compound 6

[0202]

[0203] Chemical formula: C 23 H 31 DF3N5O4

[0204] Molecular weight: 500.54

[0205] LC-MS (ESI, m / z, C) 23 H 31 DF3N5O4, 501, M+H)

[0206] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.03-4.94(m,1H), 4.45-4.41(m,1H), 3.94-3.91(m,1H), 3.73-3.69(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) , 0.98 (s, 9H), 0.85 (s, 3H). Example 18:

[0207] Synthesis of Compound 7

[0208]

[0209] Chemical formula: C 23 H 29 D3F3N5O4

[0210] Molecular weight: 502.55

[0211] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0212] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.02-4.94(m,1H), 4.44-4.41(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.98(s,9H),0.85(s,3H). Example 19:

[0213] Synthesis of Compound 8

[0214]

[0215] Chemical formula: C 23 H 29 D3F3N5O4

[0216] Molecular weight: 502.55

[0217] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0218] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.03-4.94(m,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 20:

[0219] Synthesis of Compound 9

[0220]

[0221] Chemical formula: C 23 H 27 D5F3N5O4

[0222] Molecular weight: 504.57

[0223] LC-MS (ESI, m / z, C) 23 H 27 D5F3N5O4, 505, M+H)

[0224] 1 H NMR (400 MHz, DMSO)δ : 8.32(s,1H), 8.18(s,1H), 7.79(s,1H), 4.50(m,1H), 4.24(s,1H), 2.20-1.90(m,5H), 1.3(d,1H,J=8Hz), 0.97-0.89(m,16H).

[0225] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.02-4.94(m,1H), 4.43-4.41(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 21:

[0226] Synthesis of Compound 10

[0227]

[0228] Chemical formula: C 23 H 30 D2F3N5O4

[0229] Molecular weight: 501.55

[0230] LC-MS (ESI, m / z, C) 23 H 30 D2F3N5O4, 5O2, M+H)

[0231] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.02(m,1H), 7.67(s,1H), 4.44-4.41(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 22:

[0232] Synthesis of Compound 11

[0233]

[0234] Chemical formula: C 23 H 29 D3F3N5O4

[0235] Molecular weight: 502.55

[0236] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O2, M+H)

[0237] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.67(s,1H), 4.44-4.40(m,1H), 3.92-3.90(m,1H), 3.71-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 23:

[0238] Synthesis of Compound 12

[0239]

[0240] Chemical formula: C 23 H 27 D5F3N5O4

[0241] Molecular weight: 504.57

[0242] LC-MS (ESI, m / z, C) 23 H 27 D5F3N5O4, 505, M+H)

[0243] 1 H NMR (400 MHz, DMSO)δ : 8.32(s,1H), 8.18(s,1H), 7.79(s,1H), 4.24(s,1H), 3.45-3.35(m,2H), 2.2-1.9(m,4H), 1.3(d,1H,J=8Hz), 0.97-0.89(m,16H).

[0244] 1H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.04-9.01(m,1H), 7.67(s,1H), 4.44-4.40(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 24:

[0245] Synthesis of Compound 13

[0246]

[0247] Chemical formula: C 23 H 28 D4F3N5O4

[0248] Molecular weight: 503.56

[0249] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0250] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.04-9.02(m,1H), 7.68(s,1H), 4.44-4.40(m,1H), 3.93-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 25:

[0251] Synthesis of Compound 14

[0252]

[0253] Chemical formula: C 23 H 27 D5F3N5O4

[0254] Molecular weight: 504.57

[0255] LC-MS (ESI, m / z, C)23 H 27 D5F3N5O4, 505, M+H)

[0256] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 3.93-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 26:

[0257] Synthesis of Compound 15

[0258]

[0259] Chemical formula: C 23 H 25 D7F3N5O4

[0260] Molecular weight: 506.58

[0261] LC-MS (ESI, m / z, C) 23 H 25 D7F3N5O4, 507, M+H)

[0262] 1 H NMR (600 MHz, DMSO)δ : 9.43-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.45-4.40(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 27:

[0263] Synthesis of Compound 16

[0264]

[0265] Chemical formula: C 23 H 31 DF3N5O4

[0266] Molecular weight: 500.54

[0267] LC-MS (ESI, m / z, C) 23 H 31 DF3N5O4, 501, M+H)

[0268] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 5.02-4.94(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 28:

[0269] Synthesis of Compound 17

[0270]

[0271] Chemical formula: C 23 H 29 D3F3N5O4

[0272] Molecular weight: 502.55

[0273] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0274] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.01-4.94(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 29:

[0275] Synthesis of Compound 18

[0276]

[0277] Chemical formula: C 23 H 30 D2F3N5O4

[0278] Molecular weight: 501.55

[0279] LC-MS (ESI, m / z, C) 23 H 30 D2F3N5O4, 5O2, M+H)

[0280] 1 H NMR (600 MHz, DMSO)δ : 9.43-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H),2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H),1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 30:

[0281] Synthesis of Compound 19

[0282]

[0283] Chemical formula: C 23 H 29 D3F3N5O4

[0284] Molecular weight: 502.55

[0285] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0286] 1H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.98(s,9H),0.85(s,3H). Example 31:

[0287] Synthesis of Compound 20

[0288]

[0289] Chemical formula: C 23 H 28 D4F3N5O4

[0290] Molecular weight: 503.56

[0291] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0292] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H),2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 32:

[0293] Synthesis of Compound 21

[0294]

[0295] Chemical formula: C 23 H 27 D5F3N5O4

[0296] Molecular weight: 504.57

[0297] LC-MS (ESI, m / z, C) 23 H 27 D5F3N5O4, 505, M+H)

[0298] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 33:

[0299] Synthesis of Compound 22

[0300]

[0301] Chemical formula: C 23 H 30 D2F3N5O4

[0302] Molecular weight: 501.55

[0303] LC-MS (ESI, m / z, C) 23 H 30 D2F3N5O4, 5O2, M+H)

[0304] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.01-4.95(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 34:

[0305] Synthesis of Compound 23

[0306]

[0307] Chemical formula: C 23 H 28 D4F3N5O4

[0308] Molecular weight: 503.56

[0309] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0310] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.01-4.94(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 35:

[0311] Synthesis of Compound 24

[0312]

[0313] Chemical formula: C 23 H 28 D4F3N5O4

[0314] Molecular weight: 503.56

[0315] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0316] 1 H NMR(600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.01-4.94(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 36:

[0317] Synthesis of Compound 25

[0318]

[0319] Chemical formula: C 23 H 26 D6F3N5O4

[0320] Molecular weight: 505.57

[0321] LC-MS (ESI, m / z, C) 23 H 26 D6F3N5O4, 5O6, M+H)

[0322] 1 H NMR(600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 37:

[0323] Synthesis of Compound 26

[0324]

[0325] Chemical formula: C 23 H 29 D3F3N5O4

[0326] Molecular weight: 502.55

[0327] LC-MS (ESI, m / z, C) 23 H 29 D3F3N5O4, 5O3, M+H)

[0328] 1H NMR (600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.98(s,9H),0.85(s,3H). Example 38:

[0329] Synthesis of Compound 27

[0330]

[0331] Chemical formula: C 23 H 28 D4F3N5O4

[0332] Molecular weight: 503.56

[0333] LC-MS (ESI, m / z, C) 23 H 28 D4F3N5O4, 5O4, M+H)

[0334] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H),2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 39:

[0335] Synthesis of Compound 28

[0336]

[0337] Chemical formula: C 23 H 26 D6F3N5O4

[0338] Molecular weight: 505.57

[0339] LC-MS (ESI, m / z, C) 23 H 26 D6F3N5O4, 5O6, M+H)

[0340] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.03(m,1H), 7.68(s,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 40:

[0341] Synthesis of Compound 29

[0342]

[0343] Chemical formula: C 23 H 27 D5F3N5O4

[0344] Molecular weight: 504.57

[0345] LC-MS (ESI, m / z, C) 23 H 27 D5F3N5O4, 505, M+H)

[0346] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 41:

[0347] Synthesis of Compound 30

[0348]

[0349] Chemical formula: C 23 H 26 D6F3N5O4

[0350] Molecular weight: 505.57

[0351] LC-MS (ESI, m / z, C) 23 H 26 D6F3N5O4, 5O6, M+H)

[0352] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 3.93-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H),1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 42:

[0353] Synthesis of Compound 31

[0354]

[0355] Chemical formula: C 23 H 24 D8F3N5O4

[0356] Molecular weight: 507.58

[0357] LC-MS (ESI, m / z, C) 23 H 24 D8F3N5O4, 508, M+H)

[0358] 1 H NMR (600 MHz, DMSO)δ : 9.43-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.98(s,9H), 0.85(s,3H). Example 43:

[0359] Synthesis of Compound 32

[0360]

[0361] Chemical formula: C 23 H 23D8F3N5O4

[0362] Molecular weight: 508.59

[0363] LC-MS (ESI, m / z, C) 23 H 23 D8F3N5O4, 509, M+H)

[0364] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.85(s,3H). Example 44:

[0365] Synthesis of Compound 33

[0366]

[0367] Chemical formula: C 23 H 21 D 11 F3N5O4

[0368] Molecular weight: 510.60

[0369] LC-MS (ESI, m / z, C) 23 H 21 D 11 F3N5O4, 511, M+H)

[0370] 1H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 45:

[0371] Synthesis of Compound 34

[0372]

[0373] Chemical formula: C 23 H 22 D 10 F3N5O4

[0374] Molecular weight: 509.60

[0375] LC-MS (ESI, m / z, C) 23 H 22 D 10 F3N5O4, 510, M+H)

[0376] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 46:

[0377] Synthesis of Compound 35

[0378]

[0379] Chemical formula: C 23 H 21 D11 F3N5O4

[0380] Molecular weight: 510.60

[0381] LC-MS (ESI, m / z, C) 23 H 21 D 11 F3N5O4, 511, M+H)

[0382] 1 H NMR (600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.00(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.85(s,3H). Example 47:

[0383] Synthesis of Compound 36

[0384]

[0385] Chemical formula: C 23 H 20 D 12 F3N5O4

[0386] Molecular weight: 511.61

[0387] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0388] 1H NMR (600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 48:

[0389] Synthesis of Compound 37

[0390]

[0391] Chemical formula: C 23 H 19 D 13 F3N5O4

[0392] Molecular weight: 512.61

[0393] LC-MS (ESI, m / z, C) 23 H 19 D 13 F3N5O4, 513, M+H)

[0394] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 49:

[0395] Synthesis of Compound 38

[0396]

[0397] Chemical formula: C 23 H 22 D 10 F3N5O4

[0398] Molecular weight: 509.60

[0399] LC-MS (ESI, m / z, C) 23 H 22 D 10 F3N5O4, 510, M+H)

[0400] 1 H NMR(600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 50:

[0401] Synthesis of Compound 39

[0402]

[0403] Chemical formula: C 23 H 20 D 12 F3N5O4

[0404] Molecular weight: 511.61

[0405] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0406] 1 H NMR(600 MHz, DMSO)δ: 9.43-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 51:

[0407] Synthesis of Compound 40

[0408]

[0409] Chemical formula: C 23 H 20 D 12 F3N5O4

[0410] Molecular weight: 511.61

[0411] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0412] 1 H NMR(600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 52:

[0413] Synthesis of Compound 41

[0414]

[0415] Chemical formula: C 23 H 18 D 14 F3N5O4

[0416] Molecular weight: 513.62

[0417] LC-MS (ESI, m / z, C) 23 H 18 D 14 F3N5O4, 514, M+H)

[0418] 1H NMR(600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.43-4.40(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H. Example 53:

[0419] Synthesis of Compound 42

[0420]

[0421] Chemical formula: C 23 H 21 D 11 F3N5O4

[0422] Molecular weight: 510.60

[0423] LC-MS (ESI, m / z, C) 23 H 21 D 11 F3N5O4, 511.3, M+H)

[0424] 1 H NMR (600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.85(s,3H). Example 54:

[0425] Synthesis of Compound 43

[0426]

[0427] Chemical formula: C 23 H 20 D 12 F3N5O4

[0428] Molecular weight: 511.61

[0429] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0430] 1 H NMR(600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.0(m,1H), 7.68(s,1H),4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 55:

[0431] Synthesis of Compound 44

[0432]

[0433] Chemical formula: C 23 H 18 D 14 F3N5O4

[0434] Molecular weight: 513.62

[0435] LC-MS (ESI, m / z, C) 23 H 18 D 14 F3N5O4, 514.3, M+H)

[0436] 1 H NMR (600 MHz, DMSO)δ : 9.43-9.40(m,1H), 9.05-9.1(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 56:

[0437] Synthesis of Compound 45

[0438]

[0439] Chemical formula: C 23 H 19 D 13 F3N5O4

[0440] Molecular weight: 512.61

[0441] LC-MS (ESI, m / z, C) 23 H 19 D 13 F3N5O4, 513, M+H)

[0442] 1 H NMR (600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 57:

[0443] Synthesis of Compound 46

[0444]

[0445] Chemical formula: C 23 H 18 D 14 F3N5O4

[0446] Molecular weight: 513.62

[0447] LC-MS (ESI, m / z, C) 23 H 18 D 14 F3N5O4, 514, M+H)

[0448] 1H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 58:

[0449] Synthesis of Compound 47

[0450]

[0451] Chemical formula: C 23 H 16 D 16 F3N5O4

[0452] Molecular weight: 515.63

[0453] LC-MS (ESI, m / z, C) 23 H 16 D 16 F3N5O4, 516, M+H)

[0454] 1 H NMR (600 MHz, DMSO)δ : 9.45-9.41(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 4.43-4.40(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 59:

[0455] Synthesis of Compound 48

[0456]

[0457] Chemical formula: C 23 H 22 D 10 F3N5O4

[0458] Molecular weight: 509.60

[0459] LC-MS (ESI, m / z, C) 23 H22 D 10 F3N5O4, 510, M+H)

[0460] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 60:

[0461] Synthesis of Compound 49

[0462]

[0463] Chemical formula: C 23 H 20 D 12 F3N5O4

[0464] Molecular weight: 511.61

[0465] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0466] 1 H NMR (600 MHz, DMSO)δ : 9.44-9.40(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 61:

[0467] Synthesis of Compound 50

[0468]

[0469] Chemical formula: C 23 H 21 D 11 F3N5O4

[0470] Molecular weight: 510.60

[0471] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 511, M+H)

[0472] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.41(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H),2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H),1.03(s,3H) ,0.85(s,3H). Example 62:

[0473] Synthesis of Compound 51

[0474]

[0475] Chemical formula: C 23 H 20 D 12 F3N5O4

[0476] Molecular weight: 511.61

[0477] LC-MS (ESI, m / z, C) 23 H 20 D 12 F3N5O4, 512, M+H)

[0478] 1H NMR (600 MHz, DMSO)δ : 9.45-9.40(m,1H), 9.05-9.00(m,1H), 7.68(s,1H), 4.15(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 63:

[0479] Synthesis of Compound 52

[0480]

[0481] Chemical formula: C 23 H 18 D 14 F3N5O4

[0482] Molecular weight: 513.62

[0483] LC-MS (ESI, m / z, C) 23 H 18 D 14 F3N5O4, 514, M+H)

[0484] 1 H NMR(600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 64:

[0485] Synthesis of Compound 53

[0486]

[0487] Chemical formula: C 23 H 17 D 15 F3N5O4

[0488] Molecular weight: 514.63

[0489] LC-MS (ESI, m / z, C) 23 H 17 D 15 F3N5O4, 515, M+H)

[0490] 1 H NMR(600 MHz, DMSO)δ: 9.45-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H),1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 65:

[0491] Synthesis of Compound 54

[0492]

[0493] Chemical formula: C 23 H 21 D 11 F3N5O4

[0494] Molecular weight: 510.60

[0495] LC-MS (ESI, m / z, C) 23 H 21 D 11 F3N5O4, 511, M+H)

[0496] 1 H NMR(600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H) ,0.85(s,3H). Example 66:

[0497] Synthesis of Compound 55

[0498]

[0499] Chemical formula: C 23 H 19 D 13 F3N5O4

[0500] Molecular weight: 512.61

[0501] LC-MS (ESI, m / z, C) 23 H 19 D 13 F3N5O4, 513, M+H)

[0502] 1 H NMR(600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 5.0-4.94(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 67:

[0503] Synthesis of Compound 56

[0504]

[0505] Chemical formula: C 23 H 19 D 13 F3N5O4

[0506] Molecular weight: 512.61

[0507] LC-MS (ESI, m / z, C) 23 H 19 D 13 F3N5O4, 513, M+H)

[0508] 1H NMR (600 MHz, DMSO)δ : 9.45-9.40(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 68:

[0509] Synthesis of Compound 57

[0510]

[0511] Chemical formula: C 23 H 17 D 15 F3N5O4

[0512] Molecular weight: 514.63

[0513] LC-MS (ESI, m / z, C) 23 H 17 D 15 F3N5O4, 515, M+H)

[0514] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 69:

[0515] Synthesis of Compound 58

[0516]

[0517] Chemical formula: C 23 H 20 D 12 F3N5O4

[0518] Molecular weight: 511.61

[0519] LC-MS (ESI, m / z, C) 23 H 20 D12 F3N5O4, 512, M+H)

[0520] 1 H NMR (600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.06-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.42(m,1H),2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 70:

[0521] Synthesis of Compound 59

[0522]

[0523] Chemical formula: C 23 H 19 D 13 F3N5O4

[0524] Molecular weight: 512.61

[0525] LC-MS (ESI, m / z, C) 23 H 19 D 13 F3N5O4, 513, M+H)

[0526] 1 H NMR(600 MHz, DMSO)δ: 9.43-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H),2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 71:

[0527] Synthesis of Compound 60

[0528]

[0529] Chemical formula: C 23 H 17D 15 F3N5O4

[0530] Molecular weight: 514.63

[0531] LC-MS (ESI, m / z, C) 23 H 17 D 15 F3N5O4, 515, M+H)

[0532] 1 H NMR(600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.01(m,1H), 7.68(s,1H), 3.14(m,1H), 3.04(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 72:

[0533] Synthesis of Compound 61

[0534]

[0535] Chemical formula: C 23 H 18 D 14 F3N5O4

[0536] Molecular weight: 513.62

[0537] LC-MS (ESI, m / z, C) 23 H 18 D 14 F3N5O4, 514, M+H)

[0538] 1 H NMR (600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.42(m,1H), 2.19(m,1H), 2.10(m,1H),1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H),0.85(s,3H). Example 73:

[0539] Synthesis of Compound 62

[0540]

[0541] Chemical formula: C 23 H 17 D 15 F3N5O4

[0542] Molecular weight: 514.63

[0543] LC-MS (ESI, m / z, C) 23 H 17 D 15 F3N5O4, 515, M+H)

[0544] 1 H NMR (600 MHz, DMSO)δ: 9.44-9.40(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 3.92-3.90(m,1H), 3.70-3.68(m,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H),1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H). Example 74:

[0545] Synthesis of Compound 63

[0546]

[0547] Chemical formula: C 23 H 15 D 17 F3N5O4

[0548] Molecular weight: 516.64

[0549] LC-MS (ESI, m / z, C) 23 H 15 D 17 F3N5O4, 517.3, M+H)

[0550] 1 H NMR (600 MHz, DMSO)δ: 9.45-9.41(m,1H), 9.05-9.02(m,1H), 7.68(s,1H), 2.19(m,1H), 2.10(m,1H), 1.73(s,2H), 1.57(m,1H), 1.33-1.31(m,1H), 1.03(s,3H), 0.85(s,3H).

[0551] Example 75:

[0552] In vitro anti-SARS-CoV-2 virus experiment

[0553] Cell plating: Vero E6 cells were plated at a density of 3 × 10⁶ cells / cm². 5 Cells / well were seeded into 12-well plates, and DMEM medium with 10% FBS was added. The plates were then incubated overnight at 37°C with 5% CO2. Drug treatment: The culture medium for Vero cells was removed from the 12-well plates, and VeroE6 cells were washed with PBS buffer. The compound (final concentration 100 nM) was added to 50 μL / well of cell culture, and the plates were incubated at 37°C with 5% CO2 for 1 hour. 50 μL / well of culture medium was used as a control. Virus infection: Cells were infected with SARS-CoV-2 virus for 2 hours. The virus-drug mixture was removed, and DMEM medium with 10% FBS was added. The plates were incubated at 37°C with 5% CO2 for 2–3 days. PCR assay: The supernatant of the culture medium was collected and incubated at 56°C for 30 min. Viral RNA was extracted using a viral RNA extraction kit, and PCR was performed using a viral nucleic acid detection kit according to the instructions. The CT value displayed by the PCR instrument was used to calculate the 22. -ΔCT The formula for calculating the viral replication inhibition rate is: (1-2) -ΔCT ) × 100%, of which, 2 -ΔCT The values ​​represent the relative viral replication rates between the drug group and the control group (tannic acid). The results are shown in Table 2.

[0554] Table 2. Viral replication rate results in the drug group and the control group.

[0555] Group Chemical 1 Chemical 2 Chemicals 16 Chemicals 32 PF-07321332 Comparison Inhibition rate (%) 71.5 73.5 72.6 70.4 72.9 54.1

[0556] Example 76:

[0557] This example targets SARS-CoV-2 virus M. Pro Protease activity inhibition assay

[0558] Detection principle: 3-chymotrypsin-like protease, i.e., the main protease (M... Pro Also known as 3CL ProEncoded by ORF1 (located in nsp5), this protein is situated in the central region of the replicase gene and is a key protein in the replication of the novel coronavirus RNA. Its mechanism of action is as follows: After invading cells, the novel coronavirus utilizes the host cell to synthesize two very long replicase polypeptides (ppla and pplab), essential for its own replication. These replicase polypeptides need to be further cleaved into multiple proteins (such as RdRp and helicase), which are then assembled into the replication transcription machinery required for the virus to initiate the replication of its own genetic material. Pro The replicase polypeptide has at least 11 cleavage sites. Only when these sites are properly cleaved can the replication transcription machinery assemble and initiate viral replication. Given M... Pro Proteases are crucial in viral replication, and no similar proteins exist in the human body; therefore, the main protease M... Pro This could become a key potential drug target against SARS-CoV-2. The effects of nucleoside derivatives on SARS-CoV-2-M were evaluated using fluorescence resonance energy transfer (FRET). Pro Inhibitory activity of proteases.

[0559] Specific detection method: The total volume of the enzymatic reaction system was 120 μL, the final concentration of the protease was 30 nM, the final concentration of the substrate was 20 μM, and the buffer solution of the reaction system included 50 mM Tris and 1 mM EDTA at pH 7.3. SARS-CoV-2-M was added to a 96-well plate. Pro The protease and different concentrations of the target compound were incubated at 30 °C for 10 min. The substrate was then added and the sample was quickly transferred to a microplate reader for reading. The excitation and emission wavelengths were 340 nm and 405 nm, respectively. The assay lasted 10 min, with fluorescence readings taken every 30 s. The final result was calculated by fitting the reaction rate to the readings from the first 2 mins and comparing it with the control group (DMSO). The inhibition rate was calculated. Using Graghpad Prism 7 plots, the IC50 values ​​of the SARS-CoV-2 viral nucleoside derivatives at the corresponding time points were calculated; specific values ​​are shown in Table 3.

[0560] Table 3: SARS-CoV-2-M Pro IC50 of proteases 50 value

[0561] serial number IC50 (μM) Compound 1 2.948 ± 0.265 μM Compound 2 2.786 ± 0.375 μM Compound 16 2.723 ± 0.476 μM Compound 32 2.835 ± 0.503 μM PF-07321332 2.761 ± 0.382 μM Example 77:

[0562] This example illustrates the pharmacokinetic study of the compound in rats.

[0563] Pharmacokinetic studies were conducted on male Wistar-Hannover rats aged 7–10 weeks. All animals were housed individually during the pharmacokinetic studies. Food and water were provided freely (administered while the animals were feeding). Animals were fasted overnight and fed 4 hours after administration. Blood samples were collected via jugular vein cannulation at predetermined time points following gavage administration of the compound (10 mg / kg). At the end of the study, animals were euthanized by overdose anesthesia followed by exsanguination. Blood samples were collected in tubes containing K2EDTA and stored on ice until centrifugation to obtain plasma, which was then stored at -20°C.

[0564] LC-MS / MS analysis of plasma samples: Plasma samples were processed using protein precipitation with a 500:50 acetonitrile:methanol mixture containing propranolol (50 ng / ml) as an internal standard, and quantification was performed using a standard curve (0.1–2500 ng / ml) prepared from blank plasma. Analytes in plasma samples were quantified using LC-MS / MS. Briefly, a Waters ACQUITY ultra-high performance liquid chromatography system coupled with a Sciex 6500 triple quadrupole mass spectrometer was used. Chromatographic separation was performed using a Waters Acquity UPLC BEH C18 column (1.7 m, 2.1 50 mm). The mobile phase was optimized to achieve good separation between analytes. Typically, solvent A consisted of a 0.025% formic acid and 1 mM ammonium acetate aqueous / acetonitrile solution (95:5 v / v), and solvent B consisted of a 0.025% formic acid and 1 mM ammonium acetate aqueous / acetonitrile solution (5:95 v / v). The gradient typically starts at 3-30% B until approximately 1.2 minutes, then increases to 50-65% B until 1.6 minutes, and then decreases to 10-30% B until approximately 1.7-1.9 minutes. Analyst 1.7 software is used for peak integration and standard curve regression.

[0565] Pharmacokinetic analysis: Pharmacokinetic parameters were calculated using non-compartmental analysis (Watson v.7.5, Thermo Scientific). The area under the plasma concentration-time curve from t=0 to infinity (AUC0-∞) was estimated using the linear trapezoidal rule. The results are shown in Table 4 below. The compounds of this invention exhibit better and longer half-lives and higher plasma exposures in animals, thus demonstrating better therapeutic effects.

[0566] Table 4: Pharmacokinetic parameters of the compounds in rats

[0567] serial number Dosage (mg / kg) <![CDATA[C max (ng / mL)]]> <![CDATA[T max (h)]]> <![CDATA[AUC 0-∞ (ng·h / mL)]]> <![CDATA[T 1 / 2 (h) <!-- 54 -->]]> Compound 1 10 1393 2 1974 3.5 Compound 2 10 1480 2 2325 4.2 Compound 16 10 1452 2 2294 4 Compound 32 10 1429 2 2011 3.5 PF-07321332 10 1445 2 1982 2.9

[0568] Example 78:

[0569] For the preparation method of oral tablets containing deuterated cyano compounds (taking compound 2 as an example)

[0570] Pharmaceutical carriers used in oral tablets include modifiers, fillers, binders, disintegrants, additives, flow aids, lubricants, film coating materials, plasticizers, and colorants.

[0571] Components effect Content (mg / tablet) Compound 2 Drug ingredients 200 starch fillers, disintegrants 100 Calcium hydrogen phosphate filler 20 Pregelatinized starch filler 40 Citric acid regulator 2 Sodium bisulfite additive 0.5 10% starch paste adhesives Appropriate amount magnesium stearate lubricant 1.5 White Opal Coated premix Approximately 4 Water, ethanol solvent Appropriate amount

[0572] Operating instructions:

[0573] Compound 2 was ground and sieved according to the above formula. It was then mixed evenly with fillers, disintegrants, and milled and sieved regulators and additives. 10% starch slurry was added and the mixture was stirred in a mixer to form a soft mass. The soft mass was then granulated on a shaking machine, dried in an oven, and mixed evenly with a lubricant before being pressed into a core. The core was then coated with Opadry to form a film-coated sheet.

[0574] For the preparation method of capsules of deuterated cyano compounds (taking compound 2 as an example)

[0575] Pharmaceutical carriers used in capsules include fillers, binders, disintegrants, additives, and lubricants.

[0576] Components effect Content (mg / capsule) Compound 2 Drug ingredients 200 lactose monohydrate filler 82 Pregelatinized starch fillers, adhesives 38 Sodium carboxymethyl starch Disintegrant 12.5 magnesium stearate lubricant 1.5

[0577] Operating instructions:

[0578] Compound 2 and each excipient were ground and sieved according to the above formula. They were then mixed evenly with fillers, binders, and disintegrants in a certain proportion. The mixture was added to a dry granulator and pressed into strips, which were then crushed into granules by a crusher. The granules were then mixed evenly with an appropriate amount of lubricant and disintegrant and filled into capsules.

[0579] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0580] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the disclosed patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this patent should be determined by the appended claims.

Claims

1. A deuterated cyano compound, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures: , , or .

2. A pharmaceutical composition, characterized by, It contains a pharmaceutically acceptable carrier and the compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2, wherein It includes additional treatment drugs, namely antiviral drugs.

4. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 2, wherein Used to prepare drugs that inhibit 3CL protease.

5. Use according to claim 4, characterized in that, The pharmaceutical composition described herein is used to prepare drugs for treating and preventing COVID-19 infection.

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