NOVEL DEUTERATED CYANO COMPOUNDS, PREPARATION METHODS, COMPOSITIONS AND APPLICATIONS
20250002529 ยท 2025-01-02
Inventors
Cpc classification
C07K5/06034
CHEMISTRY; METALLURGY
International classification
Abstract
Deuterated cyano compounds useful as a 3CL protease inhibitor, methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of treating a viral infection in a human by administering the compounds.
Claims
1.-13. (canceled)
14. A deuterated cyano compound represented by Formula I: ##STR00143## wherein R.sub.1 to R.sub.17 are each independently hydrogen or deuterium and at least one of R.sub.1 to R.sub.17 is deuterium; or a pharmaceutically acceptable salt, isomer, or prodrug thereof.
15. The compound of claim 14, wherein at least one of R.sub.1 to R.sub.2 is deuterium.
16. The compound of claim 14, wherein at least one of R.sub.4 to R.sub.5 is deuterium.
17. The compound of claim 14, wherein at least one of R.sub.6 to R.sub.7 is deuterium.
18. The compound of claim 14, wherein R.sub.8 is deuterium.
19. The compound of claim 14, wherein each of R.sub.9 to R.sub.17 are deuterium.
20. The compound of claim 14, selected from the group consisting of: ##STR00144## ##STR00145## ##STR00146## ##STR00147## or a pharmaceutically acceptable salt thereof.
21. A method for preparing the compound of formula I of claim 14, comprising the steps of: ##STR00148## ##STR00149## (1) condensing compound I-1 with compound I-2 in an organic solvent in the presence of a condensing agent to provide compound I-3; (2) hydrolyzing compound I-3 in an organic solvent in the presence of alkali to provide compound I-4; (3) condensing compound I-4 with compound I-5 in an organic solvent in the presence of a condensing agent to provide the compound of formula I.
22. A pharmaceutical composition comprising the compound as defined in claim 14, and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 22, further comprising an antiviral drug.
24. A method of treating a viral infection in a human comprising administering to the human the pharmaceutical composition of claim 22.
25. The method of claim 24, wherein the viral infection is selected from the group consisting of human coronavirus, SARS-CoV-2, a SARS coronavirus, and a MERS coronavirus.
26. A method of treating a viral infection in a human comprising administering to the human the pharmaceutical composition of claim 23.
27. The method of claim 26, wherein the viral infection is selected from the group consisting of human coronavirus, SARS-CoV-2, a SARS coronavirus, and a MERS coronavirus.
28. A method of inhibiting 3CL protease comprising contacting the 3CL protease with a compound of claim 14.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0008] The invention provides novel deuterated cyano compounds, preparation methods, compositions containing the compounds, and applications using the compounds.
[0009] The invention is directed to deuterated cyano compounds represented by Formula I, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
##STR00001## [0010] wherein R.sub.1 to R.sub.17 are a combination of hydrogen isotopes (including the isotopes protium and deuterium); and [0011] wherein at least one of R.sub.1 to R.sub.17 is deuterium, and pharmaceutically acceptable salts, isomers, and prodrugs thereof.
[0012] In one embodiment, at least one of R.sub.1 to R.sub.2 is deuterium in the compound of formula I.
[0013] In one embodiment, at least one of R.sub.4 to R.sub.5 is deuterium in the compound of formula I.
[0014] In one embodiment, at least one of R.sub.6 to R.sub.7 is deuterium in the compound of formula I.
[0015] In one embodiment, R.sub.8 is deuterium in the compound of formula I.
[0016] In one embodiment, each of R.sub.9 to R.sub.17 are deuterium in the compound of formula I.
[0017] In one embodiment, at least one of R.sub.1 to R.sub.2 is deuterium, at least one of R.sub.6 to R.sub.7 is deuterium, and R.sub.9 to R.sub.17 are all deuterium in the compound of formula I.
[0018] The invention is also directed to a method for preparing the deuterated cyano compounds comprising the following steps:
##STR00002## ##STR00003## [0019] (1) intermediate I-3 is obtained by condensing compound I-1 with compound I-2 by the action of a condensing agent in an organic solvent; [0020] (2) intermediate I-4 is obtained by the hydrolyzing intermediate I-3 under the action of alkali in an organic solvent; and [0021] (3), compound I is obtained by condensing compound I-4 with compound I-5 by the action of condensing agent in an organic solvent.
[0022] In certain embodiments, the invention includes pharmaceutical compositions characterized in that they contain a pharmaceutically acceptable carrier and a compound of formula I, or a pharmaceutically acceptable salt thereof.
[0023] In certain embodiments, the invention is directed to a pharmaceutical composition characterized in that it includes an additional therapeutic agent which is an antiviral drug.
[0024] The invention is directed to the use of the above-mentioned pharmaceutical compositions to prepare a 3CL protease inhibitor.
[0025] The invention is directed to the use of the pharmaceutical compositions to treat a viral infection in humans, wherein the virus is selected from the group consisting of human coronavirus, novel coronavirus (SARS-CoV-2), SARS coronavirus, and MERS coronavirus.
[0026] In various embodiments, the compound has one of the structures shown below in Table 1.
TABLE-US-00001 TABLE 1 Representative Compounds Sr. No. Structure 1
[0027] In certain embodiments, the invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In one embodiment, the pharmaceutical composition is in the form of a tablet; a capsule; a pill; or an aqueous solution, which may be a buffered solution, such as saline or phosphate buffers.
[0028] In certain embodiments, the invention is directed to the use of the compounds described herein to prepare a medicament for the treatment or prevention of a viral infection, such as human coronavirus, novel coronavirus (SARS-CoV-2), SARS coronavirus, or MERS coronavirus.
[0029] In certain embodiments, the invention is directed to a method of preparing the cyano compounds.
[0030] The novel deuterated cyano compounds exhibit better pharmacokinetic properties, better therapeutic effects, and better drug-forming properties than PF-07321332 on the basis of comparable activity as a viral inhibitor. Also disclosed are methods of preparing the compounds, pharmaceutical compositions containing the compounds, and applications using the compounds to treat a viral infection. The methods of making the compounds can be scaled up, and the compounds have good clinical value.
EXAMPLES
[0031] The following detailed descriptions are exemplary and explanatory only and not limiting.
[0032] In the following examples, all solvents and reagents used are commercially available and used as is, unless otherwise indicated.
[0033] The procedures described below can be used to synthesize compounds 1 to 63.
[0034] The following abbreviations are used herein: [0035] BOP: benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate [0036] (Boc).sub.2O: di-tert-butyl dicarbonate [0037] DCM: dichloromethane [0038] D.sub.2O: heavy water [0039] EA: ethyl acetate [0040] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide [0041] HCl/EA: ethyl hydroacetate solution [0042] HOBt: 1-hydroxybenzotriazole [0043] LiHMDS: lithium bis(trimethylsilyl) amine [0044] MeOH: methanol [0045] MTBE: methyl tert-butyl ether [0046] NaOH: sodium hydroxide [0047] NH.sub.3/MeOH: ammonia in methanol [0048] Ni: raney Nickel [0049] NMM: N-Methylmorpholine [0050] SM1: L-Glutamic acid [0051] SOCl.sub.2: dichlorosulfoxide [0052] TEA: triethylamine [0053] THF: tetrahydrofuran [0054] Ru/C: ruthenium carbon
Example 1
Synthesis of(S)-2-Amino-3-((S)-2-carbonylpyrrolidin-3-yl) propionitrile Hydrochloride (Compound H)
Representative Route
##STR00067## ##STR00068##
Preparation of Intermediate Compound A
[0055] A solution of L-glutamic acid (SM1:100 g, 0.68 mol) in MeOH (500 mL) was cooled to about 5 to about 5 C., and SOCl.sub.2 (202 g, 1.70 mol) was added dropwise. After addition, the temperature was raised to reflux. Then the solution was stirred for reaction. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated to dryness. The resulting crude product was dissolved in MeOH (1 L), and TEA (172 g, 1.70 mol) was added dropwise. The resulting solution was cooled to about 5 to about 5 C., and (Boc).sub.2O (148.4 g, 1 eq) was added dropwise. The resulting solution was stirred at about 50 to about 60 C. for about 3 to about 5 hours and then concentrated to dryness. The resulting residue was diluted with saturated sodium bicarbonate (500 mL), then extracted 3 times with MTBE (1 L, 0.5 L, and 0.5 L). The combined organic phase was dried with anhydrous sodium sulfate, and concentrated under vacuum to provide 178 g of compound A as pale yellow oil in a 95% yield. LC-MS (ESI, m/z, C.sub.12H.sub.21NO.sub.6, 276, M+H).
[0056] .sup.1H NMR (400 MHz, CDCl.sub.3) : 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).
Preparation of Intermediate Compound B
[0057] A solution of Compound A (150 g, 0.545 mol) in THF (450 mL) was cooled to 78 C. LiHMDS (1 M, 1.2 L, 1.2 mol) was added dropwise at controlled temperature. After addition, the reaction solution was stirred for 2 hours in a state of thermal insulation. Bromoacetonitrile (98 g, 0.817 mol) was then added dropwise at the above temperature, and the reaction was stirred for 4 hours. After completion of the reaction as indicated by TLC, the reaction solution was quenched by the dropwise addition of a solution of tetrahydrofuran in acetic acid, washed with saturated sodium chloride aqueous solution, and the organic phase dried with anhydrous sodium sulfate and concentrated to obtain crude compound B, which was purified by column chromatography (PE:EA=1:1) to obtain compound B as a pale yellow oil (142 g) in 95% yield. LC-MS (ESI, m/z, C.sub.14H.sub.22N.sub.2O.sub.6, 315, M+H).
[0058] .sup.1H NMR (400 MHz, CDCl.sub.3) : 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).
Preparation of Intermediate Compound D
[0059] To a solution of Compound B (50 g, 0.159 mol) and glacial acetic acid (150 mL) in MeOH (150 mL) was added Raney nickel (10 g) in a hydrogenation cylinder. The gas in the hydrogenation cylinder was replaced with hydrogen gas, and the hydrogen gas maintained at 50-60 psi. The resulting reaction mixture was stirred, maintaining heat and pressure for 4 hours. After completion of the reaction as indicated by TLC, the hydrogen was replaced with nitrogen and the resulting mixture filtered and the filtrate concentrated to dryness. The resulting crude product was dissolved in THF (500 mL), TEA (100 mL) added, and the resulting reaction solution heated to 50-60 C. and stirred for 16 hours. After completion of the reaction as indicated by TLC, the reaction solution was diluted with water (150 mL). The aqueous phase was separated and extracted twice with DCM. The obtained organic phases were combined, dried, and concentrated to afford compound D as a crude oil. The crude oil was purified by column chromatography to yield 27.8 g compound D as a white solid powder in 61% yield. LC-MS (ESI, m/z, C.sub.13H.sub.22N.sub.2O.sub.5, 287, M+H).
[0060] .sup.1H NMR (400 MHz, CDCl.sub.3) : 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).
Preparation of Intermediate Compound E
[0061] To a solution of Compound D (27 g, 0.094 mol) in MeOH (270 mL) was added NaOH (10 g, 0.25 mol) in a reaction flask and the resulting reaction mixture stirred for 4 hours. After the reaction was completed, the reaction mixture 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 with 1N hydrochloric acid solution at 0-10 C., the aqueous phase extracted twice with EA, and the combined organic phases concentrated to provide 25 g of compound E as a white solid powder with a yield of 97%. LC-MS (ESI, m/z, C.sub.13H.sub.20N.sub.2O.sub.5, 273, M+H).
[0062] .sup.1H NMR (400 MHz, CDCl3) : 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).
Preparation of Intermediate Compound F
[0063] To a solution of compound E (25.0 g, 0.092 mol) in THF (250 mL) was added TEA (10.2 g, 0.10 mol) in a reaction flask. The resulting reaction solution was stirred for 30 minutes and cooled to about 5 to about 5 C. Ethyl chloroformate (13.0 g, 0.12 mol) was then added dropwise. After addition, the reaction solution was stirred for 1 hour, and then NH.sub.3/MeOH (10 M, 100 mL) was added dropwise at a temperature of about 5 to about 5 C. After addition, the resulting reaction solution was warmed to room temperature with stirring for another 2 hours. After completion of the reaction as indicated by TLC, the reaction solution was concentrated and replaced with EA (250 mL) and washed with saturated sodium chloride aqueous solution. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound F as a white solid in 92% yield. LC-MS (ESI, m/z, C.sub.12H.sub.21N.sub.3O.sub.4, 272, M+H).
Preparation of Intermediate Compound G
[0064] To a solution of compound F (23.0 g, 0.085 mol) and TEA (38.6 g, 0.382 mol) in DCM (230 mL) was added TFAA (10.2 g, 0.10 mol) in a reaction flask at about 5 to about 5 C. After addition, the resulting reaction solution was warmed to room temperature and stirred for 12 hours. After completion of the reaction as indicated by TLC, the reaction solution was washed with water and saturated sodium chloride aqueous solution successively, dried with anhydrous sodium sulfate, filtered, and concentrated to afford compound G (18.2 g) as a white solid powder in 85% yield. LC-MS (ESI, m/z, C.sub.13H.sub.20N.sub.2O.sub.3, 253, M+H).
Preparation of Intermediate Compound H
[0065] Compound G (18.2 g, 0.072 mol) was added to a 4 mol/L solution of ethyl acetate hydrochloride (150 mL) at a temperature of 0-10 C. After stirring for 1 hour, the reaction solution was warmed to room temperature and stirred for 2 hours. After completion of the reaction as indicated by TLC, the reaction solution was concentrated to dryness to afford compound H (13.0 g) as a white solid in 95% yield. LC-MS (ESI, m/z, C.sub.7H.sub.12ClN.sub.3O, 154, M(free base)+H).
[0066] .sup.1H NMR (400 MHz, DMSO) : 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
(S)-Synthesis of 2-Amino-3-((S)-2-carbonylpyrrolidin-3-yl-5,5-dideuterated) Propionitrile Hydrochloride (Compound H-2D1)
Representative Route
##STR00069## ##STR00070##
[0067] Refer to Example 1 for the preparation of Compound B.
[0068] To a solution of compound B (50 g, 0.159 mol) and cobalt chloride (20.6 g) in THF (500 mL) in a reaction flask at 0-10 C. was added sodium borodeuteride (6.7 g, 0.16 mol) in portions. After addition, the reaction was warmed to room temperature and stirred for 4 hours. After completion of the reaction as indicated by TLC, the reaction was quenched with water and dilute hydrochloric acid at about 5 to about 5 C. and the aqueous phase extracted with EA. The combined organic phases were concentrated and replaced with THF (500 mL) and TEA (100 mL) was added. The resulting reaction solution was heated to 50-60 C. and stirred for 16 hours. After completion of the reaction as indicated by TLC, the reaction solution was diluted with water (150 mL) and the layers separated. The aqueous phase was extracted twice with DCM and the organic phases combined and concentrated to dryness to afford compound D-2D1 as crude oil. The crude oil was purified by column chromatography to afford compound D-2D1 (32.1 g) as white powder in 70% yield. LC-MS (ESI, m/z, C.sub.13H.sub.20D.sub.2N.sub.2O.sub.5, 289, M+H).
[0069] Refer to Example 1 for the preparation of subsequent intermediates.
[0070] Compound H-2D1:15.3 g was obtained. LC-MS (ESI, m/z, C.sub.7H.sub.10D.sub.2ClN.sub.3O, 156, M(free base)+H).
[0071] .sup.1H NMR (400 MHz, DMSO) : 8.42 (s, 2H), 8.26 (s, 1H), 7.82 (s, 1H), 3.56 (m, 1H), 2.19-1.92 (m, 5H).
Example 3
Synthesis of (s)-2-Amino-3-((s)-2-carbonylpyrrolidin-3-yl) propionitrile-2-deuterated Hydrochloride (Compound H-1D)
Representative Route
##STR00071##
[0072] Refer to Example 1 for the preparation of Intermediate Compound E.
Preparation of Intermediate Compound E-1D.
[0073] To a solution of Compound E (10 g, 36.7 mmol) and NaOH (4.4 g, 0.11 mol) in heavy water (100 mL) was added Ru/C (0.5 g, 5 wt %) in a hydrogenation flask. Hydrogen was exchanged 3 times and the reaction was stirred at 0.1-0.12 MPa and 70-75 C. for 52 hours. The reaction was monitored by HNMR until the reaction was indicated to be completed. The reaction mixture was then cooled and filtered. The pH of the resulting filtrate was adjusted to 5-6 and the filtrate extracted three times with EA. The combined organic phases were concentrated to dryness to afford compound E-1D (9.2 g) in a yield of 92%. LC-MS (ESI, m/z, C.sub.12H.sub.19DN.sub.2O.sub.5, 274, M+H).
[0074] Refer to Example 1 for the preparation of subsequent intermediates.
[0075] Obtain Compound H-1D: 4.8 g. LC-MS (ESI, m/z, C.sub.7H.sub.11DClN.sub.3O, 155.2, M(free base)+H).
[0076] .sup.1H NMR (400 MHz, DMSO) : 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
Synthesis of (s)-2-Amino-3-((s)-2-carbonylpyrrolidin-3-yl-3-deuterated) propionitrile-2-deuterated Hydrochloride (Compound H-2D2)
Representative Route.
##STR00072##
[0077] Refer to Example 1 for the preparation of intermediate compound F-1D.
Preparation of Intermediate Compound F-2D2.
[0078] To a solution of compound F-1D (13.6 g, 0.05 mol) in heavy water (150 mL) in a reaction flask was added potassium carbonate (20.7 g, 0.15 mol). The resulting reaction mixture was stirred at 80 C. for 48 hours, extracted with EA, the organic phase dried with anhydrous sodium sulfate. Then the organic phase was purified by supercritical fluid chromatography (SFC), and concentrated to dryness to afford compound F-2D2 (6.3 g) as a white solid in 46% yield. LC-MS (ESI, m/z, C.sub.12H.sub.19D.sub.2N.sub.3O.sub.4, 274, M+H).
[0079] Refer to Example 1 for the preparation of subsequent intermediates.
[0080] Compound H-2D2 was obtained: 3.6 g. LC-MS (ESI, m/z, C.sub.7H.sub.10D.sub.2ClN.sub.3O, 156, M(free base)+H).
[0081] .sup.1H NMR (400 MHz, DMSO) : 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
Synthesis of (s)-2-Amino-3-((s)-2-carbonylpyrrolidin-3-yl-3-deuterated-5,5-dideuterated) propionitrile-2-deuterated Hydrochloride (Compound H-4D)
##STR00073##
[0082] Chemical Formula: C.sub.7H.sub.8D.sub.4ClN.sub.3O. Molecular Weight: 193.67.
[0083] Compound H-4D can be synthesized according to representative routes described in Examples 2 and 4. LC-MS (ESI, m/z, C.sub.7H.sub.8D.sub.4ClN.sub.3O, 158, M(free base)+H).
[0084] .sup.1H NMR (400 MHz, DMSO) : 8.43 (s, 2H), 8.24 (s, 1H), 7.81 (s, 1H), 2.20-1.94 (m, 4H).
Example 6
Synthesis of(S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamide) butanoic Acid (K)
Representative Route.
[0085] A solution of methyl trifluoroacetate (10.2 g, 80 mmol) in anhydrous tetrahydrofuran was
##STR00074##
added to a reaction flask and cooled to about 5 to about 5 C. After the mixture was stirred for 15 minutes at controlled temperature, L-tertleucine (10 g, 76.2 mmol) was added. The resulting reaction solution was stirred for 1 hour at control temperature. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated to provide crude compound K, which was purified by column chromatography to afford compound K (15.6 g) as white solid powder in 90% yield. LC-MS (ESI, m/z, C.sub.8H.sub.12F.sub.3NO.sub.3, 228, M+H).
[0086] .sup.1H NMR (400 MHz, DMSO) : 12.22 (s, 1H), 8.30 (s, 1H), 4.09 (s, 1H), 0.92 (s, 9H).
Example 7
Synthesis of(S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamide)-2-deutero-butyric Acid (K-1D)
Representative Route
##STR00075##
Preparation of Intermediate Compound SM2-1D.
[0087] To a solution of L-tertleucine (10 g, 76.2 mmol) and NaOH (4.4 g, 0.11 mol) in heavy water (100 mL) was added Ru/C (0.5 g, 5 wt %) in a hydrogenation flask. Hydrogen was exchanged 3 times and the reaction mixture stirred at 0.1-0.12 MPa and 70-75 C. for 52 hours. The reaction was monitored by HNMR until the reaction was indicated to be complete. The reaction mixture was then cooled and filtered. The pH of the resulting filtrate was adjusted to 5-6, and the filtrate was extracted three times with EA. The combined organic phases were concentrated to dryness to afford compound SM2-1D (9.5 g) in a yield of 94%. LC-MS (ESI, m/z, C.sub.6H.sub.12DNO.sub.2, 133, M+H).
Preparation of Intermediate compound K-1D.
[0088] A solution of methyl trifluoroacetate (9.6 g, 75.4 mmol) in anhydrous tetrahydrofuran was added to a reaction flask and cooled to about 5 to 5 C. After 15 minutes of stirring, SM2-1D (9.5 g, 71.8 mmol) was added. The resulting reaction solution was stirred for 1 hour at controlled temperature. After completion of the reaction as indicated by TLC, diluted hydrochloric acid was added, then the mixture was concentrated to obtain crude compound K-1D. Crude compound K-1D was further purified by column chromatography to afford compound K-1D (15.1 g) as white solid powder in 92% yield. LC-MS (ESI, m/z, C.sub.8H.sub.11DF.sub.3NO.sub.3, 229, M+H).
[0089] .sup.1H NMR (400 MHz, DMSO) : 12.18 (s, 1H), 8.14 (s, 1H), 0.91 (s, 9H).
Example 8
Synthesis of(S)-3,3-dideuteromethyl-2-(2,2,2-trifluoroacetamide)-4,4,4-deuterated-butyric Acid (K-9D)
Representative Route
##STR00076##
[0090] Chemical Formula: C.sub.8H.sub.3D.sub.9F.sub.3NO.sub.3. Molecular Weight: 236.24.
[0091] Compound K-9D can be synthesized according to the representative route described in Example 6. LC-MS (ESI, m/z, C.sub.8H.sub.3D.sub.9F.sub.3NO.sub.3, 237, M+H).
[0092] .sup.1H NMR (400 MHz, DMSO) : 12.23 (s, 1H), 8.30 (s, 1H), 4.19 (s, 1H).
Example 9
Synthesis of(S)-3,3-dideuteromethyl-2-(2,2,2-trifluoroacetamide)-2-4,4,4-deuterated-butyric Acid (K-10D)
##STR00077##
[0093] Chemical Formula: C.sub.8H.sub.2D.sub.10F.sub.3NO.sub.3. Molecular Weight: 237.24.
[0094] Compound K-10D can be synthesized according to the representative route described in Example 7. LC-MS (ESI, m/z, C.sub.8H.sub.2D.sub.10F.sub.3NO.sub.3, 238.1, M+H).
[0095] .sup.1H NMR (400 MHz, DMSO) : 12.22 (s, 1H), 8.18 (s, 1H).
Example 10
Synthesis of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-deuterium-carboxylate (SM3-1D)
Representative Route.
##STR00078##
[0096] To a solution of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-carboxylate (SM3:10 g, 48.6 mmol) and NaOH (9.7 g, 0.24 mol) in heavy water (100 mL) was added Ru/C (0.5 g, 5 wt %) in a hydrogenation flask. Hydrogen was exchanged 3 times and the reaction was stirred at 0.1-0.12 MPa and 70-75 C. for 52 hours. The reaction was monitored by HNMR until the reaction was shown to be completed. The reaction mixture was then cooled and filtered. The pH of the resulting filtrate was adjusted to 5-6, and the filtrate extracted three times with EA. The combined organic phases were concentrated to dryness to afford compound M (7.0 g) in a yield of 92%.
[0097] A solution of Compound M in MeOH (100 mL) was added to a reaction flask. Hydrogen chloride gas was applied to the resulting reaction solution at 0-10 C. until the solution was saturated. The reaction was refluxed for 1 hour and warmed to room temperature. The reaction was monitored by TLC until finished and then filtered and dried to afford compound SM3-1D (8.9 g) as a white solid in 96% yield. LC-MS (ESI, m/z, C.sub.9H.sub.15DClNO.sub.2, 171, M(free base)+H).
[0098] .sup.1H NMR (400 MHz, DMSO) : 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
Synthesis of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4,4-deuterium-carboxylate (SM3-3D)
Representative Route.
##STR00079##
[0099] To a solution of compound SM3-1D (10 g, 48.4 mmol) in heavy water (150 mL in a reaction flask) was added potassium carbonate (31.6 g, 0.23 mol). The resulting reaction mixture was stirred at 60 C. for 48 hours, then extracted with EA. The combined organic phase was dried with anhydrous sodium sulfate, and filtered. The mixture was combined with a solution of hydrochloric acid in EA (4 mol/L, 150 mL) and stirred for 4 hours. The resulting reaction mixture was then concentrated to dryness to afford 9.3 g of compound SM3-3D in a yield of 92%. LC-MS (ESI, m/z, C.sub.9H.sub.13D.sub.3ClNO.sub.2, 173, M(free base)+H).
[0100] .sup.1H NMR (400 MHz, DMSO) : 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
Synthesis of Compound 1.
Representative Route.
Preparation of Intermediate Compound M.
##STR00080##
[0101] To a solution of compound K (5 g, 22 mmol) and SM3 (4.9 g, 22 mmol) in acetonitrile (100 mL) in a reaction flask were sequentially added BOP (9.7 g, 22 mmol) and TEA (4.4 g, 44 mmol). After stirring at room temperature for 2 hours, the reaction was shown by TLC to be complete. After addition of water (50 mL), the reaction was extracted three times with EA. The combined organic phases were washed with 2 mol/L HCl, 5% NaHCO.sub.3 and water successively, dried with anhydrous magnesium sulfate, and concentrated to dryness to obtain compound M (8.0 g) as an almost white solid in 96.1% yield. LC-MS (ESI, m/z, C.sub.17H.sub.25F.sub.3N.sub.2O.sub.4, 379, M+H).
Preparation of Compound 1.
[0102] Compound M (8 g, 21.1 mmol) was dissolved in THF (80 mL) and MeOH (80 mL) at room temperature and an aqueous solution of lithium hydroxide (1.5 g, 62.8 mmol) (15 mL) was added. After being stirred at room temperature for 2 hours, the resulting reaction mixture was cooled to 0-10 C. Ethyl acetate was added to the mixture. Then the solution was acidified with 1N HCl, and the aqueous phase extracted twice with EA. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness to afford the crude product. The crude product was further purified by column chromatography to obtain hydrolyzed compound M.
[0103] To a solution of hydrolyzed compound M (obtained in the previous step) in DMF (100 mL) in a reaction flask at about 0 to about 10 C. was added sequentially EDCI (4.9 g, 25.6 mmol), HOBt (3.4 g, 25.2 mmol), and NMM (4.3 g, 42.5 mmol). The resulting reaction mixture was stirred for 30 minutes at controlled temperature, and then H-2D1 (4.0 g, 21 mmol) was added in portions. After addition, the reaction mixture warmed to room temperature and stirred overnight. The reaction was shown to be complete by TLC. Water (80 mL) was added to the reaction mixture and the resulting mixture extracted three times with EA. The combined organic phases were washed with 0.5 mol/L HCl and 5% NaHCO.sub.3 successively, washed with water, dried with anhydrous magnesium sulfate, and concentrated to dryness to provide crude product 1. The crude product was further purified by column chromatography to provide compound 1 (8.4 g) as an off-white solid in 79.7% yield. LC-MS (ESI, m/z, C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4, 502, M+H).
[0104] .sup.1H NMR (600 MHz, DMSO) : 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).
[0105] Examples 13-74 below were prepared using a method similar to that described in Example 12.
Example 13
Synthesis of Compound 2
##STR00081##
[0106] Chemical Formula: C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4. Molecular Weight: 500.54. LC-MS (ESI, m/z, C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4, 501, M+H).
[0107] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 3.
##STR00082##
[0108] Chemical Formula: C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4. Molecular Weight: 501.55. LC-MS (ESI, m/z, C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4, 502, M+H).
[0109] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 4.
##STR00083##
[0110] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H).
[0111] .sup.1H NMR (600 MHz, DMSO): 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
Synthesis of Compound 5.
##STR00084##
[0112] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0113] .sup.1H NMR (600 MHz, DMSO): 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
Synthesis of Compound 6.
##STR00085##
[0114] Chemical Formula: C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4. Molecular Weight: 500.54. LC-MS (ESI, m/z, C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4, 501, M+H).
[0115] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 7.
##STR00086##
[0116] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H)
[0117] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 8.
##STR00087##
[0118] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H).
[0119] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 9.
##STR00088##
[0120] Chemical Formula: C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4. Molecular Weight: 504.57. LC-MS (ESI, m/z, C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4, 505, M+H).
[0121] 1H NMR (400 MHz, DMSO) : 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=8 Hz), 0.97-0.89 (m, 16H).
[0122] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 10.
##STR00089##
[0123] Chemical Formula: C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4. Molecular Weight: 501.55. LC-MS (ESI, m/z, C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4, 502, M+H).
[0124] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 11.
##STR00090##
[0125] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 502, M+H).
[0126] 1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 12.
##STR00091##
[0127] Chemical Formula: C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4. Molecular Weight: 504.57. LC-MS (ESI, m/z, C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4, 505, M+H).
[0128] .sup.1H NMR (400 MHz, DMSO) : 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=8 Hz), 0.97-0.89 (m, 16H).
[0129] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 13.
##STR00092##
[0130] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0131] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 14.
##STR00093##
[0132] Chemical Formula: C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4. Molecular Weight: 504.57. LC-MS (ESI, m/z, C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4, 505, M+H).
[0133] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 15.
##STR00094##
[0134] Chemical Formula: C.sub.23H.sub.25D.sub.7F.sub.3N.sub.5O.sub.4. Molecular Weight: 506.58. LC-MS (ESI, m/z, C.sub.23H.sub.25D.sub.7F.sub.3N.sub.5O.sub.4, 507, M+H).
[0135] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 16.
##STR00095##
[0136] Chemical Formula: C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4. Molecular Weight: 500.54. LC-MS (ESI, m/z, C.sub.23H.sub.31DF.sub.3N.sub.5O.sub.4, 501, M+H).
[0137] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 17.
##STR00096##
[0138] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H).
[0139] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 18.
##STR00097##
[0140] Chemical Formula: C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4. Molecular Weight: 501.55. LC-MS (ESI, m/z, C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4, 502, M+H).
[0141] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 19.
##STR00098##
[0142] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H).
[0143] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 20.
##STR00099##
[0144] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0145] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 21.
##STR00100##
[0146] Chemical Formula: C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4. Molecular Weight: 504.57. LC-MS (ESI, m/z, C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4, 505, M+H).
[0147] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 22.
##STR00101##
[0148] Chemical Formula: C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4. Molecular Weight: 501.55. LC-MS (ESI, m/z, C.sub.23H.sub.30D.sub.2F.sub.3N.sub.5O.sub.4, 502, M+H).
[0149] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 23.
##STR00102##
[0150] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0151] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 24.
##STR00103##
[0152] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0153] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 25.
##STR00104##
[0154] Chemical Formula: C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4. Molecular Weight: 505.57. LC-MS (ESI, m/z, C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4, 506, M+H).
[0155] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 26.
##STR00105##
[0156] Chemical Formula: C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4. Molecular Weight: 502.55. LC-MS (ESI, m/z, C.sub.23H.sub.29D.sub.3F.sub.3N.sub.5O.sub.4, 503, M+H).
[0157] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 27.
##STR00106##
[0158] Chemical Formula: C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4. Molecular Weight: 503.56. LC-MS (ESI, m/z, C.sub.23H.sub.28D.sub.4F.sub.3N.sub.5O.sub.4, 504, M+H).
[0159] .sup.1H NMR (600 MHz, DMSO) : 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
##STR00107##
Synthesis of Compound 28.
[0160] Chemical Formula: C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4. Molecular Weight: 505.57. LC-MS (ESI, m/z, C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4, 506, M+H).
[0161] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 29.
##STR00108##
[0162] Chemical Formula: C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4. Molecular Weight: 504.57. LC-MS (ESI, m/z, C.sub.23H.sub.27D.sub.5F.sub.3N.sub.5O.sub.4, 505, M+H).
[0163] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 30.
##STR00109##
[0164] Chemical Formula: C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4. Molecular Weight: 505.57. LC-MS (ESI, m/z, C.sub.23H.sub.26D.sub.6F.sub.3N.sub.5O.sub.4, 506, M+H).
[0165] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 31.
##STR00110##
[0166] Chemical Formula: C.sub.23H.sub.24D.sub.8F.sub.3N.sub.5O.sub.4. Molecular Weight: 507.58. LC-MS (ESI, m/z, C.sub.23H.sub.24D.sub.8F.sub.3N.sub.5O.sub.4, 508, M+H).
[0167] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 32.
##STR00111##
[0168] Chemical Formula: C.sub.23H.sub.23D.sub.9F.sub.3N.sub.5O.sub.4. Molecular Weight: 508.59. LC-MS (ESI, m/z, C.sub.23H.sub.23D.sub.9F.sub.3N.sub.5O.sub.4, 509, M+H).
[0169] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 33.
##STR00112##
[0170] Chemical Formula: C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4. Molecular Weight: 510.60. LC-MS (ESI, m/z, C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4, 511, M+H).
[0171] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 34.
[0172] Chemical Formula: C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4. Molecular Weight: 509.60. LC-MS (ESI, m/z,
##STR00113##
C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4, 510, M+H).
[0173] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 35.
##STR00114##
[0174] Chemical Formula: C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4. Molecular Weight: 510.60. LC-MS (ESI, m/z, C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4, 511, M+H).
[0175] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 36.
##STR00115##
[0176] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0177] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 37.
##STR00116##
[0178] Chemical Formula: C.sub.23H.sub.19D.sub.13F.sub.3N.sub.5O.sub.4. Molecular Weight: 512.61. LC-MS (ESI, m/z, C.sub.23H.sub.19D.sub.13F.sub.3N.sub.5O.sub.4, 513, M+H).
[0179] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 38.
##STR00117##
[0180] Chemical Formula: C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4. Molecular Weight: 509.60. LC-MS (ESI, m/z, C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4, 510, M+H).
[0181] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 39.
##STR00118##
[0182] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0183] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 40.
##STR00119##
[0184] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0185] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 41.
##STR00120##
[0186] Chemical Formula: C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4. Molecular Weight: 513.62. LC-MS (ESI, m/z, C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4, 514, M+H).
[0187] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 42.
##STR00121##
[0188] Chemical Formula: C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4. Molecular Weight: 510.60. LC-MS (ESI, m/z, C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4, 511.3, M+H).
[0189] .sup.1H NMR (600 MHz, DMSO): 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
Synthesis of Compound 43.
##STR00122##
[0190] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0191] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 44.
##STR00123##
[0192] Chemical Formula: C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4. Molecular Weight: 513.62. LC-MS (ESI, m/z, C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4, 514.3, M+H).
[0193] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 45.
##STR00124##
[0194] Chemical Formula: C.sub.23H.sub.19D.sub.13F.sub.3N.sub.5O.sub.4. Molecular Weight: 512.61. LC-MS (ESI, m/z, C.sub.23H.sub.19D.sub.13F.sub.3N.sub.5O.sub.4, 513, M+H).
[0195] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 46.
##STR00125##
[0196] Chemical Formula: C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4. Molecular Weight: 513.62. LC-MS (ESI, m/z, C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4, 514, M+H).
[0197] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 47.
##STR00126##
[0198] Chemical Formula: C.sub.23H.sub.16D.sub.16F.sub.3N.sub.5O.sub.4. Molecular Weight: 515.63. LC-MS (ESI, m/z, C.sub.23H.sub.16D.sub.16F.sub.3N.sub.5O.sub.4, 516, M+H).
[0199] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 48.
##STR00127##
[0200] Chemical Formula: C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4. Molecular Weight: 509.60. LC-MS (ESI, m/z, C.sub.23H.sub.22D.sub.10F.sub.3N.sub.5O.sub.4, 510, M+H).
[0201] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 49.
##STR00128##
[0202] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0203] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 50.
##STR00129##
[0204] Chemical Formula: C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4. Molecular Weight: 510.60. LC-MS (ESI, m/z, C.sub.23H.sub.21D.sub.11F.sub.3N.sub.5O.sub.4, 511, M+H).
[0205] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 51.
##STR00130##
[0206] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.3N.sub.5O.sub.4, 512, M+H).
[0207] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 52.
##STR00131##
[0208] Chemical Formula: C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4. Molecular Weight: 513.62. LC-MS (ESI, m/z, C.sub.23H.sub.18D.sub.14F.sub.3N.sub.5O.sub.4, 514, M+H).
[0209] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 53.
##STR00132##
[0210] Chemical Formula: C.sub.23H.sub.17D.sub.14F.sub.5N.sub.5O.sub.4. Molecular Weight: 514.63. LC-MS (ESI, m/z, C.sub.23H.sub.17D.sub.14F.sub.5N.sub.5O.sub.4, 515, M+H).
[0211] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 54.
##STR00133##
[0212] Chemical Formula: C.sub.23H.sub.21D.sub.11F.sub.5N.sub.5O.sub.4. Molecular Weight: 510.60. LC-MS (ESI, m/z, C.sub.23H.sub.21D.sub.11F.sub.5N.sub.5O.sub.4, 511, M+H).
[0213] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 55.
##STR00134##
[0214] Chemical Formula: C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4. Molecular Weight: 512.61. LC-MS (ESI, m/z, C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4, 513, M+H).
[0215] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 56.
[0216] Chemical Formula: C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4. Molecular Weight: 512.61. LC-MS (ESI, m/z,
##STR00135##
C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4, 513, M+H).
[0217] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 57.
##STR00136##
[0218] Chemical Formula: C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O. Molecular Weight: 514.63. LC-MS (ESI, m/z, C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O.sub.4, 515, M+H).
[0219] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 58.
##STR00137##
[0220] Chemical Formula: C.sub.23H.sub.20D.sub.12F.sub.5N.sub.5O. Molecular Weight: 511.61. LC-MS (ESI, m/z, C.sub.23H.sub.20D.sub.12F.sub.5N.sub.5O.sub.4, 512, M+H).
[0221] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 59.
##STR00138##
[0222] Chemical Formula: C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4. Molecular Weight: 512.61. LC-MS (ESI, m/z, C.sub.23H.sub.19D.sub.13F.sub.5N.sub.5O.sub.4, 513, M+H).
[0223] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 60.
##STR00139##
[0224] Chemical Formula: C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O.sub.4. Molecular Weight: 514.63. LC-MS (ESI, m/z, C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O.sub.4, 515, M+H).
[0225] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 61.
##STR00140##
[0226] Chemical Formula: C.sub.23H.sub.18D.sub.14F.sub.5N.sub.5O.sub.4. Molecular Weight: 513.62. LC-MS (ESI, m/z, C.sub.23H.sub.18D.sub.14F.sub.5N.sub.5O.sub.4, 514, M+H).
[0227] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 62.
##STR00141##
[0228] Chemical Formula: C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O.sub.4. Molecular Weight: 514.63. LC-MS (ESI, m/z, C.sub.23H.sub.17D.sub.15F.sub.5N.sub.5O.sub.4, 515, M+H).
[0229] .sup.1H NMR (600 MHz, DMSO) : 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
Synthesis of Compound 63.
##STR00142##
[0230] Chemical Formula: C.sub.23H.sub.15D.sub.17F.sub.5N.sub.5O.sub.4. Molecular Weight: 516.64. LC-MS (ESI, m/z, C.sub.23H.sub.15D.sub.17F.sub.5N.sub.5O.sub.4, 517.3, M+H).
[0231] .sup.1H NMR (600 MHz, DMSO) : 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).
Example 75
In Vitro Anti-SARS-CoV-2 Virus Assay
[0232] Cell plating: Vero E6 cells were seeded in 12-well plates at 310.sup.5 cells/well, 10% FBS supplemented DMEM medium was added, and the plates were incubated overnight in a 37 C., 5% CO.sub.2 incubator. Drug effect: After removing the cell culture media from the Vero cells in the 12-well plate, the VeroE6 cells were washed with PBS buffer and compound (final concentration 100 nM) was added to provide a 50 L/well cell solution and the plate incubated in a 37 C., 5% CO.sub.2 incubator for 1 hour. A 50 L/well medium was set as a control. The cells were infected with the virus: After infecting the cells for 2 hours with SARS-CoV-2 virus, the virus and drug mixture were removed, and 10% FBS supplemented DMEM medium was added to the wells, and the cells were incubated in a 37 C., 5% CO.sub.2 incubator for 2-3 days. PCR measurement: the supernatant of the culture medium was collected and retained in an incubator at 56 C. for 30 min. The viral RNA was extracted with a viral RNA extraction kit. The PCR reaction was performed with the viral nucleic acid detection kit following the instructions. The 2.sup.CT value was calculated from the CT value displayed by the PCR instrument. The calculation formula of the virus replication inhibition rate was: (12.sup.CT)100%, where the 2.sup.CT value was the relative viral replication rate of the drug groups and the control group (tannic acid). The results are shown below in Table 2.
TABLE-US-00002 TABLE 2 The Inhibition of Virus Replication in the Drug Groups and the Control Group Com- Com- Com- Com- pound pound pound pound PF- Group 1 2 16 32 07321332 Control Inhibition 71.5 73.5 72.6 70.4 72.9 54.1 rate (%)
Example 76
This Embodiment is the Detection of the Inhibition of the Protease Activity Targeting SARS-CoV-2 Virus M.SUP.Pro
[0233] Detection principle and mechanism of action: 3-chymotrypsin-like protease, the main protease (M.sup.Pro, also known as 3CL.sup.Pro), is encoded by ORF1 (localized to nsp5), located in the central region of the replicase gene. It is a key protein during the RNA replication of the novel coronavirus. When the new coronavirus invades the cell, the virus uses the host cell to synthesize two ultra-long replicase polypeptides (ppla and pplab) for self-replication. However, these replicase polypeptides need to be cleaved correctly into multiple proteins (e.g., RdRp, helicase, etc.), which are further assembled into the replication transcription machinery required for the virus to initiate replication of its own genetic material. These replicase polypeptides have at least 11 M.sup.Pro cleavage sites, and only when such sites are correctly cleaved by M.sup.Pro, the replication transcription machine can be assembled and viral replication can be initiated. Because of the important role of M.sup.Pro protease during viral replication and the absence of any human protease counterparts for the virus to utilize, M.sup.Pro has become a potential key drug target against the novel coronaviruses. The inhibitory activity on the SARS-CoV-2-M.sup.Pro protease by the nucleoside derivatives was evaluated by a fluorescence resonance energy transfer method.
[0234] Specifically, the enzymatic reactions occurred in the wells of 96-well plates, and the total volume of the entire enzymatic reaction system was 120 L, with the final concentration of protease at 30 nM and the final substrate concentration at 20 M. The buffer solution of the reaction system included 50 mM Tris, 1 mM EDTA, pH 7.3. Substrate was added after the SARS-CoV-2-M.sup.Pro protease and different concentrations of target compounds were incubated in the wells of 96-well plates at 30 C. for 10 min. After the substrate was added, the 96-well plates were placed immediately into a plate reader for measurement. Excitation and emission wavelengths were 340 nm and 405 nm, respectively, and fluorescence values were read every 30 seconds for 10 minutes. The final results were fitted to the reaction rate with a reading from the first 2 min and compared to the control group (DMSO) to calculate the inhibitory rates. IC.sub.50 values of the SARS-CoV-2 viral nucleoside derivatives at corresponding time points were calculated using Graphpad prism 7 plot, which are shown below in Table 3.
TABLE-US-00003 TABLE 3 IC.sub.50 Values for SARS-COV-2-M.sup.Pro Protease Number IC50 (M) Compound 1 2.948 0.265 M Compound 2 2.786 0.375 M Compound 16 2.723 0.476 M Compound 32 2.835 0.503 M PF-07321332 2.761 0.382 M
Example 77
This Embodiment is a Pharmacokinetic Study of the Compounds in Rats.
[0235] Male Wistar-Hannover rats aged 7 to 10 weeks were used to conduct the pharmacokinetic study. All animals were housed individually during the pharmacokinetic study. Food and water were provided ad libitum (administration occurred when feeding). Animals were fasted overnight and fed 4 hours post-administration. Blood samples were collected via jugular vein cannula at predetermined time points. At study completion, animals were euthanized by overdose inhalation of anesthesia followed by exsanguination. Blood samples were collected into tubes containing K.sub.2EDTA and stored on ice until plasma was obtained by centrifugation and stored in a freezer maintained at 20 C.
[0236] LC-MS/MS analysis of plasma samples: a protein precipitation method using 500/50 volume ratio of acetonitrile and methanol was developed to process the plasma samples. And reference substance were added into several blank plasma samples to afford various concentrations ranging from 0.1 ng/ml to 2500 ng/ml. Then a flat volume of internal standard propranolol (50 ng/ml) were added into each sample to be quantified. Internal standard method was performed to establish a calibration curve using the ratio of the peak intensity of reference substance to internal standard as ordinate and the concentration of reference substance as abscissa. Quantification was performed by analyzing plasma samples with LC-MS/MS, i.e. Waters ACQUITY ultra performance liquid chromatography system coupled with a Sciex 6500 triple quadrupole mass spectrometer. A Waters Acquity UPLC BEH C18 column (1.7 m, 2.150 mm) was used to separate the constituents. A gradient mobile phase was used to achieve good separation between analytes. Typically, the mobile phase consisted of solvent A (0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (95:5 v/v)) and solvent B (0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (5:95 v/v)) and the gradient generally started from 330% B to approximately 1.2 minutes, increases to 5065% B to 1.6 minutes, and then decreases to 10-30% B until about 1.71.9 minutes. Analyst 1.7 software was used for peak integration and standard curve regression.
[0237] Pharmacokinetic analysis: pharmacokinetic parameters were calculated using noncompartmental analysis (Watson v.7.5, Thermo Scientific). The area under the plasma concentration-time curve from t=0 to infinity (AUC.sub.0-) was estimated using the linear trapezoidal rule. The results are shown below in Table 4. The data shows that the compounds of the invention have long half-lives and higher plasma exposures in animals and, thus, will have a better therapeutic effect than PF-07321332.
TABLE-US-00004 TABLE 4 pharmacokinetic parameters of the compound in rats Dose C.sub.max T.sub.max AUC.sub.0~ T.sub.1/2 Number (mg/kg) (ng/ml) (h) (ng .Math. h/ml) (h) 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
Example 78
Preparation of Oral Tablets Containing Deuterated Cyano Compounds (Using Compound 2 as an Example).
[0238] The pharmaceutical carriers used for oral tablets are modifiers, fillers, binders, disintegrants, additives, glidants, lubricants, film coating materials, plasticizers, colorants, and the like.
TABLE-US-00005 Content Components Effect (mg/tablet) Compound 2 Pharmaceutical 200 Ingredients Starch Filler, Disintegrant 100 Calcium hydrogen Filler 20 phosphate Pregelatinized Starch Filler 40 Citric acid Modifier 2 Sodium bisulfite Additives 0.5 10% Starch Pulp Binders q.s. Magnesium stearate Lubricant 1.5 Opadry White Coating premix About 4 Water, Ethanol Solvent q.s.
Operating Method:
[0239] Compound 2 was milled and sieved then mixed well with the filler, disintegrant, modifier, and additive. The 10% starch slurry was added to provide a soft material in a stirrer, the soft material was made into wet granules on a rocker, dried in an oven, mixed well with lubricant, and pressed into tablet cores. Film-coated tablets were obtained by coating the tablet cores with Opadry.
Preparation of Capsules for Deuterated Cyano Compounds (Using Compound 2 as an Example).
[0240] The pharmaceutical carriers used for the capsules are fillers, binders, disintegrants, additives, lubricants, and the like.
TABLE-US-00006 Content Components Effect (mg/capsule) Compound 2 Pharmaceutical 200 Ingredients Lactose Monohydrate Filler 82 Pregelatinized Starch Filler, Binder 38 Sodium carboxymethyl starch Disintegrant 12.5 Magnesium stearate Lubricant 1.5
Operating Method:
[0241] Compound 2 and each excipient were milled and sieved according to the above formula, and then mixed well with filler, binder in a certain proportion and disintegrant in partial proportion. The resulting mixture was then added to a dry granulator and compressed into strips, and the strips crushed into granules by a crusher. The granules were mixed well with an appropriate amount of lubricant and residual amount of disintegrant and filled into capsules.
[0242] Each of the technical features of the above described embodiments may be combined in any combination, and all possible combinations of each of the technical features in the above embodiments are not described in order to make the description concise, however, as long as there is no contradiction in the combination of these technical features, it should be considered within the scope of this specification.
[0243] The above described embodiments express only several embodiments of the invention, which are described in more specific and detail, but are understood as not limiting the scope of the invention. It should be noted that for those of ordinary skill in the art, a number of modifications and improvements may be made without departing from the inventive concept, all of which fall within the scope of protection of the invention.