6-Substituted 3-Fluoro-2-Pyridinaldoxime, 3-Fluoro-2-pyridine hydroxamic acid, and 3-Fluoro-2-Pyridinamidoxime scaffolds
11370772 · 2022-06-28
Assignee
Inventors
Cpc classification
C07B2200/05
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D401/06
CHEMISTRY; METALLURGY
International classification
C07D401/06
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
Abstract
Disclosed is a compound of formula (II), as well as to a process for preparing the compounds of formula (II) by a chemoselective Sonogashira reaction. It also relates to a pharmaceutical composition including at least one compound of formula (II) and at least one pharmaceutically acceptable support. Finally, it relates to the use of such a compound as a medicine, preferably in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent; in the treatment of neurological diseases such as Alzheimer's disease; and/or in the treatment of cancer; and/or for use as antiviral drug.
Claims
1. A compound of formula (II), or one of its pharmaceutically acceptable salts: ##STR00218## wherein: W′ is F or Cl; —X′—Y′— is —C≡C or —X′—Y′— is Br and R2 does not exist; R′l is H; Z′ is ═N—OH; R′2 is a group chosen from aralkyl; or a compound of formula (I), or one of its pharmaceutically acceptable salts: ##STR00219## wherein: —X—Y— is —CH2-CH2-, —C≡C—, —CH═CH—, or —X—Y— is Br and R2 does not exist; R1 is H, NHOH or —NH2; Z is O or ═N—OH; R2 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, halogen, cyano, R—O—CO—R′— wherein R and R′ are each independently alkyl groups, —R3-N(R4) (R5), alkylsulfonamide, alkenyl, a biomolecule, a fluorescent probe, radical A and radical B, wherein radical A or radical B may be linked to —Y—X— by an alkyl group: ##STR00220## or R2 is an alkyl group linked to the following radical: ##STR00221## R3 is an alkyl group, and R4 and R5 are identical or different and each independently represent H, R6-O—CO— with R6 being an alkyl group, a carboxybenzyl group, a pyridine group, a 7-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl radical, a quinolin-4-yl radical, an acridin-9-yl radical or R4 and R5 form together with the nitrogen atom a 1,3-dioxoisoindolin-2-yl, with the exception of 6-bromo-3-fluoro-2-pyridine hydroxamic acid, of 6-bromo-3-fluoropicolinaldehyde and of 6-bromo-3-fluoro-2-pyridinecarboxamide.
2. The compound of claim 1 wherein in formula (I): —X—Y— is —CH2-CH2-, —C≡C— or —CH═CH; R1 is H; Z is ═N—OH; R2 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, halogen, cyano, —R—O—CO—R′— wherein R and R′ are both independently alkyl groups, —R3-N(R4) (R5), alkylsulfonamide, alkenyl, radical A and radical B, wherein radical A or radical B may be linked to —Y—X— by an alkyl group: ##STR00222## or R2 is an alkyl group linked to the following radical: ##STR00223## R3 is an alkyl group, and R4 and R5 are identical or different and each independently represent H, R6-O—CO— with R6 being an alkyl group, a carboxybenzyl group, a pyridine group, a 7-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl radical, a quinolin-4-yl radical, an acridin-9-yl radical or R4 and R5 form together with the nitrogen atom a 1,3-dioxoisoindolin-2-yl.
3. The compound of claim 1, having scaffold 1 below: ##STR00224## Scaffold 1 wherein R1 and Z are as defined in claim 1, with the exception of 6-bromo-3-fluoro-2-pyridine hydroxamic acid.
4. The compound of claim 1, wherein in formula (I) R1 is H and Z is ═N—OH.
5. The compound of claim 1, wherein in formula (I) R1 is —NHOH and Z is O, with the exception of 6-bromo-3-fluoro-2-pyridine hydroxamic acid.
6. The compound of claim 1, wherein in formula (I) R1 is —NH2 and Z is ═N—OH.
7. The compound of claim 1, wherein in formula (I): —X—Y— is —CH2-CH2-, —C≡C— or —CH═CH; R1 is —NHOH; Z is O; and R2 is a group chosen from alkyl, haloalkyl, hydroxyalkyl, aryl or aralkyl.
8. The compound of claim 1, wherein in formula (I): —X—Y— is —CH2-CH2-, —C≡C— or —CH═CH; R1 is —NH2; Z is ═N—OH; and R2 is a group chosen from alkyl, haloalkyl, hydroxyalkyl, aryl or aralkyl.
9. The compound of claim 1, which is chosen among the following: (Z)-6-bromo-3-fluoropicolinaldehyde oxime 2: ##STR00225## 3-fluoro-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 3a: ##STR00226## 3-fluoro-6-(pentadec-1-yn-1-yl)picolinaldehyde oxime 3b: ##STR00227## 6-(3-cyclohexylprop-1-yn-1-yl)-3-fluoropicolinaldehyde oxime 3c: ##STR00228## 3-fluoro-6-(6-hydroxyhex-1-yn-1-yl)picolinaldehyde oxime 3d: ##STR00229## Methyl 6-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)hex-5-ynoate 3e: ##STR00230## 6-((1-aminocyclohexyl)ethynyl)-3-fluoropicolinaldehyde oxime 3f: ##STR00231## 3-fluoro-6-(hex-5-en-1-yn-1-yl)picolinaldehyde oxime 3g: ##STR00232## 6-((4-ethylphenyl)ethynyl)-3-fluoropicolinaldehyde oxime 3h: ##STR00233## 6-(4-chlorobut-1-yn-1-yl)-3-fluoropicolinaldehyde oxime 3i: ##STR00234## 6-((3,6-dihydropyren-4-yl)ethynyl)-3-fluoropicolinaldehyde oxime 3j: ##STR00235## 4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)but-3-yne-1-sulfonamide 3k: ##STR00236## tert-butyl (4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)carbam-ate 31: ##STR00237## 4-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)benzonitrile 3m: ##STR00238## 6-(5-(1,3-dioxoisoindolin-2-yl)pent-1-yn-1-yl)-3-fluoropicolinaldehyde oxime 3n: ##STR00239## 3-fluoro-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)picolinaldehyde oxime 3o: ##STR00240## 3-fluoro-6-((3-hydroxyoxetan-3-yl)ethynyl)picolinaldehyde oxime 3p: ##STR00241## Benzyl 3-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)azetidine-1-carb-oxylate 3q: ##STR00242## 3-fluoro-6-(pyridin-3-ylethynyl)picolinaldehyde oxime 3r: ##STR00243## Benzyl (3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)(pyridin-4-yl)carbamate 3s: ##STR00244## Methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(5-fluoro-6-((hydroxyimino)methyl)pyri-din-2-yl)pent-4-ynoate 3t: ##STR00245## N-(9-((3aR,4R,6R,6aR)-6-(((3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 3u: ##STR00246## (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 3v: ##STR00247## 3-fluoro-6-(10-(5-fluoro-6-((E)-(hydroxyimino)methyl)pyridin-2-yl)deca-1,9-diyn-1-yl)picolinaldehyde oxime 3w: ##STR00248## 6-(4-((7-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)but-1-yn-1-yl)-3-flu-oropicolinaldehyde oxime 3x: ##STR00249## 3-fluoro-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 3y: ##STR00250## 6-(4-(1,2,3,4-tetrahydroacridin-9-ylamino)but-1-yn-1-yl)-3-fluoropicolinaldehyde oxime 3z: ##STR00251## 6-bromo-3-fluoropicolinaldehyde oxime (Labelled) 4: ##STR00252## 3-fluoro-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 5: ##STR00253## 6-bromo-3-fluoro-N′-hydroxypicolinimidamide 7: ##STR00254## 6-bromo-3-fluoro-N′-hydroxypicolinimidamide (Labelled) 8: ##STR00255## 3-fluoro-N′-hydroxy-6-(5-phenylpent-1-yn-1-yl)picolinimidamide 10: ##STR00256## 3-fluoro-N-hydroxy-6-(5-phenylpent-1-yn-1-yl)picolinamide 12: ##STR00257## 3-fluoro-6-(5-phenylpentyl)picolinaldehyde oxime 13: ##STR00258## 6-(3-cyclohexylpropyl)-3-fluoropicolinaldehyde oxime 14: ##STR00259## 6-(4-ethylphenethyl)-3-fluoropicolinaldehyde oxime 15: ##STR00260## 3-fluoro-6-(2-(pyridin-3-yl)ethyl)picolinaldehyde oxime 16: ##STR00261## 3-fluoro-6-(2-(3-hydroxyoxetan-3-yl)ethyl)picolinaldehyde oxime 17: ##STR00262## 3-fluoro-6-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl)picolinaldehyde oxime 18: ##STR00263## 3-fluoro-6-(10-(5-fluoro-6-((E)-(hydroxyimino)methyl)pyridin-2-yl)decyl)picolin-aldehyde oxime 19: ##STR00264## N-(9-((3aR,4R,6R,6aR)-6-((3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)propoxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 20: ##STR00265## 3-fluoro-6-((E)-6-hydroxyhex-1-en-1-yl)picolinaldehyde oxime 21: ##STR00266## Methyl (E)-6-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)hex-5-enoate 22: ##STR00267## 3-fluoro-6-((E)-2-(pyren-4-yl)vinyl)picolinaldehyde oxime 23: ##STR00268## 3-fluoro-6-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butyl)picolinaldehyde oxime 24: ##STR00269## 9-((4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)butyl)amino)-1,2,3,4-tetrahydroacridin-10-ium chloride 25: ##STR00270## 3-fluoro-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 26: ##STR00271## 3-fluoro-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime 27: ##STR00272## 4-((4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)butyl)ammonio)quinolin-1-ium chloride 28: ##STR00273## 3-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)pyridin-1-ium chloride 29: ##STR00274## 3-(2-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethyl)pyridin-1-ium- chloride 30: ##STR00275## 5-bromo-3-fluoropicolinaldehyde oxime 31: ##STR00276## 3-fluoro-5-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 32: ##STR00277## 5-bromo-2-fluoronicotinaldehyde oxime 33: ##STR00278## 2-fluoro-5-(5-phenylpent-1-yn-1-yl)nicotinaldehyde oxime 34: ##STR00279## 3-bromo-6-chloropicolinaldehyde oxime 35: ##STR00280## 6-chloro-3-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 36: ##STR00281## 6-bromo-4-chloronicotinaldehyde oxime 37: ##STR00282## 4-chloro-6-(5-phenylpent-1-yn-1-yl)nicotinaldehyde oxime 38: ##STR00283## 3-fluoro-N′-hydroxy-6-(pentadec-1-yn-1-yl)picolinimidamide 46: ##STR00284## 6-((4-ethylphenyl)ethynyl)-3-fluoro-N′-hydroxypicolinimidamide 47: ##STR00285## 3-fluoro-N′-hydroxy-6-(4-morpholinobut-1-yn-1-yl)picolinimidamide 48: ##STR00286## 3-fluoro-N′-hydroxy-6-((3-hydroxyoxetan-3-yl)ethynyl)picolinimidamide 49: ##STR00287## 6-((l-aminocyclohexyl)ethynyl)-3-fluoro-N′-hydroxypicolinimidamide 50: ##STR00288## (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-fluoro-6-((E)-N′-hydroxycarbam-imidoyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 51: ##STR00289##
10. A process for preparing a compound of formula (I) of claim 1, comprising a Sonogashira coupling reaction between a 6-bromo-3-fluoro-2-pyridinaldoxime, a 6-bromo-3-fluoro-2-pyridinhydroxamic acid or a 6-bromo-3-fluoro-2-pyridinamidoxime and a compound comprising a terminal alkyne or a dialkyne compound having two terminal alkyne groups.
11. A pharmaceutical composition comprising at least one compound of formula (II) or (I) according to claim 1, and at least one pharmaceutically acceptable support.
12. The compound of claim 1, wherein radical A or radical B may be linked to —Y—X— by an ethyl group, and R6 is a 4-pyridino.
13. The compound of claim 2, wherein radical A or radical B may be linked to —Y—X— by an ethyl group, and R6 is a 4-pyridino.
14. The process of claim 10, further comprising a reduction step by reaction with hydrogen.
Description
EXAMPLES
Example 1: Synthesis of Compounds of the Invention
I—General Methods
(1) All starting materials and reagents were purchased from commercial sources, and used as received without further purification. Air and H.sub.2O sensitive reactions were performed in flame dried glassware under Ar atmosphere. Moisture sensitive reagents were introduced via a dry syringe. Anhydrous solvents were supplied over molecular sieves, and used as received. Petroleum ether (PE) refers to the 40-60° C. boiling fraction. Reactions were monitored by thin-layer chromatography (TLC) with silica gel 60 F.sub.254 0.25 mm pre-coated glass plates. Compounds were visualized by using UV.sub.254 and/or phosphomolybdic acid stain [3 g 12MoO.sub.3.H.sub.3PO.sub.4.xH.sub.2O in 100 mL EtOH] followed by heating with a heat gun. Flash column chromatography was performed using Macherey-Nagel silica gel 60 (15-40 μm). NMR experiments were recorded with a Bruker Avance 400 spectrometer at 400 MHz for .sup.1H nuclei and at 100 MHz for .sup.13C nuclei. The chemical shifts are expressed in part per million (ppm) relative to TMS (δ=0 ppm) and the coupling constant J in Hertz (Hz). NMR multiplicities are reported using the following abbreviations: br=broad, s=singlet, d=doublet, t=triplet, q=quadruplet, m=multiplet. HRMS were recorded on a Bruker micrOTOF spectrometer.
II—Experimental Procedures
A) With 6-bromo-3-fluoropicolinaldehyde oxime (Compound 2)
(2) ##STR00140##
(3) A solution of picolinaldehyde (2 g, 9.804 mmol, 1 equiv), hydroxylamine hydrochloride (2.7 g, 19.61 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (2.4 g, 29.412 mmol, 3 equiv) in dry ethanol (75 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the oxime 2 as a white solid (2.1 g, quant. yield). R.sub.f (20% EA+PE) 0.50; IR (neat) v.sub.max cm.sup.−1 3248, 1579, 1442, 1287, 1236, 1187, 1108, 985, 937, 825, 720, 669, 620, 521; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.18 (s, 1H, H.sub.7), 7.61-7.55 (m, 2H, H.sub.4, H.sub.5); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 160.21, *157.60 (C3), 144.54, *144.50 (C13), 142.24, *142.12 (C2), 136.78, *136.75 (C6), 131.05, *131.0 (C5), 128.95, *128.74 (C4) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.5Br.sub.1F.sub.1N.sub.2O.sub.1.sup.+ 218.9564 found 218.9564.
a) Synthesis 3-fluoro-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime (Compound 3a)
(4) ##STR00141##
(5) Method 1:
(6) To a degassed solution of oxime 2 (249 mg, 1.144 mmol, 1.1 equiv) in THF/Et.sub.3N (8 mL/3 mL), Pd[PPh.sub.3].sub.4 (180 mg, 0.156 mmol, 0.15 equiv) and CuI (60 mg, 0.312 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 150 mg, 1.04 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 3a as a white solid (270 mg, 92%). R.sub.f (20% EA+PE) 0.40; IR (neat) v.sub.max 3246, 2943, 2228, 1466, 1238, 973, 849, 693, 707, 653, 567, 463 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.46 (br s, 1H, OH), 8.26 (s, 1H, H.sub.18), 7.36-7.11 (m, 7H, Ar), 2.71 (t, J=7.5 Hz, 2H, H.sub.11), 2.37 (t, J=7.1 Hz, 2H, H.sub.9), 1.88 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.04, *155.39 (C3), 145.78, *145.73 (C18), 141.27 (C12), 140.04, *139.99 (C2), 139.53, *139.42 (C6), 128.47, 128.39, 128.34 (C5, C13, C14, C16, C17), 125.93 (C15), 124.60, *124.40 (C4), 91.07 (C7), 79.42 (C8), 34.83 (C11), 29.70 (C10), 18.67 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.42; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16F.sub.1N.sub.2O.sub.1.sup.+ 283.1210 found 283.1241.
(7) Method 2:
(8) To a degassed solution of oxime 2 (83 mg, 0.381 mmol, 1.1 equiv) in THF/Et.sub.3N (2 mL/1 mL), Pd[PPh.sub.3].sub.4 (40 mg, 0.035 mmol, 0.1 equiv) and CuI (13 mg, 0.070 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 2 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 50 mg, 0.348 mmol, 1 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 30 min. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 3a as a white solid (90 mg, 92%).
b) 3-fluoro-6-(pentadec-1-yn-1-yl)picolinaldehyde oxime (Compound 3b)
(9) ##STR00142##
(10) To a degassed solution of oxime 2 (60 mg, 0.240 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (42 mg, 0.036 mmol, 0.15 equiv) and CuI (14 mg, 0.072 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1b (1-pentadecyne, 50 mg, 0.240 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 6:94) to afford the desired coupled fluoro oxime 3b as a white solid (64 mg, 77%). R.sub.f (20% EA+PE) 0.70; IR (neat) v.sub.max 3293, 2918, 2850, 2225, 1580, 1465, 1243, 1186, 997, 986, 835, 717, 652, 562 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.04 (br s, 1H, OH), 8.31 (s, 1H, H.sub.22), 7.41-7.32 (m, 2H, Ar), 2.40 (t, J=7.1 Hz, 2H, H.sub.9), 1.60 (quintet, J=7.1, 7.4 Hz, 2H, H.sub.10), 1.41 (m, 2H, H.sub.11), 1.23 (s, 1H, H.sub.12—H.sub.20), 0.85 (t, J=6.7 Hz, 1H, H.sub.21); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.09, *155.44 (C3), 146.18, *146.13 (C22), 140.29, *140.24 (C2), 139.48, *139.37 (C6), 128.51, *128.46 (C5), 124.60, *124.40 (C4), 91.80 (C7), 79.00 (C8), 31.94, 29.67, 29.52, 29.37, 29.16, 29.03, 28.28, 22.71, 19.36, 14.14 (C9-C21), 29.70 (C10), 18.67 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.58; HRMS (ESI.sup.+) m/z calcd for C.sub.21H.sub.32F.sub.1N.sub.2O.sub.1.sup.+ 347.2461 found 347.2493.
c) 6-(3-cyclohexylprop-1-yn-1-yl)-3-fluoropicolinaldehyde oxime (Compound 3c)
(11) ##STR00143##
(12) To a degassed solution of oxime 2 (89 mg, 0.409 mmol, 1 equiv) in THF/Et.sub.3N (5 mL/2 mL), Pd[PPh.sub.3].sub.4 (71 mg, 0.061 mmol, 0.15 equiv) and CuI (23 mg, 0.123 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1c (3-cyclohexyl-1-propyne, 50 mg, 0.409 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 3c as a white solid (60 mg, 56%). R.sub.f (20% EA+PE) 0.55; IR (neat) v.sub.max 3282, 2921, 2849, 2229, 1579, 1460, 1239, 1179, 983, 835, 711, 655, 557, 464 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.50 (s, 1H, OH), 8.30 (s, 1H, H.sub.16), 7.42-7.31 (m, 2H, H.sub.4, H.sub.5), 2.30 (d, J=6.6 Hz, 2H, H.sub.9), 1.84 (d, J=12.7 Hz, 2H, Cyhexyl), 1.71-1.51 (m, 4H, Cyhexyl), 1.33-0.95 (m, 5H, Cyhexyl); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.01, *155.36 (C3), 146.08, *146.03 (C16), 140.24, *140.20 (C2), 139.45, 139.34 (C6), 128.46, *128.41 (C5), 124.56, *124.36 (C4), 90.74 (C7), 79.84 (C8), 37.12, 32.80, 27.07, 26.15, 26.06 (C9-C15) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.60; HRMS (ESI.sup.+) m/z calcd for C.sub.15H.sub.18F.sub.1N.sub.2O.sub.1.sup.+ 261.1427 found 261.1398.
d) 3-fluoro-6-(6-hydroxyhex-1-yn-1-yl)picolinaldehyde oxime (Compound 3d)
(13) ##STR00144##
(14) To a degassed solution of oxime 2 (111 mg, 0.51 mmol, 1 equiv) in THF/Et.sub.3N (5 mL/2 mL), Pd[PPh.sub.3].sub.4 (89 mg, 0.077 mmol, 0.15 equiv) and CuI (29 mg, 0.153 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1d (5-hexyne-1-ol, 50 mg, 0.51 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:1) to afford the desired coupled fluoro oxime 3d as a white solid (100 mg, 83%). R.sub.f (pure EA) 0.65; IR (neat) v.sub.max 3245, 3077, 2937, 2424, 2235, 1723, 1584, 1472, 1463, 1270, 1251, 1191, 1056, 1026, 992, 972, 861, 730, 714, 653, 545 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.21 (s, 1H, H.sub.13), 7.60 (dd, J=8.6, 9.8 Hz, 1H, H.sub.4), 7.45 (dd, J=3.8, 8.6 Hz, 1H, H.sub.5), 3.62 (t, J=6.1 Hz, 2H, H.sub.12), 2.49 (t, J=6.6 Hz, 2H, H.sub.9), 1.71 (m, 4H, H.sub.10, H.sub.11); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 159.53, *156.89 (C3), 145.01, *144.97 (C13), 141.54, *141.42 (C2), 141.30, *141.25 (C6), 129.97, *129.92 (C5), 126.39, *126.19 (C4), 92.21 (C7), 80.30 (C8), 62.52 (C12), 32.93 (C11ss), 26.01 (C10), 19.78 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −125.01; HRMS (ESI.sup.+) m/z calcd for C.sub.12H.sub.14F.sub.1N.sub.2O.sub.2.sup.+ 237.1009 found 237.1034.
e) Methyl 6-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)hex-5-ynoate (Compound 3e)
(15) ##STR00145##
(16) To a degassed solution of oxime 2 (86 mg, 0.396 mmol, 1 equiv) in THF/Et.sub.3N (5 mL/2 mL), Pd[PPh.sub.3].sub.4 (69 mg, 0.059 mmol, 0.15 equiv) and CuI (23 mg, 0.119 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1e (methyl 5-hexynoate, 50 mg, 0.396 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the desired coupled fluoro oxime 3e as a white solid (90 mg, 86%). R.sub.f (50% EA+PE) 0.55; IR (neat) v.sub.max 3291, 2951, 2235, 1728, 1582, 1480, 1250, 1239, 1171, 1107, 973, 834, 717, 654, 568, 461 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.05 (s, 1H, OH), 8.31 (s, 1H, H.sub.15), 8.42-8.31 (m, 2H, H.sub.4, H.sub.5), 3.66 (s, 1H, H.sub.14), 2.49 (t, J=7.2 Hz, 4H, H9, H.sub.11), 1.93 (quintet, J=7.2 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 173.46 (C14), 158.12, *155.47 (C3), 145.81, *145.75 (C15), 139.88, *139.83 (C2), 139.56, *139.46 (C6), 128.54, *128.49 (C5), 124.56, *124.40 (C4), 89.98 (C7), 79.75 (C8), 51.64 (C14), 32.83 (C11), 23.37 (C10), 18.73 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.46; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.14F.sub.1N.sub.2O.sub.3.sup.+ 265.0968 found 265.0983.
f) 6-((1-aminocyclohexyl)ethynyl)-3-fluoropicolinaldehyde oxime (Compound 3f)
(17) ##STR00146##
(18) To a degassed solution of oxime 2 (88 mg, 0.406 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (47 mg, 0.041 mmol, 0.1 equiv) and CuI (15 mg, 0.081 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 3f (1-ethynyl-cyclohexylamine, 50 mg, 0.406 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to MeOH/EtOAc 5:95) to afford the desired coupled fluoro oxime 4f as a light yellowish solid (90 mg, 85%). R.sub.f (5% MeOH+EA) 0.30; IR (neat) v.sub.max 3280, 3323, 2936, 2858, 2561, 1812, 1579, 1523, 1459, 1245, 1164, 1058, 1006, 973, 931, 840, 677, 622, 529, 453 cm.sup.−1; H NMR (400 MHz, DMSO-d6) δ (ppm) 12.00 (s, 1H, OH), 8.13 (s, 1H, H.sub.15), 8.06 (t, J=91 Hz, 1H, H.sub.4), 7.51 (dd, J=3.2, 9.1 Hz, 1H, H.sub.5), 1.93-1.08 (m, 11H, Cyhexyl); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.42, *154.77 (C3), 145.09, *145.02 (C15), 140.03, *139.92 (C2), 138.93, *138.88 (C6), 128.46, *128.41 (C5), 125.32, *125.13 (C4), 96.53 (C8), 80.55 (C7), 49.38, 25.01, 22.76 (Cyhexyl) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −121.43; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.17F.sub.1N.sub.3O.sub.1.sup.+ 262.1387 found 262.1350.
g) 3-fluoro-6-(hex-5-en-1-yn-1-yl)picolinaldehyde oxime (Compound 3g)
(19) ##STR00147##
(20) To a degassed solution of oxime 2 (136 mg, 0.624 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (72 mg, 0.062 mmol, 0.1 equiv) and CuI (24 mg, 0.125 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1g (1-hexene-5-yne, 50 mg, 0.624 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 3g as a white solid (110 mg, 81%). R.sub.f (20% EA+PE) 0.30; IR (neat) V.sub.max 3160, 3068, 2920, 2849, 2231, 1579, 1487, 1459, 1248, 1187, 1114, 982, 915, 842, 815, 700, 629, 525 cm.sup.−1; H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.30 (br s, 1H, OH), 8.31 (s, 1H, H.sub.13), 7.41-7.31 (m, 2H, H.sub.4, H.sub.5), 5.88 (m, 1H, H.sub.11), 5.07 (m, 1H, H.sub.12), 2.50 (t, J=7.2 Hz, 1H, H.sub.9), 2.37 (q, J=7.2 Hz, 1H, H.sub.10), 1.88 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.08, *155.43 (C3), 146.09, *146.04 (C13), 140.03, *139.98 (C2), 139.53, *139.42 (C6), 136.53 (C11), 128.48, *128.39 (C5), 124.59, *124.39 (C4), 115.91 (C12), 90.66 (C7), 79.35 (C8), 32.31 (C10), 19.09 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.20. HRMS (ESI.sup.+) m/z calcd for C.sub.12H.sub.12F.sub.1N.sub.2O.sub.1.sup.+ 219.0951 found 219.0928.
h) 6-((4-ethylphenyl)ethynyl)-3-fluoropicolinaldehyde oxime (Compound 3h)
(21) ##STR00148##
(22) To a degassed solution of oxime 2 (84 mg, 0.384 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (45 mg, 0.038 mmol, 0.1 equiv) and CuI (15 mg, 0.077 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1h (4-ethylphenylacetylene, 50 mg, 0.384 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 15:85) to afford the desired coupled fluoro oxime 3h as a light yellowish solid (95 mg, 92%). R.sub.f (20% EA+PE) 0.45; IR (neat) v.sub.max 3284, 2963, 2928, 2216, 1578, 1510, 1456, 1270, 1242, 1196, 993, 936, 828, 722, 677, 625, 546, 496 cm.sup.−1; H NMR (400 MHz, Acetone-d6) δ (ppm) 11.09 (br s, 1H, OH), 8.23 (s, 1H, H.sub.17), 7.71 (dd, J=8.6, 9.7 Hz, 1H, H.sub.4), 7.65 (dd, J=3.8, 8.6 Hz, 1H, H.sub.5), 7.53 (d, J=8.1 Hz, 2H, H.sub.10, H.sub.14), 7.29 (d, J=8.1 Hz, 2H, H.sub.11, H.sub.13), 2.68 (q, J=7.4 Hz, 2H, H.sub.15), 1.22 (q, J=7.4 Hz, 2H, H.sub.16); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.09, *156.43 (C3), 146.85, 146.76, 146.70 (C12, C17), 141.71, *141.56 (C2), 140.26, *140.21 (C6), 132.80 (C10, C14), 129.53, *129.45 (C5), 129.17 (C11, C13), 125.86, *125.66 (C4), 120.14 (C9), 89.51 (C7), 88.04 (C8), 29.44 (C15), 15.79 (C16) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.63; HRMS (ESI.sup.+) m/z calcd for C.sub.16H.sub.14F.sub.1N.sub.2O.sub.1.sup.+ 269.1084 found 269.1085.
i) 6-(4-chlorobut-1-yn-1-yl)-3-fluoropicolinaldehyde oxime (Compound 3i)
(23) ##STR00149##
(24) To a degassed solution of oxime 2 (123 mg, 0.565 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (65 mg, 0.057 mmol, 0.1 equiv) and CuI (22 mg, 0.113 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne ii (4-chloro-1-butyne, 50 mg, 0.565 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the desired coupled fluoro oxime 3i as a white solid (100 mg, 78%). R.sub.f (30% EA+PE) 0.45; IR (neat) v.sub.max 3271, 2245, 1579, 1455, 1293, 1240, 1178, 984, 940, 838, 726, 693, 658, 639, 535, 465 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.38 (br s, 1H, OH), 8.31 (s, 1H, H.sub.13), 7.46-7.34 (m, 2H, H.sub.4, H.sub.5), 3.67 (t, J=7.2 Hz, 2H, H.sub.10), 2.89 (t, J=7.2 Hz, 2H, H.sub.9); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.30, *155.65 (C3), 145.77, 145.72 (C11), 139.72, *139.60 (C2), 139.38, *139.33 (C6), 128.72, *128.67 (C5), 124.69, *124.49 (C4), 86.62 (C8), 80.61 (C7), 41.49 (C9), 23.65 (C10) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −121.60. HRMS (ESI.sup.+) m/z calcd for C.sub.10H.sub.9Cl.sub.1F.sub.1N.sub.2O.sub.1.sup.+ 219.0951 found 219.0928.
j) 6-((3,6-dihydropyren-4-yl)ethynyl)-3-fluoropicolinaldehyde oxime (Compound 3j)
(25) ##STR00150##
(26) To a degassed solution of oxime 2 (53 mg, 0.240 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (38 mg, 0.033 mmol, 0.15 equiv) and CuI (13 mg, 0.066 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1j (1-ethynylpyren, 50 mg, 0.221 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to MeOH/EtOAc 5:95) to afford the desired coupled fluoro oxime 3j as a light yellowish solid (60 mg, 81%). R.sub.f (20% EA+PE) 0.50; IR (neat) v.sub.max 3252, 3047, 2436, 2207, 1581, 1464, 1251, 1205, 1119, 997, 836, 713, 692, 677, 635, 609, 539, 459 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.09 (s, 1H, OH), 8.62 (d, J=9.2 Hz, 1H, Ar), 8.44-8.23 (m, 8H, Ar), 8.16 (t, J=7.8 Hz, 1H, Ar), 7.99-7.91 (m, 2H, Ar) 7.71 (dd, J=3.8, 8.9 Hz, 1H), 7.53 (t, J=8.6 Hz, 1H); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.86, *155.20 (C3), 145.10, *145.04 (C25), 140.60, *140.19 (C2), 138.49, *138.44 (C6), 131.56, 130.71, 130.42, 129.97, 129.21, 128.85, 127.21, 126.88, 126.28, 126.24, 125.60, 125.40, 124.99, 124.61, 123.55, 123.27, 115.33, (Ar), 93.40 (C7), 87.39 (C8) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −120.05; HRMS (ESI.sup.+) m/z calcd for C.sub.24H.sub.14F.sub.1N.sub.2O.sub.1.sup.+ 365.1123 found 365.1085.
k) 4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)but-3-yne-1-sulfonamide (Compound 3k)
(27) ##STR00151##
(28) To a degassed solution of oxime 2 (82 mg, 0.375 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (43 mg, 0.038 mmol, 0.1 equiv) and CuI (14 mg, 0.075 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1k (but-3-yne-1-sulfonamide, 50 mg, 0.375 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 3:1) to afford the desired coupled fluoro oxime 3k as a light yellowish solid (55 mg, 54%). R.sub.f (80% EA+PE) 0.35; IR (neat) v.sub.max 3347, 3266, 3001, 2237, 1557, 1462, 1327, 1248, 1140, 983, 852, 716, 699, 642, 587, 492 cm.sup.−1; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 11.08 (br s, 1H, OH), 8.20 (s, 1H, H.sub.11), 7.68 (t, J=8.8 Hz, 1H, H.sub.4), 7.54 (dd, J=3.4, 8.8 Hz, 1H, H.sub.5), 6.28 (2s, 3H, —NH.sub.2), 3.41 (t, J=7.4 Hz, 2H, H.sub.10), 3.29 (t, J=7.5 Hz, 2H, H.sub.10), 2.99 (t, J=7.4 Hz, 2H, H.sub.9), 2.83 (t, J=7.5 Hz, 2H, H.sub.9) (* doubling of the alkyne moiety signals were observed due to the resolution); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.08, *156.43 (C3), 146.61, *146.56, (C11), 141.44, *141.33 (C2), 140.10, *140.05 (C6), 129.45, *129.40 (C5), 125.81, *125.61 (C4), 87.35, 81.34 (C8), 75.48, 67.05 (C7), 53.72, 53.48 (C10), 15.60, 15.53 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.98; HRMS (ESI.sup.+) m/z calcd for C.sub.10H.sub.11F.sub.1N.sub.31S.sub.1.sup.+ 272.0481 found 275.0500.
l) tert-butyl (4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)carbam-ate (Compound 3l)
(29) ##STR00152##
(30) To a degassed solution of oxime 2 (64 mg, 0.295 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (34 mg, 0.029 mmol, 0.1 equiv) and CuI (11 mg, 0.059 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 3I (4-(NHBoc)-1-butyne, 50 mg, 0.295 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 35:65) to afford the desired coupled fluoro oxime 41 as a light yellowish solid (50 mg, 55%). R.sub.f (50% EA+PE) 0.70; IR (neat) v.sub.max 3301, 2925, 2240, 1675, 1511, 1464, 1404, 1348, 1243, 1165, 1144, 987, 839, 788, 639, 577, 463 cm.sup.−1; .sup.1H NMR ** (400 MHz, CDCl.sub.3) δ (ppm) 11.20, 9.66 (2br s, 1.5H, OH), 8.32, 8.20 (2s, 1.5H, H.sub.11), 7.44-7.23 (m, 3H, H.sub.4, H.sub.5), 6.78, 5.22 (2s, 1.5H, —NH), 3.38 (q, J=6.4 Hz, 3H, H.sub.10), 2.61 (t, J=6.4 Hz, 3H, H.sub.9), 1.48, 1.42 (2s, 13.5H, -Boc); .sup.13C NMR ** (100 MHz, CDCl.sub.3) δ (ppm) 158.09, 157.51, 155.79, 155.46, 144.95, 144.56, 139.78, 139.67, 139.42, 139.33, 134.71, 129.90, 129.86, 128.47, 128.22, 125.33, 125.14, 124.62, 124.42 (Ar, —C═NOH), 88.59, *88.33 (C8), 80.65 (-Boc), *80.04, 79.66 (C7), *40.35, 39.13 (C10), 28.38 ((-Boc), *21.21, 20.97 (C9); .sup.19F NMR **(400 MHz, CDCl.sub.3) δ (ppm) −122.01, −122.68; (**rotameric mixture); HRMS (ESI.sup.+) m/z calcd for C.sub.15H.sub.19F.sub.1N.sub.3O.sub.3.sup.+ 308.1383 found 308.1405.
m) 4-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)benzonitrile (Compound 3m)
(31) ##STR00153##
(32) To a degassed solution of oxime 2 (86 mg, 0.393 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (45 mg, 0.039 mmol, 0.1 equiv) and CuI (15 mg, 0.079 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1m (4-ethynylbenzonitrile, 50 mg, 0.393 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:4) to afford the desired coupled fluoro oxime 3m as a light yellowish solid (30 mg, 29%). (20% EA+PE) 0.45; IR (neat) v.sub.max 3247, 2229, 1602, 1503, 1464, 1284, 1248, 1198, 994, 930, 838, 733, 673, 605, 556 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO) δ (ppm) 12.08 (s, 1H, OH), 8.19 (s, 1H, H.sub.16), 7.98-7.75 (m, 6H, Ar); .sup.13C NMR (100 MHz, DMSO) δ (ppm) 158.04, *155.37 (C3), 144.95, *144.89 (C16), 140.72, *140.61 (C2), 137.53, *137.49 (C6), 132.70, 132.51 (C10, C11, C13, C14), 129.38, *129.33 (C5), 125.96 (C9), 125.65, *125.45 (C4), 118.28 (C15), 111.78 (C12), 91.04 (C7), 86.68 (C8) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO) δ (ppm) −119.12; HRMS (ESI.sup.+) m/z calcd for C.sub.15H.sub.9F.sub.1N.sub.3O.sub.1.sup.+ 266.0689 found 266.0724.
n) 6-(5-(1,3-dioxoisoindolin-2-yl)pent-1-yn-1-yl)-3-fluoropicolinaldehyde oxime (Compound 3n)
(33) ##STR00154##
(34) To a degassed solution of oxime 2 (102 mg, 0.469 mmol, 1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (81 mg, 0.070 mmol, 0.15 equiv) and CuI (27 mg, 0.141 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1n (N-(4-pentynyl) phthalimide, 100 mg, 0.469 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:1 to EtOAc/PE 6:4) to afford the desired coupled fluoro oxime 3n as a white solid (50 mg, 30%). R.sub.f (50% EA+PE) 0.55; IR (neat) v.sub.max 3320, 2941, 2233, 1771, 1762, 1689, 1580, 1460, 1399, 1245, 1184, 1019, 971, 883, 834, 723, 662, 529 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.26 (s, 1H, OH), 8.22 (s, 1H, H.sub.15), 7.75 (dd, J=3.0, 5.5 Hz, 2H, H.sub.16, H.sub.17), 7.61 (dd, J=3.0, 5.5 Hz, 2H, H.sub.15, H.sub.18), 7.30 (t, J=8.7 Hz, 1H, H.sub.4), 7.23 (dd, J=3.9, 8.7 Hz, 1H, H.sub.5), 3.78 (t, J=6.9 Hz, 2H, H.sub.11), 2.45 (t, J=6.9 Hz, 2H, H.sub.9), 1.97 (quintet, J=6.9 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 168.35 (C13, C20), 158.03, *155.38 (C3), 146. 04, *145.99 (C21), 139.74, *139.70 (C2), 139.46, *139.35 (C6), 133.89 (C10, C11), 132.03 (C14, C19), 128.49, *128.44 (C5), 124.47, *124.27 (C4), 123.24 (C15, C18), 89.76 (C7), 79.81 (C8), 37.24 (C11), 26.89 (C10), 17.11 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.10; HRMS (ESI.sup.+) m/z calcd for C.sub.19H.sub.15F.sub.1N.sub.3O.sub.3.sup.+ 352.1096 found 352.1092.
o) 3-fluoro-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)picolinaldehyde oxime (Compound 3o)
(35) ##STR00155##
(36) To a degassed solution of oxime 2 (86 mg, 0.396 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (46 mg, 0.040 mmol, 0.10 equiv) and CuI (15 mg, 0.079 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1o (4-ethynyltetrahydro-2H-pyran-4-ol, 50 mg, 0.396 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 3:1 to pure EtOAc) to afford the desired coupled fluoro oxime 3o as a light yellowish solid (90 mg, 86%). R.sub.f (50% EA+PE) 0.55; IR (neat) v.sub.max 3272, 3075, 2955, 2924, 2858, 1582, 1465, 1243, 1155, 1097, 1001, 982, 845, 727, 679, 637, 555, 475 cm.sup.−1; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 11.07 (br s, 1H, OH), 8.20 (s, 1H, H.sub.15), 7.68 (dd, J=8.6, 9.6 Hz, 1H, H.sub.4), 7.56 (dd, J=3.7, 8.6 Hz, 1H, H.sub.5), 4.91 (brs, 1H, OH), 3.85, 3.65 (2m, 4H, H.sub.11/H.sub.13), 1.91, 1.81 (2m, 4H, H9/H.sub.10); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.14, *156.49 (C3), 146.57, *146.51, (C15), 141.56, *141.44 (C2), 139.88, *139.83 (C6), 129.56, *129.51 (C5), 125.81, *125.62 (C4), 93.28 (C8), 83.06 (C7), 65.88 (C9), 65.02 (C11, C13), 40.72 (C10, C14) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.77; HRMS (ESI.sup.+) m/z calcd for O.sub.13H.sub.14F.sub.1N.sub.2O.sub.3.sup.+ 265.0974 found 265.0983.
p) 3-fluoro-6-((3-hydroxyoxetan-3-yl)ethynyl)picolinaldehyde oxime (Compound 3p)
(37) ##STR00156##
(38) To a degassed solution of oxime 2 (111 mg, 0.51 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (60 mg, 0.051 mmol, 0.1 equiv) and CuI (20 mg, 0.102 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1p (3-ethynyloxetan-3-ol 50 mg, 0.51 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 4:1) to afford the desired coupled fluoro oxime 3p as a light yellowish solid (110 mg, 91%). R.sub.f(Pure EA) 0.65; IR (neat) v.sub.max 3357, 3014, 1622, 1583, 1465, 1384, 1279, 1247, 1176, 1105, 986, 957, 899, 855, 676, 608, 568 cm.sup.−1; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 11.09 (br s, 1H, OH), 8.20 (s, 1H, H.sub.13), 7.71 (t, J=8.6 Hz, 1H, H.sub.4), 7.60 (dd, J=3.5, 8.8 Hz, 1H, H.sub.5), 5.69 (s, 1H, —OH), 4.83, 4.69 (d, J=6.4 Hz, 4H, H.sub.10, H.sub.12); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.33, *156.67 (C3), 146.55, *146.49, (C11), 141.76, *141.65 (C2), 139.41, *139.36 (C6), 129.45, *129.59 (C5), 125.92, *125.72 (C4), 89.67 (C8), 84.90, (C10, C12), 83.97 (C7), 67.54 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.22; HRMS (ESI.sup.+) m/z calcd for C.sub.10H.sub.11F.sub.1N.sub.3O.sub.1S.sub.1.sup.+ 272.0481 found 275.0500.
q) Benzyl 3-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)azetidine-1-carb-oxylate (Compound 3q)
Benzyl 3-ethynylazetidine-1-carboxylate (Compound 1q)
(39) ##STR00157##
(40) To a solution of amine (50 mg, 0.425 mmol, 1 equiv) in THF/Water (3 mL/1.5 mL) at 0° C., was added K.sub.2CO.sub.3 (117 mg, 0.850 mmol, 2 equiv) and benzyl chloroformate (773 μL, 0.51 mmol, 1.2 equiv). The ice bath was removed and the resulting mixture was allowed to warm to room temperature and stirred it for overnight. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the protected compound 1q as a light yellowish solid (80 mg, 87%). R.sub.f (20% EA+PE) 0.55; IR (neat) v.sub.max 3290, 2962, 2891, 1701, 1449, 1413, 1355, 1293, 1123, 1027, 767, 696, 643, 606, 562, 497, 469 cm.sup.−1; .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm) 7.37-7.29 (m, 5H, phenyl), 5.08 (s, 1H, —CH.sub.2Ph), 4.21 (t, J=8.6 Hz, 2H), 4.01 (dd, J=6.3, 8.3 Hz, 2H) 3.34 (m, 1H), 2.28 (d, J=2.5 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3) δ (ppm) 156.08, 136.45, 128.48, 128.09, 128.01 (Ar), 83.59, 71.88, 66.77, 55.36, 19.49.
Benzyl 3-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)azetidine-1-carb-oxylate (Compound 3q)
(41) ##STR00158##
(42) To a degassed solution of oxime 2 (61 mg, 0.279 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (32 mg, 0.028 mmol, 0.1 equiv) and CuI (11 mg, 0.056 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1q (50 mg, 0.279 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the desired coupled fluoro oxime 3q as a light yellowish solid (75 mg, 76%). R.sub.f (40% EA+PE) 0.30; IR (neat) v.sub.max 3272, 2958, 2924, 2239, 1704, 1682, 1583, 1460, 1419, 1358, 1246, 1128, 978, 837, 733, 697, 633, 606, 562 cm.sup.−1; .sup.1H NMR ** (400 MHz, CDCl.sub.3) δ (ppm) 9.38 (s, 1H, OH), 8.31, (s, 1H, H.sub.13), 7.44-7.26 (m, 7H, Ar), 5.09 (s, 2H, —CH.sub.2Bn), 4.27 (t, J=8.5 Hz, 2H, H.sub.10/H.sub.12), 4.13 (dd, J=6.4, 8.5 Hz, 2H, H.sub.10/H.sub.12), 3.59 (m, 1H, H.sub.9); .sup.13C NMR ** (100 MHz, CDCl.sub.3) δ (ppm) 158.31, 155.65 155.81, 153.17, 145.52, 145.48, 139.95, 139.84, 139.03, 136.33, 136.27, 135.67, 129.89, 129.84, 128.46, 128.01, 128.05, 128.02, 125.42, 125.23, 124.69, 124.45 (Ar), 91.40, 89.34 (C8), 81.93, 80.67 (C7), 66.93, 66.85 (—CH.sub.2Bn), 55.19 (C10/C12), 20.08, 19.99 (C9); .sup.19F NMR **(400 MHz, CDCl.sub.3) δ (ppm) −121.42, −122.16; (** rotamers); HRMS (ESI.sup.+) m/z calcd for C.sub.19H.sub.17F.sub.1N.sub.3O.sub.3.sup.+ 354.1258 found 354.1248.
r) 3-fluoro-6-(pyridin-3-ylethynyl)picolinaldehyde oxime (Compound 3r)
(43) ##STR00159##
(44) To a degassed solution of oxime 2 (133 mg, 0.611 mmol, 1.05 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.087 mmol, 0.15 equiv) and CuI (33 mg, 0.174 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1r (4-ethynylpyridine, 60 mg, 0.582 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 45:55) to afford the desired coupled fluoro oxime 3r as a white solid (110 mg, 79%). R.sub.f (60% EA+PE) 0.25; IR (neat) v.sub.max 3071, 2287, 2126, 1596, 1572, 1482, 1456, 1247, 1201, 1110, 995, 837, 799, 697, 636, 529 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.07 (s, 1H, OH), 8.82 (br d, J=1.8 Hz, 1H, H.sub.14), 8.65 (dd, J=1.5, 4.9 Hz, 1H, H.sub.12), 8.19 (s, 1H, H.sub.15), 8.06 (dt, J=1.8, 7.9 Hz, 1H, H.sub.10), 7.90 (dd, J=8.6, 10.4 Hz, 1H, H.sub.4), 7.78 (dd, J=3.7, 8.6 Hz, 1H, H.sub.5), 7.50 (m, 1H, H.sub.11); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.68, *155.55 (C3), 151.92 (C12), 149.74 (C14), 144.99, *144.94 (C15), 140.62, *140.53 (C2), 139.02 (C10), 137.77, *137.73 (C6), 129.14, *129.10 (C5), 125.62, *125.46 (C4), 123.74 (C11), 118.33 (C9), 90.34 (C7), 85.20 (C8) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −119.52; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.9F.sub.1N.sub.3O.sub.1.sup.+ 242.0749 found 242.0724.
s) Benzyl (3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)(pyridin-4-yl)carbamate (Compound 3s)
(45) ##STR00160##
(46) To a degassed solution of oxime 2 (65 mg, 0.30 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (35 mg, 0.03 mmol, 0.1 equiv) and CuI (11 mg, 0.06 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1s (80 mg, 0.30 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the desired coupled fluoro oxime 3s as a light yellowish solid (75 mg, 62%). R.sub.f (Pure EA) 0.38; IR (neat) v.sub.max 2922, 1730, 1595, 1496, 1463, 1389, 1359, 1214, 1146, 1051, 973, 845, 821, 734, 693, 633, 544, 477 cm.sup.−1; .sup.1H NMR ** (400 MHz, Acetone-d6) δ (ppm) 11.29 (br s, 1H, OH), 8.56 (br d, J=3.6 Hz, 2H, H.sub.13, H.sub.15), 8.18 (s, 1H, H.sub.17), 7.64-7.42 (m, 9H, Ar), 5.31 (s, 2H, —Cbz), 4.90 (s, 2H, H.sub.9) (** more number of peaks observed in aromatic region due to rotamers); **.sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.31, 156.66, 154.52, 151.38, 149.65, 146.54, 146.47, 141.80, 141.68, 139.36, 139.31, 137.24, 135.07, 135.02, 134.0, 132.80, 132.71, 129.60, 129.57, 129.45, 129.08, 128.94, 128.85, 128.65, 119.37 (Ar, —C═NOH), 85.31 (C7), 83.39 (C8), 68.87 (-Cbz), 39.86 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom and also due to **rotameric nature); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.06; HRMS (ESI.sup.+) m/z calcd for C.sub.22H.sub.18F.sub.1N.sub.4O.sub.3.sup.+ 405.1341 found 405.1357.
t) Methyl(S)-2-((tert-butoxycarbonyl)amino)-5-(5-fluoro-6-((hydroxyimino)methyl)pyri-din-2-yl)pent-4-ynoate (Compound 3t)
Methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-ynoate (Compound 1t)
(47) ##STR00161##
(48) To a solution of amino ester (190 mg, 1.495 mmol, 1 equiv) in DCM (15 mL) at RT (room temperature), was added TEA (625 μL, 4.485 mmol, 3 equiv) and Boc-anhydride (652 mg, 2.99 mmol, 2 equiv). The resulting mixture was stirred for overnight at RT. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the protected compound it as a light yellowish solid (80 mg, 87%). R.sub.f (20% EA+PE) 0.65; IR (neat) v.sub.max 3294, 2979, 1746, 1709, 1501, 1366, 1355, 1249, 1158, 1061, 1025, 868, 779, 759, 643 cm.sup.−1; .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm) 5.32 (br d, J=7.3 Hz, 1H, —NH), 4.44 (m, 1H, H.sub.4), 3.75 (s, 3H, —CH.sub.3), 2.01 (t, J=2.6 Hz, 1H, H.sub.1), 1.42 (s, 9H, -Boc); .sup.13C NMR (75 MHz, CDCl.sub.3) δ (ppm) 171.09 (—CO), 155.04 (-Boc), 80.17 (-Boc), 78.48 (C2), 71.57 (C1), 52.61 (C4), 51.88 (C7), 28.25 (-Boc), 22.51 (C3).
Methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(5-fluoro-6-((hydroxyimino)methyl)pyri-din-2-yl)pent-4-ynoate (Compound 3t)
(49) ##STR00162##
(50) To a degassed solution of oxime 2 (67 mg, 0.308 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (36 mg, 0.031 mmol, 0.1 equiv) and CuI (12 mg, 0.062 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne it (N-(Boc)-L-propargylglycine methyl ester, 70 mg, 0.308 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 3:7) to afford the desired coupled fluoro oxime 3t as a light yellowish solid (75 mg, 76%). R.sub.f (30% EA+PE) 0.25; IR (neat) v.sub.max 3331, 2978, 2928, 2242, 1744, 1693, 1504, 1462, 1366, 1247, 1159, 1059, 978, 841, 735, 645, 575 cm.sup.−1; .sup.1H NMR ** (400 MHz, CDCl.sub.3) δ (ppm) 9.55 (br s, 1H, OH), 8.31, (s, 1H, H.sub.14), 7.41-7.31 (m, 2H, H.sub.4, H.sub.5), 5.56 (br d, J=8.2 Hz, 1H, —NH), 4.57 (m, 1H, H.sub.10), 3.77 (s, 3H, H.sub.13), 2.96 (m, 2H, H.sub.9), 1.42 (s, 9H, -Boc); .sup.13C NMR ** (100 MHz, CDCl.sub.3) δ (ppm) 171.13 (C11), 158.23, *155.75 (C3), 155.13 (-Boc), 145.10, *145.06 (C14), 139.83, *139.72 (C2), 139.18, *139.14 (C6), 128.76, *128.72 (C5), 124.59, *124.39 (C4), 85.19 (C8), 81.59 (-Boc), 80.32 (C7), 52.74 (C10), 51.97 (C13), 28.26 (-Boc), 23.76 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR **(400 MHz, CDCl.sub.3) δ (ppm) −121.42, −122.16; (** rotamers); HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.21F.sub.1N.sub.3O.sub.5.sup.+ 366.1449 found 366.1460.
u) N-(9-((3aR,4R,6R,6aR)-6-(((3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide (Compound 3u)
(51) ##STR00163##
(52) To a degassed solution of oxime 2 (107 mg, 0.490 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (85 mg, 0.074 mmol, 0.15 equiv) and CuI (25 mg, 0.134 mmol, 0.30 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1u (200 mg, 0.445 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 7:3) to afford the desired coupled fluoro oxime 3u as a light yellowish solid (160 mg, 61%). R.sub.f (Pure EA) 0.38; IR (neat) v.sub.max 3201, 2926, 1698, 1611, 1582, 1457, 1357, 1246, 1211, 1074, 845, 797, 709, 644, 623, 541 cm.sup.−1; .sup.1H NMR ** (400 MHz, Acetone-d6) δ (ppm) 8.73, 8.60, 8.19 (3s, 3H, Ar, —C═NOH), 8.13 (m, 2H, Ar), 7.66-7.52 (m, 5H, Ar), 6.36 (d, J=2.3 Hz, 1H, —CH), 5.52 (dd, J=2.3, 6.1 Hz, 1H, —CH), 5.16 (dd, J=2.5, 6.1 Hz, 1H, —CH), 4.55-43-0.39 (m, 3H, —CH, —CH.sub.2), 3.90 (dd, J=4.5, 10.3 Hz, 1H, —CH.sub.2), 3.82 (dd, J=4.5, 10.3 Hz, 1H, —CH.sub.2), 1.59 (s, 3H, —CH.sub.3), 1.38 (s, 3H, —CH.sub.3); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 166.43, *159.26, 156.61, 152.87, 151.17, 146.04, *145.98, 143.67, 141.60, *141.50, 139.43, *139.38, 135.05, 133.38, 132.81, 132.72, 129.92, *129.87, 129.57, 129.50, 129.27, *125.85, 125.65 (Ar), 114.48 (—C—), 91.82 (—CH), 86.89 (—CH), 85.66 (—C), 85.55 (—CH), 85.42 (—C), 83.1 (—CH), 71.06 (—CH.sub.2), 59.46 (—CH.sub.2), 27.57 (—CH.sub.3), 25.59 (—CH.sub.3) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom and also due to **rotameric nature); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −121.06; HRMS (ESI.sup.+) m/z calcd for C.sub.15H.sub.19F.sub.1N.sub.3O.sub.3.sup.+ 308.1383 found 308.1405.
v) (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-fluoro-6-((Z)-(hydroxyimino)me-thyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 3v
(53) ##STR00164##
(54) To a degassed solution of oxime 2 (65 mg, 0.296 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (47 mg, 0.040 mmol, 0.15 equiv) and CuI (15 mg, 0.080 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1v (100 mg, 0.269 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the desired coupled fluoro oxime 3v as a light yellowish solid (75 mg, 55%). R.sub.f (50% EA+PE) 0.70; .sup.1H NMR ** (400 MHz, CD.sub.3OD) δ (ppm) 8.16-8.04 (3s, 3H, Ar, —C═NOH), 7.45 (t, J=8.8, 1H, H.sub.4), 7.23 (dd, J=3.3, 8.8 Hz, 1H, H.sub.5), 6.24 (br d, J=1.2 Hz, 1H, —CH), 5.49 (dd, J=1.8, 6.0 Hz, 1H, —CH), 5.31 (dd, J=1.2, 6.0 Hz, 1H, —CH), 4.59 (d, J=1.8 Hz, 1H, —CH), 3.50 (m, 1H, —CH.sub.2), 2.99 (m, 1H, —CH.sub.2), 2.22 (m, 1H, —CH.sub.2), 2.03 (m, 1H, —CH.sub.2), 1.48 (s, 3H, —CH.sub.3), 1.27 (s, 3H, —CH.sub.3); .sup.13C NMR ** (100 MHz, CD.sub.3OD) δ (ppm) 172.16, 159.60, 157.27, 156.96, 153.92, 150.32, 144.76, 142.54, 141.45, 141.33, 140.47, 130.03, 130.00, 126.34, 126.14, 120.54, 115.18 (Ar), *92.50 (C16), 88.99 (C8), 88.76 (C15), 85.42 (C14), 85.30 (C13), 80.97 (C7), 38.69 (C10), 27.29 (C28), 25.53 (C29), 20.42 (C9); .sup.19F NMR **(400 MHz, CDCl.sub.3) δ (ppm) −122.54; (** rotamers); HRMS (ESI.sup.+) m/z calcd for C.sub.23H2.sub.4F.sub.1N.sub.8O.sub.5.sup.+ 511.1882 found 511.1848.
w) 3-fluoro-6-(10-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)deca-1,9-diyn-1-yl)picolinaldehyde oxime (Compound 3w)
(55) ##STR00165##
(56) To a degassed solution of oxime 2 (162 mg, 0.745 mmol, 2 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (86 mg, 0.075 mmol, 0.2 equiv) and CuI (28 mg, 0.149 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1w (1,9-decadiyne, 50 mg, 0.373 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 4:6) to afford the desired coupled fluoro oxime 3w as a white solid (80 mg, 52%). R.sub.f (60% EA+PE) 0.20; IR (neat) V.sub.max 3273, 2940, 2859, 2232, 1580, 1464, 1239, 1183, 978, 943, 842, 714, 656, 566, 468 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO) δ (ppm) 11.97 (br s, 1H, OH), 8.12 (s, 1H, H.sub.12, H.sub.12′), 7.75 (dd, J=8.5, 10.3 Hz, 1H, H.sub.4, H.sub.4′), 7.50 (dd, J=3.7, 8.5 Hz, 1H, H.sub.5, H.sub.5′), 2.46 (t, J=6.9 Hz, 2H, H.sub.9, H.sub.9′), 1.58 (m, 2H, H.sub.10, H.sub.10′), 1.58 (m, 2H, H.sub.11, H.sub.11′); .sup.13C NMR (100 MHz, DMSO) δ (ppm) 157.41, *154.77 (C3), 145.20, 145.13 (C12), 139.91, *139.88 (C2), 139.93, *139.89 (C6), 128.31, *128.26 (C5), 125.32, *125.12 (C4), 90.67 (C8), 79.46 (C7), 27.81 (C9), 27.65 (C10), 18.33 (C11) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO) δ (ppm) −121.33. HRMS (ESI.sup.+) m/z calcd for C.sub.22H.sub.21F.sub.2N.sub.4O.sub.2.sup.+ 411.1666 found 411.1627.
x) 6-(4-((7-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)but-1-yn-1-yl)-3-flu-oropicolinaldehyde oxime (Compound 3λ)
(57) ##STR00166##
(58) To a degassed solution of oxime 2 (40 mg, 0.185 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (21 mg, 0.019 mmol, 0.1 equiv) and CuI (7 mg, 0.037 mmol, 0.2 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1× (50 mg, 0.185 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to MeOH/EtOAc 5:95) to afford the desired coupled fluoro oxime 3× as a white solid (70 mg, 93%). R.sub.f (10% MeOH+EA) 0.50; IR (neat) v.sub.max 3374, 2243, 1567, 1539, 1461, 1417, 1403, 1351, 1248, 1135, 1027, 997, 841, 820, 749, 691, 642, 546, 500, 461 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO) δ (ppm) 11.99 (br s, 1H, OH), 8.32 (s, 1H, H.sub.20), 8.09 (s, 1H, H.sub.25), 7.76 (dd, J=8.8, 10.0 Hz, 1H, H.sub.4), 7.69 (d, J=8.8 Hz, 1H, H.sub.21), 7.51 (dd, J=1.9, 8.8 Hz, 1H, H.sub.23), 7.40 (dd, J=3.3, 8.8 Hz, 1H, H.sub.5), 6.86 (t, J=6.6 Hz, 1H, —NH), 3.76 (q, J=6.8 Hz, 2H, H.sub.10), 3.20 (t, J=7.2 Hz, 2H, H.sub.16), 2.86 (t, J=7.6 Hz, 2H, H.sub.14), 2.74 (t, J=6.8 Hz, 2H, H.sub.9), 2.04 (m, 2H, H.sub.15); .sup.13C NMR (100 MHz, DMSO) δ (ppm) 168.75 (C17), 157.20, *155.09 (C3), 146.59 (C12), 145.21, 145.16 (C25), 140.04, *139.95 (C2), 138.60, *138.56 (C6), 130.36 (C22), 128.31, *128.27 (C5), 128.22 (C21), 127.85 (C19), 125.29, *125.13 (C4), 120.95 (C20, C23), 119.88 (C17), 113.52 (C13), 88.15 (C8), 80.49 (C7), 42.53 (C10), 34.14 (C11), 30.61 (C14), 22.73 (C15), 21.01 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO) δ (ppm) −120.87; HRMS (ESI.sup.+) m/z calcd for C.sub.22H.sub.19Cl.sub.1F.sub.1N.sub.4O.sub.1.sup.+ 409.1242 found 409.1226.
y) 3-fluoro-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime (Compound 3y)
(59) ##STR00167##
(60) To a degassed solution of oxime 2 (49 mg, 0.224 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (35 mg, 0.031 mmol, 0.15 equiv) and CuI (12 mg, 0.061 mmol, 0.23 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1y (40 mg, 0.204 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to MeOH/EtOAc 5:95) to afford the desired coupled fluoro oxime 3y as a yellowish solid (55 mg, 81%). R.sub.f (20% MeOH+EA) 0.30; IR (neat) v.sub.max 3335, 2922, 2239, 1584, 1451, 1402, 1343, 1244, 1119, 993, 835, 807, 759, 694, 675, 644, 572 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.39 (d, J=5.5 Hz, 1H, Ar), 8.23 (s, 1H, oxime), 8.13 (dd, J=0.9, 8.5 Hz, 1H, Ar), 7.82 (br d, J=8.5 Hz, 1H, Ar), 7.67-7.58 (m, 2H, Ar), 7.48-7.41 (m, 2H, Ar), 6.65 (d, J=5.5 Hz, 1H, Ar), 3.73 (t, J=6.9 Hz, 2H, H.sub.10), 2.88 (t, J=6.9 Hz, 2H, H.sub.9); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 152.61, 151.21, 148.88, 144.71, *144.69, 141.67, 141.58, 140.91, 140.87, 133.27, *133.19, 130.82, 130.18, *130.08, 130.03, *129.97, 128.81, 126.44, 126.28, 125.99, 122.43, 120.45 (Ar), 89.66 (C8), 81.27 (C7), 42.62 (C10), 20.08 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −125.02; HRMS (ESI.sup.+) m/z calcd for C.sub.19H.sub.16F.sub.1N.sub.4O.sub.1.sup.+ 335.1280 found 335.1303.
z) 6-(4-(1,2,3,4-tetrahydroacridin-9-ylamino)but-1-yn-1-yl)-3-fluoropicolinaldehyde oxime (Compound 3z)
(61) ##STR00168##
(62) To a degassed solution of oxime 2 (96 mg, 0.439 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (69 mg, 0.060 mmol, 0.15 equiv) and CuI (23 mg, 0.12 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1z (100 mg, 0.399 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to MeOH/EtOAc 5:95) to afford the desired coupled fluoro oxime 3z as a yellowish solid (135 mg, 87%). R.sub.f (20% MeOH+EA) 0.35; IR (neat) v.sub.max 3063, 2925, 2854, 2237, 1640, 1581, 1456, 1245, 1178, 982, 831, 757, 695, 668, 635, 539 cm.sup.−1; **.sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.36 (s, 1H, oxime), 8.66-7.92 (m, 2H, Ar), 7.51 (m, Ar), 7.40-7.26 (m, 2H, Ar), 7.20 (dd, J=3.8, 8.6 Hz, 1H, Ar), 4.55 (br s, 1H, —NH), 3.72 (t, J=6.1 Hz, 2H, H.sub.10), 3.05 (t, J=6.1 Hz, 2H, tacrine), 2.76 (t, J=6.1 Hz, 2H, H.sub.9), 2.67 (t, J=6.3 Hz, 2H, tacrine), 1.85-1.76 (m, 4H, H.sub.10, tacrine); **.sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 158.18, 158.02, 155.52, 150.72, 144.71, 144.67, 140.59, 140.48, 139.06, 139.01, 132.13, 132.03, 131.92, 128.83, 128.65, 128.55, 128.42, 128.02, 127.98, 127.69, 124.49, 124.29, 124.22, 122.66, 120.17, 117.10 (Ar), 87.41 (C8), 81.42 (C7), 47.08 (C10), 21.93 (C9), 33.02, 24.82, 22.80, 22.39 (tacrine) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom and ** cis and trans mixture); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −125.02; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.22F.sub.1N.sub.4O.sub.1.sup.+ 389.1755 found 389.1772.
B) With 6-bromo-3-fluoropicolinaldehyde oxime (Labelled) (Compound 4)
(63) ##STR00169##
(64) A solution of picolinaldehyde (204 mg, 1 mmol, 1 equiv), .sup.15N labelled hydroxylamine hydrochloride (106 mg, 1.5 mmol, 1.5 equiv), and CH.sub.3CO.sub.2Na (246 mg, 3 mmol, 3 equiv) in dry ethanol (10 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the oxime 4 as a white solid (230 mg, quant. yield). R.sub.f (20% EA+PE) 0.50; IR (neat) v.sub.max 3257, 2859, 1722, 1442, 1187, 1107, 968, 825, 727, 668, 619, 518 cm.sup.−1; H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.18 (d, J=2.5 Hz, 1H, H.sub.7), 7.61-7.55 (m, 2H, H.sub.4, H.sub.5); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) 127.91, 127.93.
3-fluoro-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime (compound 5)
(65) ##STR00170##
(66) To a degassed solution of oxime 4 (78 mg, 0.364 mmol, 1.05 equiv) in THF/Et.sub.3N (1 mL/3 mL), Pd[PPh.sub.3].sub.4 (60 mg, 0.052 mmol, 0.15 equiv) and CuI (20 mg, 0.104 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 50 mg, 0.347 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 5 as a white solid (70 mg, 72%). R.sub.f (20% EA+PE) 0.40; IR (neat) v.sub.max 3177, 2933, 2876, 2226, 1568, 1445, 1159, 985, 807, 734, 703, 657, 638, 557, 490 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.49-8.90 (br s, 1H, OH), 8.26 (s, 1H, H.sub.18), 7.39-7.08 (m, 7H, Ar), 2.71 (t, J=7.5 Hz, 2H, H.sub.11), 2.37 (t, J=7.1 Hz, 2H, H.sub.9), 1.88 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158. 07, *155.42 (C3), 145.90, *145.86 (C18), 141.28 (C12), 140.09, *140.04 (C2), 139.54, *139.45 (C6), 128.50, 128.37, (C5, C13, C14, C16, C17), 125.95 (C15), 124.60, *124.40 (C4), 91.06 (C7), 79.44 (C8), 34.86 (C11), 29.72 (C10), 18.71 (C9); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −122.425, −122.453 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) 122.415; ESI MS.sup.+ m/z for C.sub.17H.sub.17F.sub.1N.sub.2O.sub.1.sup.+ 284.1275.
6-bromo-3-fluoro-N′-hydroxypicolinimidamide (Compound 7)
(67) ##STR00171##
(68) A solution of picolinonitrile 6 (compound purchased from Aldrich, see structure below) (100 mg, 0.498 mmol, 1 equiv), hydroxylamine hydrochloride (52 mg, 0.746 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (79 g, 0.746 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc—MeOH/EtOAc 5:95) to afford the amidoxime 7 as a white solid (110 mg, 95%). R.sub.f (30% EA+PE) 0.35; IR (neat) v.sub.max 3473, 3369, 3057, 2923, 1665, 1563, 1450, 1239, 1112, 952, 835, 768, 756, 657, 551 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.27 (s, 1H, —OH), 7.82-7.70 (m, 2H, H.sub.4, H.sub.5), 5.80 (s, 2H, —NH.sub.2); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.98, *155.36 (C3), 147.29, *147.20 (C7), 139.41, *139.26 (C2), 133.67, *133.65 (C6), 129.63, *129.57 (C5), 128.93, *128.71 (C4) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −199.96; HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.6Br.sub.1F.sub.1N.sub.3O.sub.1.sup.+ 233.9660 found 233.9673.
(69) Picolinonitrile 6 is as follows:
(70) ##STR00172##
(E)-6-bromo-3-fluoro-N′-hydroxypicolinimidamide (Labelled) (Compound 8)
(71) ##STR00173##
(72) A solution of picolinonitrile 6 (purchased from Aldrich) (100 mg, 0.498 mmol, 1 equiv), .sup.15N labelled hydroxylamine hydrochloride (52 mg, 0.746 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (79 g, 0.746 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc—MeOH/EtOAc 5:95) to afford the amidoxime 8 as a light yellowish solid (115 mg, quant. yield). R.sub.f (30% EA+PE) 0.35; IR (neat) v.sub.max 3473, 3369, 3059, 2925, 1651, 1561, 1450, 1238, 1110, 935, 833, 764, 753, 656, 621, 552 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.26 (s, 1H, —OH), 7.82-7.68 (m, 2H, H.sub.4, H.sub.5), 5.80 (s, 2H, —NH.sub.2); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.99, *155.36 (C3), 147.27, *147.18 (C7), 139.46, *139.35 (C2), 133.68, *133.65 (C6), 129.63, *129.58 (C5), 128.93, *128.71 (C4) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −199.98; ESI.sup.+ m/z for C.sub.6H.sub.6Br.sub.1F.sub.1N.sub.3O.sub.1 is 233.9660.
3-fluoro-6-(5-phenylpent-1-yn-1-yl)picolinonitrile 9
(73) ##STR00174##
(74) To a degassed solution of picolinonitrile 6 (153 mg, 0.763 mmol, 1.1 equiv) in THF/Et.sub.3N (8 mL/3 mL), Pd[PPh.sub.3].sub.4 (120 mg, 0.104 mmol, 0.15 equiv) and CuI (40 mg, 0.208 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (100 mg, 0.693 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 95:5) to afford the desired coupled picolinonitrile 9 as a yellowish liquid (170 mg, 93%). R.sub.f (10% EtOAc+PE) 0.40; IR (neat) v.sub.max 2934, 2232, 1571, 1461, 1257, 1107, 841, 745, 699, 656, 606, 534, 487 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 7.58 (dd, J=4.2, 8.9 Hz, 1H), 7.51 (dd, J=7.7, 8.9 Hz, 1H), 7.33-7.12 (m, 5H), 2.76 (t, J=7.5 Hz, 2H), 2.44 (t, J=7.1 Hz, 2H), 1.95 (quintet, J=7.1, 7.5 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 161.27, *158.57, 141.53, *141.48, 141.01, 131.97, *131.92, 128.44, 128.39, 126.02, 125.05, *124.89, 122.66, *122.45, 112.36, *112.31, 93.19, 78.45, 34.80 29.51, 18.62 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −116.14; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.13F.sub.1N.sub.2Na.sub.1.sup.+ 287.0949 found 287.0955.
3-fluoro-N′-hydroxy-6-(5-phenylpent-1-yn-1-yl)picolinimidamide (Compound 10)
(75) ##STR00175##
(76) To a degassed solution of amidoxime 7 (36 mg, 0.15 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (24 mg, 0.021 mmol, 0.15 equiv) and CuI (8 mg, 0.042 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 20 mg, 0.14 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 7:3—pure EtOAc) to afford the desired coupled fluoro amidoxime 10 as a light yellowish solid (32 mg, 78%). R.sub.f (50% EA+PE) 0.65; IR (neat) v.sub.max 3490, 3381, 3144, 2926, 2235, 1667, 1561, 1470, 1240, 938, 963, 838, 745, 699, 683, 646, 599, 493 cm.sup.−1; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 9.51 (br s, 1H, OH), 7.63 (dd, J=8.5, 10.5 Hz, 1H, H.sub.4), 7.53 (dd, J=3.5, 8.5 Hz, 1H, H.sub.5), 7.35-7.15 (m, 5H, Ar), 5.72 (s, 2H, —NH.sub.2), 2.80 (t, J=7.5 Hz, 2H, H.sub.11), 2.47 (t, J=7.1 Hz, 2H, H.sub.9), 1.94 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.77, *155.09 (C3), 148.56, *148.46 (C18), 141.53 (C12), 138.43, *138.36 (C2), 138.29, *138.19 (C6), 128.48, 128.35 (C5, C13, C14, C16, C17), 125.90 (C15), 125.51, *125.30 (C4), 89.96 (C7), 79.79 (C8), 34.55 (C11), 30.03 (C10), 18.10 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −116.95; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16F.sub.1N.sub.3O.sub.1Na.sub.1.sup.+ 320.1160 found 320.1170.
C) With hydroxamic acid 11 (Compound 11)
(77) Hydroxamic acid (compound 11) was purchased from Aldrich:
(78) ##STR00176##
3-fluoro-N-hydroxy-6-(5-phenylpent-1-yn-1-yl)picolinamide (Compound 12)
(79) ##STR00177##
(80) To a degassed solution of hydroxamic acid 11 (108 mg, 0.458 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (72 mg, 0.062 mmol, 0.15 equiv) and CuI (24 mg, 0.125 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 60 mg, 0.416 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:1) to afford the desired coupled fluoro amidoxime 12 as a yellowish solid (32 mg, 25%). R.sub.f (50% EA+PE) 0.65; IR (neat) v.sub.max 3264, 2923, 2856, 2231, 1689, 1651, 1455, 1247, 1027, 837, 745, 698, 651, 541 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)) 7.50-7.41 (m, 2H, Ar), 7.31-7.26 (m, 2H, Ar), 7.22-7.16 (m, 3H, Ar), 2.76 (t, J=7.5 Hz, 2H, H.sub.11), 2.43 (t, J=7.1 Hz, 2H, H.sub.9), 1.94 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 159.70 (C18), 158.67, *156.49 (C3), 141.11 (C15), 138.75, *135.74 (C6), 132.13, *132.06 (C2), 131.96, *131.61 (C5), 128.49 (C14, C16), 128.44 (C13, C17), 126.67, *126.53 (C4), 126.07 (C12), 91.82 (C7), 79.03 (C8), 34.87 (C11), 29.67 (C10), 18.65 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −116.62; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16F.sub.1N.sub.2O.sub.2.sup.+ 299.1177 found 299.1190.
III—Experimental Procedures for Hydrogenations
3-fluoro-6-(5-phenylpentyl)picolinaldehyde oxime (Compound 13)
(81) ##STR00178##
(82) To a degassed solution of fluorooxime 3a (50 mg, 0.177 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (4.7 mg, 0.0178 mmol, 0.25 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 90 min. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford oxime 13 as a white solid (50 mg, 99%); R.sub.f (20% EA+PE) 0.50; IR (neat) v.sub.max 3281, 3026, 2929, 2856, 1603, 1468, 1454, 1247, 1112, 980, 834, 745, 698, 642, 543, 499 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.94 (br s, 1H, OH), 8.30 (s, 1H), 7.31-6.98 (m, 7H), 2.72 (t, J=7.7 Hz, 2H), 2.52 (t, J=7.7 Hz, 2H), 1.67 (quintet, J=7.7 Hz, 2H), 1.58 (quintet, J=7.7 Hz, 2H); 1.31 (quintet, J=7.3, 7.9 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158. 80, *158.67, 157.70, *155.10, 144.98, *144.94, 142.58, 138.26, *138.16, 128.34, 128.23, 128.16, 125.55, 124.36, 124.33, *124.16, 37.37, 35.72, 31.16, 29.64, 28.77 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −128.97; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.20F.sub.1N.sub.2O.sub.1.sup.+ 287.1542 found 287.1554.
6-(3-cyclohexylpropyl)-3-fluoropicolinaldehyde oxime (Compound 14)
(83) ##STR00179##
(84) To a degassed solution of fluorooxime 3c (30 mg, 0.115 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (6 mg, 0.058 mmol, 0.5 equiv) was added in two portions. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 90 min. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (EtOAc/PE 1:4) to afford oxime 14 as a light yellowish solid (29 mg, 95%); R.sub.f (20% EA+PE) 0.60; IR (neat) v.sub.max 3277, 2923, 2849, 1588, 1472, 1441, 1244, 1124, 987, 947, 841, 805, 754, 736, 719, 666, 585 cm.sup.−1; **.sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.69 (br s, 1H, OH), 8.36 (s, 1H), 7.33 (dd, J=8.6, 10.0 Hz, 1H), 7.12 (dd, J=3.8, 8.6 Hz, 1H), 2.75 (t, J=7.8 Hz, 2H), 1.73-1.57 (m, 7H), 1.25-1.12 (m, 6H), 0.88-0.78 (m, 2H); **.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.99, *158.94, 157.74, *155.14, 145.17, *145.14, 138.23, *138.13, 124.34, 124.14, 37.84, 37.50, 37.06, 33.31, 27.25, 26.66, 26.36 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); **.sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −128.32, −129.07 {** 1:15 ratio of cis-trans isomers observed (italic)}; HRMS (ESI.sup.+) m/z calcd for C.sub.15H.sub.22F.sub.1N.sub.2O.sub.1.sup.+ 265.1703 found 265.1711.
6-(4-ethylphenethyl)-3-fluoropicolinaldehyde oxime (Compound 15)
(85) ##STR00180##
(86) To a degassed solution of fluorooxime 3h (35 mg, 0.130 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (7 mg, 0.065 mmol, 0.5 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 2 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (EtOAc/PE 1:4) to afford oxime 15 as a light yellowish solid (35 mg, quant. yield); R.sub.f (20% EA+PE) 0.45; IR (neat) v.sub.max 3273, 2961, 2926, 2864, 1512, 1472, 1455, 1241, 1180, 984, 836, 724, 657, 577, 512, 467 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.41 (s, 1H), 7.31 (dd, J=8.6, 9.8 Hz, 1H), 7.15-6.99 (m, 6H), 3.10 (m, 2H), 3.01 (m, 2H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.82, *155.22, 157.72, *157.68, 145.01, *144.98, 141.85, 138.47, *138.37, 138.31, 128.39, 127.81, 124.70, *124.66, 124.30, *124.11, 39.27, 35.39, 28.39, 15.58 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −128.62; HRMS (ESI.sup.+) m/z calcd for C.sub.16H.sub.18F.sub.1N.sub.2O.sub.1.sup.+ 273.1388 found 273.1398.
3-fluoro-6-(2-(pyridin-3-yl)ethyl)picolinaldehyde oxime (Compound 16)
(87) ##STR00181##
(88) To a degassed solution of fluorooxime 3r (30 mg, 0.124 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (10 mg, 0.093 mmol, 0.75 equiv) was added in three portions. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 30 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (EtOAc/PE 4:1) to afford oxime 16 as a white solid (25 mg, 82%); R.sub.f (80% EA+PE) 0.20; IR (neat) v.sub.max 2925, 2853, 2713, 1738, 1579, 1469, 1244, 1176, 1119, 979, 823, 809, 709, 669, 642, 506 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 11.04 (br s, 1H, OH), 8.45 (br d, J=1.8 Hz, 1H), 8.30 (dd, J=1.5, 4.5 Hz, 1H), 8.22 (s, 1H), 7.62 (dt, J=1.8, 7.8 Hz, 1H), 7.53 (dd, J=8.5, 10.4 Hz, 1H), 7.31-7.20 (m, 2H), 3.16-3.07 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.61, *156.0, 157.54, *157.49, 150.97, 148.32, 147.22, *147.16, 137.76, 136.70, 125.42, *125.33, 125.29, 125.*23, 124.14, 39.08, 33.03 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −127.24; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.13F.sub.1N.sub.3O.sub.1.sup.+ 246.1032 found 246.1037.
3-fluoro-6-(2-(3-hydroxyoxetan-3-yl)ethyl)picolinaldehyde oxime (Compound 17)
(89) ##STR00182##
(90) To a degassed solution of fluorooxime 3p (45 mg, 0.191 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (20 mg, 0.076 mmol, 1 equiv) was added in two portions. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 42 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (pure EtOAc) to afford oxime 17 as a light yellowish solid (40 mg, 85%); R.sub.f (pure EA) 0.35; IR (neat) v.sub.max 3352, 2948, 2876, 1592, 1472, 1450, 1311, 1260, 1223, 1110, 948, 964, 833, 643, 542, 526, 469 cm.sup.−1; **.sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 11.38 (br s, 1H, OH), 8.39 (s, 1H), 7.39 (dd, J=8.6, 9.4 Hz, 1H), 7.21 (dd, J=3.8, 8.6 Hz, 1H), 7.06 (br s, 1H, OH), 4.69 (d, J=6.7 Hz, 2H), 4.40 (d, J=6.8 Hz, 2H), 3.0 (t, J=6.2 Hz, 2H), 2.36 (t, J=6.2 Hz, 2H); **.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.55, *154.96, 157.12, *157.08, 141.61, 138.22, *138.11, 125.26, *125.13, 125.08, 83.88, 73.82, 36.23, 31.50 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); **.sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −127.36, −131.22 {** 1:10 ratio of cis-trans isomers observed (italic)}; HRMS (ESI.sup.+) m/z calcd for C.sub.11H.sub.14F.sub.1N.sub.2O.sub.3.sup.+ 241.0971 found 241.0983.
3-fluoro-6-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl)picolinaldehyde oxime (Compound 18)
(91) ##STR00183##
(92) To a degassed solution of fluorooxime 30 (40 mg, 0.151 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (8 mg, 0.076 mmol, 0.5 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 74 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (MeOH/EtOAc 5:95) to afford oxime 18 as a light yellowish liquid (32 mg, 79%); R.sub.f (5% MeOH+EA) 0.40; IR (neat) v.sub.max 3271, 2948, 2866, 1591, 1469, 1239, 1180, 1095, 982, 840, 730, 645, 543, 493 cm.sup.−1; **.sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 11.41 (br s, 1H, OH), 8.39 (s, 1H), 7.35 (dd, J=8.6, 9.5 Hz, 1H), 7.17 (dd, J=3.8, 8.6 Hz, 1H), 5.34 (br s, 1H, OH), 3.85 (td, J=3.4, 10.2 Hz, 2H), 3.74 (m, 2H), 3.0 (t, J=6.9 Hz, 2H), 1.98 (t, J=6.9 Hz, 2H), 1.69-1.61 (m, 4H); **.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.96, *157.92, 157.50, *154.92, 155.97, *155.92, 155.26, *152.65, 141.93, 139.04, *138.93, 138.22, *138.11, 135.39, *135.37, 126.05, *126.00, 125.57, *125.39, 125.01, *124.98, 124.86, *124.67, 68.62, 68.19, 63.96, 63.70, 42.31, 41.01, 38.17, 37.57, 30.56, 30.07 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); **.sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −127.74, −131.68 {** 1:5 ratio of cis-trans isomers observed (italic)}; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.18F.sub.1N.sub.2O.sub.3.sup.+ 269.1285 found 269.1296.
3-fluoro-6-(10-(5-fluoro-6-((E)-(hydroxyimino)methyl)pyridin-2-yl)decyl)picolinaldehyde oxime (Compound 19)
(93) ##STR00184##
(94) To a degassed solution of fluorooxime 3w (40 mg, 0.098 mmol, 1 equiv) in dry EtOAc/MeOH (2/1 mL), 10% Pd/C (10.4 mg, 0.098 mmol, 0.25 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 20 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preperative TLC (EtOAc/PE 4:1) to afford oxime 19 as a white solid (35 mg, 86%); R.sub.f (40% EA+PE) 0.55; IR (neat) v.sub.max 3072, 2927, 2851, 1583, 1253, 1119, 994, 844, 830, 725, 669, 648, 544 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.26 (s, 1H), 7.53 (dd, J=8.6, 10.2 Hz, 1H), 7.28 (dd, J=3.8, 8.6 Hz, 1H), 2.27 (t, J=7.5 Hz, 2H), 1.69 (p, J=7.5 Hz, 2H), 1.5-1.27 (m, 6H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 160.31, *160.26, 159.19, *156.61, 145.44, *145.40, 140.15, *140.04, 126.15, *126.00, 125.96, 38.23, 31.31, 30.69, 30.60, 30.45 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −130.58; HRMS (ESI.sup.+) m/z calcd for C.sub.22H.sub.29F.sub.2N.sub.4O.sub.2.sup.+ 419.2241 found 419.2253.
N-(9-((3aR,4R,6R,6aR)-6-((3-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)propoxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide (Compound 20)
(95) ##STR00185##
(96) To a degassed solution of fluorooxime 3u (40 mg, 0.068 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (7.2 mg, 0.068 mmol, 1 equiv) was added in two portions. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 42 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preparative TLC (pure EtOAc) to afford oxime 20 as a light yellowish thick syrup (30 mg, 75%); R.sub.f (pure EA) 0.55; IR (neat) v.sub.max 3260, 2925, 2857, 1698, 1612, 1582, 1456, 1248, 1211, 1073, 849, 709, 643, 623, 511 cm.sup.−1; **.sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 8.71 (s, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.11 (br d, J=7.6 Hz, 2H), 7.63 (m, 1H), 7.56-7.44 (m, 3H), 7.25 (dd, J=3.7, 8.5 Hz, 1H), 6.33 (br d, J=2.2 Hz, 1H), 5.47 (dd, J=2.2, 6.1 Hz, 1H), 5.09 (dd, J=2.5, 6.1 Hz, 1H), 4.48 (m, 1H), 3.70 (dd, J=4, 10.6 Hz, 1H), 3.61 (dd, J=4.4, 10.6 Hz, 1H), 3.52-3.43 (m, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.89 (p, J=7.5 Hz, 2H), 1.59 (s, 3H), 1.38 (s, 3H); **.sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 166.57, 166.53, 158.57, *158.53, 158.48, *155.88, 152.85, 151.06, 146.61, *146.55, 143.64, 143.59, 139.87, *139.77, 136.51, 136.50, 134.93, 133.41, 130.53, 129.76, 129.46, 129.27, 127.49, 126.67, 126.48, 125.45, *125.41, 125.22, *125.19, 114.34, 92.14, 92.08, 87.19, 85.71, 82.93, 82.88, 71.75, 71.62, 71.31, 71.06, 34.40, 33.94, 32.06, 30.67, 27.57, 25.62 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); **.sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −128.36, −129.16 {** 1:3 ratio of cis-trans isomers observed (italic)}; HRMS (ESI.sup.+) m/z calcd for C.sub.29H.sub.31F.sub.1N.sub.7O.sub.6.sup.+ 592.2281 found 592.2314.
3-fluoro-6-((E)-6-hydroxyhex-1-en-1-yl)picolinaldehyde oxime (Compound 21)
(97) ##STR00186##
(98) To a degassed solution of fluorooxime 3d (45 mg, 0.190 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (5 mg, 0.048 mmol, 0.25 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 4 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 4:6) to afford oxime 21 as a white solid (40 mg, 88%); R.sub.f (pure EA) 0.75; IR (neat) v.sub.max 3275, 2929, 2857, 1644, 1587, 1468, 1252, 1210, 1056, 976, 845, 726, 639, 534 cm.sup.−1; **.sub.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.61 (br s, 1H, OH), 8.37 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.16 (dd, J=3.8, 8.8 Hz, 1H), 6.38 (br d, J=11.8 Hz, 1H), 5.87 (dt, J=7.6, 11.8 Hz, 1H), 3.66 (t, J=6.0 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.64-1.49 (m, 4H); **13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.40, *154.77, 153.21, 153.16, 144.74, 138.35, *138.26, 138.02, 126.66, 125.74, 125.70, 124.06, *123.87, 67.91, 31.76, 28.00, 25.14 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −127.77; [** There is some impurity observed in the NMR spectra along with compound, which is unable to separate.]; HRMS (ESI.sup.+) m/z calcd for C.sub.12H.sub.16F.sub.1N.sub.2O.sub.2.sup.+ 239.1199 found 239.1190.
Methyl (E)-6-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)hex-5-enoate (Compound 22)
(99) ##STR00187##
(100) To a degassed solution of fluorooxime 3e (34 mg, 0.128 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (3.4 mg, 0.032 mmol, 0.25 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 4 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford oxime 22 as a white solid (30 mg, 87%); R.sub.f (20% EA+PE) 0.65; IR (neat) v.sub.max 3256, 2937, 1727, 1582, 1466, 1249, 1189, 1169, 1005, 973, 865, 844, 733, 710, 629, 611, 520 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.62 (br s, 1H, OH), 8.33 (s, 1H), 7.34 (dd, J=8.6, 10.0 Hz, 1H), 7.19 (dd, J=3.8, 8.6 Hz, 1H), 6.43 (dt, J=1.6, 11.7 Hz, 1H), 5.86 (dt, J=7.5, 11.7 Hz, 1H), 3.60 (s, 3H), 2.62 (qd, J=1.6, 7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.82 (p, J=7.6 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 174.18, 157.45, *154.81, 152.92, 152.88, 146.09, *146.04, 138.39, *138.29, 136.79, 127.42, 125.56, 125.51, 124.23, *124.04, 51.52, 33.62, 28.10, 24.72 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −126.11; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.16F.sub.1N.sub.2O.sub.3.sup.+ 267.1114 found 267.1139.
3-fluoro-6-((E)-2-(pyren-4-yl)vinyl)picolinaldehyde oxime (Compound 23)
(101) ##STR00188##
(102) To a degassed solution of fluorooxime 3j (45 mg, 0.123 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (6.5 mg, 0.061 mmol, 0.5 equiv) was added in two portions. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 12 min. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by washings with DCM and EtoAc to afford oxime 23 as a yellowish solid (30 mg, 66%); R.sub.f (30% EA+PE) 0.50; IR (neat) v.sub.max 2958, 2926, 2856, 1721, 1585, 1461, 1266, 1248, 1117, 1102, 974, 955, 839, 729, 694, 540 cm.sup.−1; .sup.1H NMR (500 MHz, DMSO) δ (ppm) 12.00 (s, 1H), 8.73 (d, J=16 Hz, 1H), 8.67 (d, J=9.4 Hz, 1H), 8.56 (d, J=8.2 Hz, 1H), 8.36-8.29 (m, 5H), 8.21 (s, 2H), 8.10 (t, J=7.7 Hz, 1H), 7.95 (dd, J=3.8, 8.6 Hz, 1H), 7.87 (dd, J=8.6, 10.3 Hz, 1H), 7.63 (d, J=16 Hz, 1H); .sup.13C NMR (125 MHz, DMSO) δ (ppm) 157.30, *155.20, 151.66, *151.64, 145.65, *145.60, 139.32, *139.24, 130.99, 130.90, 130.38, 130.34, 129.57, 128.84, 128.24, 127.99, 127.65, 127.41, 126.47, 125.66, 125.38, 125.30, *125.14, 124.25, *124.00, 123.90, 123.87, 123.74, 122.87 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO) δ (ppm) −123.84; HRMS (ESI.sup.+) m/z calcd for C.sub.24H.sub.16F.sub.1N.sub.2O.sub.1.sup.+ 367.1229 found 367.1241.
3-fluoro-6-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butyl)picolinaldehyde oxime (Compound 24)
(103) ##STR00189##
(104) To a degassed solution of fluorooxime 3z (20 mg, 0.052 mmol, 1 equiv) in dry EtOAc/MeOH (2/1 mL), 10% Pd/C (5.5 mg, 0.052 mmol, 1 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 20 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preparative TLC (EtOAc/PE 4:1) to afford oxime 24 as a white solid (20 mg, quant. yield); R.sub.f (20% MeOH+EA) 0.20; IR (neat) v.sub.max 2923, 2857, 1562, 1503, 1467, 1434, 1299, 1244, 1166, 1114, 986, 832, 749, 678, 621, 543 cm.sup.−1; *.sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.19 (s, 1H, oxime), 8.09 (brd, J=8.6 Hz, 1H, Ar), 7.73 (brd, J=8.6 Hz, 1H, Ar), 7.62-7.57 (m, 1H, Ar), 7.44-7.34 (m, 2H, Ar), 7.14 (dd, J=3.8, 8.6 Hz, 1H, Ar), 3.62 (t, J=6.9 Hz, 2H), 2.95 (br t, J=5.9 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.67 (t, J=5.9 Hz, 2H), 1.92-1.85 (m, 4H) 1.77-1.65 (m, 4H); *.sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 159.62, 159.57, 159.11, 157.80, 157.75, 157.44, 156.52, 154.27, 154.06, 146.04, 145.32, 145.29, 140.11, 140.01, 130.85, 126.60, 126.53, 126.41, 126.23, 126.16, 126.05, 126.02, 125.97, 125.86, 125.22, 124.95, 124.88, 120.54, 120.40, 116.22, 116.03 (Ar), 148.94, 37.48, 37.20, 33.27, 33.21, 31.38, 31.24, 28.12, 27.52, 26.09, 26.02, 23.99, 23.93, 23.46, 23.37 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); *.sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −123.32, −130.21 (*cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.26F.sub.1N.sub.4O.sup.+ 393.2085 found 393.2118.
9-((4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)butyl)amino)-1,2,3,4-tetrahydroacridin-10-ium chloride (Compound 25)
(105) ##STR00190##
(106) To a compound 24 (1 equiv) in methanol (0.5 mL), was added 1.2 N HCl (0.5 mL) and agitated for 2 min and kept it for 10 min at rt. The reaction mixture was concentrated under reduced pressure to get the HCl salt 25 as a white solid in quantitative yield. IR (neat) v.sub.max 2937, 2866, 1633, 1571, 1523, 1439, 1359, 1295, 1176, 990, 757, 678, 534 cm.sup.−1; .sup.1H NMR (400 MHz, D.sub.2O) δ (ppm) 8.02 (s, 1H, oxime), 7.88, 7.83 (2d, J=8.8 Hz, 1H, Ar), 7.72 (m, 1.3H, Ar), 7.57 (t, J=9.0 Hz, 1.3H, Ar), 7.47 (m, 1.3H, Ar), 7.42-7.33 (m, 2.6H, Ar), 3.72, 3.67 (2t, J=5.9 Hz, 2.6H), 2.88-2.65 (m, 5.2H), 2.36 (m, 2.6H), 1.92-1.63 (m, 11H); .sup.19F NMR (400 MHz, D.sub.2O) δ (ppm) −119.94, −125.06 (1:2 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.26F.sub.1N.sub.4O.sub.1.sup.+ 393.2085 found 393.2090.
3-fluoro-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime (Compound 26)
(107) ##STR00191##
(108) To a compound 3y (10 mg) in methanol/water (0.5 mL/0.5 mL), 1.2 N HCl (0.5 mL) and agitated for 2 min and kept it for 10 min at rt. The reaction mixture was concentrated under reduced pressure to get the HCl salt 26 as a white solid in quantitative yield. IR (neat) v.sub.max 226, 3089, 2913, 2239, 1605, 1590, 1565, 1466, 1436, 1230, 970, 961, 834, 799, 755, 681, 636, 493 cm.sup.−1; **.sup.1H NMR (500 MHz, CD.sub.3OD) δ (ppm) 8.48-8.36 (m, 2.7H), 8.23, 8.18 (2s, 1.2H), 7.95 (m, 1.4H), 7.87 (m, 1.4H), 7.84-7.62 (m, 2.7H), 7.58-7.47 (m, 1.3H), 7.06, 6.94 (2d, J=7.2 Hz, 1.3H), 3.95, 3.78 (2t, J=7.7 Hz, 2.7H), 2.99, 2.80 (2t, J=7.7 Hz, 2H); **.sup.13C NMR (120 MHz, CD.sub.3OD) δ (ppm) 159.50, 158.10, 157.38, 144.55, 144.52, 143.83, 143.81, 143.39, 139.88, 139.84, 139.47, 135.16, 133.93, 131.07, 131.03, 130.36, 130.32, 128.96, 128.79, 128.49, 127.49, 127.33, 124.03, 123.92, 121.27, 118.56, 118.47, 99.76, 99.60, 90.29, 80.93, 75.48, 67.91, 43.15, 43.08, 20.18, 19.83 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); **.sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −124.00, −127.87 **(1:3 ratio cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.19H.sub.16F.sub.1N.sub.4O.sub.1.sup.+ 335.1303 found 335.1311.
3-fluoro-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime (Compound 27)
(109) ##STR00192##
(110) To a degassed solution of fluorooxime 3y (40 mg, 0.120 mmol, 1 equiv) in dry EtOAc/MeOH (2/1 mL), 10% Pd/C (6.4 mg, 0.060 mmol, 0.5 equiv) was added as thrice as portions for every 24 hours. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 64 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by preparative TLC (EtOAc/PE 4:1) to afford oxime 27 as a white solid (36 mg, 89%). R.sub.f (30% MeOH+EA) 0.20; IR (neat) v.sub.max 3326, 2918, 2851, 1581, 1456, 1442, 1351, 996, 803, 775, 704, 614, 545, 473 cm.sup.−1; .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm) 11.85 (s, 1H, OH), 8.36 (d, J=5.3 Hz, 1H, Ar), 8.20 (dd, J=1.2, 8.4 Hz, 1H, Ar), 8.14 (s, 1H, Oxime), 7.76 (dd, J=1.0, 8.4 Hz, 1H, Ar), 7.68 (dd, J=8.5, 10.7 Hz, 1H, Ar), 7.59 (m, 1H, Ar), 7.39 (m, 1H, Ar), 7.35 (dd, J=3.8, 8.6 Hz, 1H, Ar), 7.17 (t, J=5.1 Hz, 1H), 6.53 (d, J=5.5 Hz, 1H), 3.30 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 1.79 (m, 2H) 1.69 (m, 2H); *.sup.13C NMR (125 MHz, DMSO-d6) δ (ppm) 158.19, *158.16, 157.24, *155.17, 150.99, 150.44, 148.60, 145.98, *145.93, 138.98, *138.91, 129.31, 129.21, 125.35, 125.20, 124.75, *124.72, 124.22, 124.18, 119.27, 98.60, 42.66, 36.69, 27.81, 27.27 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −126.78.
4-((4-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)butyl)ammonio)quinolin-1-ium chloride (Compound 28)
(111) ##STR00193##
(112) To a compound 27 (6 mg) in methanol/water (0.5 mL/0.5 mL), was added 1.2 N HCl (25 μL) and agitated for 2 min and kept it for 10 min at rt. The reaction mixture was concentrated under reduced pressure to get the HCl salt 28 as a white solid in quantitative yield. **.sup.1H NMR (500 MHz, CD.sub.3OD) δ (ppm) 8.19-8.11 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.89-7.81 (m, 2H), 7.71 (d, J=8.6 Hz, 1H), 7.64-7.57 (m, 2H), 6.59 (d, J=7.2 Hz, 1.3H), 3.51 (t, J=6.8 Hz, 2.7H), 2.96 (2t, J=7.7 Hz, 2H), 1.92-1.75 (m, 4H); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −125.24; HRMS (ESI) m/z calcd for C.sub.19H.sub.20F.sub.1N.sub.4O.sub.1.sup.+ 339.1616 found 339.1604.
3-((5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethynyl)pyridin-1-ium chloride (Compound 29)
(113) ##STR00194##
(114) To a compound 3r (8 mg) in water (0.5 mL), was added 1.2 N HCl (0.5 mL) and agitated for 2 min and kept it for 10 min at rt. The reaction mixture was concentrated under reduced pressure to get the HCl salt 29 as a white solid in quantitative yield. IR (neat) v.sub.max 3453, 3376, 3008, 2911, 1634, 1532, 1458, 1248, 1205, 1109, 996, 934, 844, 800, 764, 671, 628, 525 cm.sup.−1; H NMR (400 MHz, D.sub.2O) δ (ppm) 9.03 (br s, 1H), 8.81 (dt, J=1.1, 5.8 Hz, 1H), 8.74 (dt, J=1.6, 8.3 Hz, 1H), 8.35 (s, 1H), 8.12 (m, 1H), 7.79-7.71 (m, 2H); .sup.13C NMR (100 MHz, D.sub.2O) δ (ppm) 159.61, *156.96, 149.54, 144.95, 144.32, 141.42, 140.16, *140.30, 137.35, *137.30, 131.29, *131.23, 127.90, 126.71, *126.51, 123.08, 93.23, 82.28 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, D.sub.2O) δ (ppm) −120.57; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.9F.sub.1N.sub.3O.sub.1.sup.+ 242.0724 found 242.0700.
3-(2-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethyl)pyridin-1-ium-chloride (Compound 30)
(115) ##STR00195##
(116) To a compound 16 (10 mg) in methanol (0.5 mL), was added 1.2 N HCl (0.5 mL) and agitated for 2 min and kept it for 10 min at rt. The reaction mixture was concentrated under reduced pressure to get the HCl salt 30 as a white solid in quantitative yield. IR (neat) v.sub.max 2925, 2594, 2399, 1651, 1557, 1471, 1443, 1281, 1193, 1009, 990, 882, 799, 783, 685, 632, 526, 489 cm.sup.−1; .sup.1H NMR (400 MHz, D.sub.2O) δ (ppm) 8.66-8.62 (m, 2H), 8.47-8.39 (m, 2H), 8.01-7.94 (m, 2H), 7.62 (dd, J=4.2, 8.8 Hz, 1H), 3.38-3.30 (m, 4H); .sup.13C NMR (100 MHz, D.sub.2O) δ (ppm) 158.78, *156.20, 155.15, *155.11, 147.89, 142.05, 141.27, 141.10, 139.89, 136.97, *1136.78, 131.08, *130.89, 128.31, *128.25, 127.80, 35.18, 32.17 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, D.sub.2O) δ (ppm) −119.42, −124.91 (cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.13F.sub.1N.sub.3O.sub.1.sup.+ 246.1037 found 246.1019.
5-bromo-3-fluoropicolinaldehyde oxime (Compound 31)
(117) ##STR00196##
(118) A solution of commercially available 5-bromo-3-fluoropicolinaldehyde (85 mg, 0.42 mmol, 1 equiv), hydroxylamine hydrochloride (58 mg, 0.83 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (103 mg, 1.26 mmol, 3 equiv) in dry ethanol (4 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the oxime 31 as a white solid (80 mg, 88%). R.sub.f (20% EA+PE) 0.50; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 11.13 (br s, 1H, OH), 8.58 (br t, J=1.2 Hz, 1H, H.sub.6), 8.21 (s, 1H, H.sub.7), 8.01 (dd, J=1.8, 10.0 Hz, 1H, H.sub.4); *.sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.13, *156.43 (C3), 147.49, *147.45 (C6), 146.49, *146.42 (C7), 141.0, *140.10 (C2), 128.23, *128.02 (C4), 120.46, *120.44 (C5) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −119.20; HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.5Br.sub.1F.sub.1N.sub.2O.sub.1.sup.+ 218.9564 found 218.9558.
3-fluoro-5-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime (Compound 32)
(119) ##STR00197##
(120) To a degassed solution of 5-bromo-3-fluoropicolinaldehyde oxime 31 (61 mg, 028 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (49 mg, 0.042 mmol, 0.15 equiv) and CuI (16 mg, 0.084 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 40 mg, 0.28 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 32 as a white solid (25 mg, 32%). R.sub.f (20% EA+PE) 0.40; IR (neat) 3270, 2922, 2226, 1600, 1401, 1313, 1159, 1079, 983, 872, 696, 621, 578 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.44 (s, H, H.sub.6), 8.35 (s, 1H, H.sub.18), 7.42 (d, J=10.5 Hz, 1H, H.sub.4), 7.32-7.1 (m, 5H, Ar), 2.76 (t, J=7. Hz, 2H, H.sub.11), 2.4 (t, J=7.1 Hz, 2H, H.sub.9), 1.93 (quintet, J=7.1, 7.4 Hz, 2H, H.sub.10); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 158.20, *156.08 (C3), 140.46 (C6), 145.01, *144.97 (C18), 142.32 (C12), 137.62, *137.57 (C2), 128.50 (C14, C16), 128.44, (C13, C17), 126.08 (C15), 124.45 (C4), 123.26 (C5), 96.88 (C8), 69.17 (C7), 34.87 (C11), 29.70 (C10), 18.96 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −124.70; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16F.sub.1N.sub.2O.sub.1.sup.+ 283.1241 found 283.1210.
5-bromo-2-fluoronicotinaldehyde oxime (Compound 33)
(121) ##STR00198##
(122) A solution of commercially available 5-bromo-2-fluoronicotinaldehyde (1 g, 4.902 mmol, 1 equiv), hydroxylamine hydrochloride (681 mg, 9.804 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (1.2 g, 14.706 mmol, 3 equiv) in dry ethanol (40 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the oxime 33 as a white solid (1.05 g, quant. yield). R.sub.f (20% EA+PE) 0.50; IR (neat) 3218, 3004, 2921, 1618, 1559, 1479, 1427, 1312, 1249, 1159, 995, 939, 898, 834, 753, 642, 564, 478 cm.sup.−1; *.sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 11.17 (br s, 1H, OH), 8.37-8.32 (m, 2H, H.sub.4, H.sub.5), 8.17 (s, 1H, H.sub.7); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 160.62, *159.22 (C2), 149.55, *149.40 (C6), 141.22, *141.19 (C7), 139.99, *139.96 (C4), 118.97, *118.68 (C3), 117.5, *117.55 (C5) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −74.02, −77.27 (cis-trans); HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.5Br.sub.1F.sub.1N.sub.2O.sub.1.sup.+ 218.9564 found 218.9551.
2-fluoro-5-(5-phenylpent-1-yn-1-yl)nicotinaldehyde oxime (Compound 34)
(123) ##STR00199##
(124) To a degassed solution of 5-bromo-2-fluoronicotinaldehyde oxime 33 (133 mg, 0.610 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (96 mg, 0.083 mmol, 0.15 equiv) and CuI (32 mg, 0.167 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 80 mg, 0.555 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 34 as a white solid (70 mg, 45%). R.sub.f (20% EA+PE) 0.40; IR (neat) 3210, 3085, 2923, 2855, 2233, 1575, 1448, 1317, 1254, 1143, 980, 911, 830, 748, 702, 646, 582, 485 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.36 (br s, 1H, OH), 8.24-8.21 (m, 2H, H.sub.6,H.sub.18), 8.15 (dd, J=2.3, 8.8 Hz, 1H, H.sub.4), 7.31-7.16 (m, 5H, Ar), 2.76 (t, J=7.4 Hz, 2H, H.sub.11), 2.41 (t, J=7.1 Hz, 2H, H.sub.9), 1.92 (quintet, J=7.1, 7.4 Hz, 2H, H.sub.10); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 160.61, *158.18 (C2), 151.04, *150.89 (C18), 142.42, *142.39 (C6), 141.23 (C12), 139.68, *139.65 (C4), 128.48, 128.41 (C13, C14, C16, C17), 126.02 (C15), *119.64, 119.59 (C5), 114.86, *114.60 (C3), 93.95 (C8), 76.06 (C7), 34.83 (C11), 29.92 (C10), 18.76 (C9) (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −73.52; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16F.sub.1N.sub.2O.sub.1.sup.+ 283.1241 found 283.1242.
3-bromo-6-chloropicolinaldehyde oxime (Compound 35)
(125) ##STR00200##
(126) A solution of commercially available 3-bromo-6-chloropicolinaldehyde (220 mg, 1 mmol, 1 equiv), hydroxylamine hydrochloride (139 mg, 2 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (246 mg, 3 mmol, 3 equiv) in dry ethanol (8 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/Pentane 1:9) to afford the oxime 35 as a white solid (225 mg, 96%). R.sub.f (20% EA+PE) 0.70; IR (neat) 3003, 2325, 2148, 1568, 1442, 1358, 1344, 1257, 1103, 1054, 997, 927, 885, 763, 643, 542, 478 cm.sup.−1; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) 8.39 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H); HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.5Br.sub.1Cl.sub.1N.sub.2O.sub.1.sup.+ 234.9268 found 234.9259.
6-chloro-3-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime (Compound 36)
(127) ##STR00201##
(128) To a degassed solution of oxime 35 (135 mg, 0.572 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (90 mg, 0.078 mmol, 0.15 equiv) and CuI (30 mg, 0.156 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne 75 mg, 0.520 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/Pentane 1:9) to afford the desired coupled fluoro oxime 36 as a white solid (140 mg, 90%). R.sub.f (20% EA+PE) 0.60; IR (neat) 3024, 2921, 2852, 2234, 1582, 1494, 1458, 1377, 1287, 1180, 1077, 996, 922, 746, 696, 660, 579, 479 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.04-9.44 (br s, H, OH), 8.52 (s, 1H), 8.42 (s, 1H), 7.82 (br s, 1H), 7.28-7.14 (m, 5H, Ar), 2.76 (t, J=7.5 Hz, 2H, H.sub.11), 2.42 (t, J=7.0 Hz, 2H, H.sub.9), 1.92 (quintet, J=7.0, 7.5 Hz, 2H, H.sub.10); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 149.97, 144.35, 141.72, 141.23, 138.07, 129.19, 128.48, 128.35, 125.95, 123.39, 92.58, 79.47, 34.77, 29.73, 18.73; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16Cl.sub.1N.sub.2O.sub.1.sup.+ 299.0946 found 299.0945.
6-bromo-4-chloronicotinaldehyde oxime (Compound 37)
(129) ##STR00202##
(130) A solution of commercially available 6-bromo-4-chloronicotinaldehyde (240 mg, 1.089 mmol, 1 equiv), hydroxylamine hydrochloride (151 mg, 2.18 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (268 mg, 3.27 mmol, 3 equiv) in dry ethanol (8 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/Pentane 1:9) to afford the oxime 37 as a white solid (255 mg, quantitative yield). R.sub.f (20% EA+PE) 0.60; IR (neat) 3223, 3089, 2414, 1602, 1563, 1527, 1442, 1323, 1115, 1056, 984, 939, 879, 766, 680, 517, 453 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.71 (s, 1H), 8.33 (s, 1H), 7.77 (s, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 149.06, 145.10, 143.36, 142.85, 129.69, 128.61; HRMS (ESI.sup.+) m/z calcd for C.sub.6H.sub.5Br.sub.1Cl.sub.1N.sub.2O.sub.1.sup.+ 234.9268 found 234.9270.
4-chloro-6-(5-phenylpent-1-yn-1-yl)nicotinaldehyde oxime (Compound 38)
(131) ##STR00203##
(132) To a degassed solution of oxime 37 (72 mg, 0.305 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (48 mg, 0.042 mmol, 0.15 equiv) and CuI (16 mg, 0.083 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1a (5-phenyl-1-pentyne, 40 mg, 0.28 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled fluoro oxime 38 as a white solid (74 mg, 89%). R.sub.f (20% EA+PE) 0.40; IR (neat) 3028, 2924, 2854, 2746, 2227, 1578, 1494, 1456, 1306, 1288, 1068, 992, 874, 781, 745, 696, 581, 475 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.99 (br s, H, OH), 9.07 (br s, 1H), 8.43 (s, 1H), 7.38 (br s, 1H), 7.29-7.12 (m, 5H, Ar), 2.76 (t, J=7.4 Hz, 2H, H.sub.11), 2.44 (t, J=7.1 Hz, 2H, H.sub.9), 1.92 (quintet, J=7.1, 7.4 Hz, 2H, H.sub.10); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 147.99, 143.76, 143.56, 142.77, 141.19, 128.50, 128.35, 127.52, 125.95, 94.44, 79.37, 34.74, 29.65, 18.81; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16Cl.sub.1N.sub.2O.sub.1.sup.+ 299.0946 found 299.0945.
3-fluoro-6-(pentadec-yn-1-yl)picolinonitrile (Compound 39)
(133) ##STR00204##
(134) To a degassed solution of picolinonitrile 6 (43 mg, 0.216 mmol, 1.0 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (37.5 mg, 0.032 mmol, 0.15 equiv) and CuI (12.4 mg, 0.065 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1b (45 mg, 0.216 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled picolinonitrile 39 as a yellowish solid (60 mg, 85%). R.sub.f (20% EtOAc+PE) 0.60; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 7.60-7.47 (m, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.61 (m, 2H) 1.41 (m, 2H), 1.30-1.20 (m, 18H), 0.85 (t, J=6.8 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 161.26, 158.56, 141.72, 141.68, 131.91, 131.86, 125.00, 124.83, 122.71, 122.55, 112.38, 112.33, 93.94, 78.01, 31.91, 29.63, 29.60, 29.46, 29.34, 29.08, 28.96, 28.07, 22.68, 19.28, 14.11; .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −116.14.
6-((4-ethylphenyl)ethynyl)-3-fluoropicolinonitrile (Compound 40)
(135) ##STR00205##
(136) To a degassed solution of picolinonitrile 6 (68 mg, 0.337 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (53 mg, 0.046 mmol, 0.15 equiv) and CuI (18 mg, 0.092 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1h (40 mg, 0.307 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled picolinonitrile 40 as a yellowish solid (71 mg, 92%). R.sub.f (10% EtOAc+PE) 0.50; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 7.71 (m, 1H), 7.57 (dd, J=7.7, 8.9 Hz, 1H), 7.49 (m, 2H), 7.21 (m, 2H), 2.66 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −115.72.
3-fluoro-6-(4-morpholinobut-1-yn-1-yl)picolinonitrile (Compound 42)
(137) ##STR00206##
(138) To a degassed solution of picolinonitrile 6 (75 mg, 0.375 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (65 mg, 0.056 mmol, 0.15 equiv) and CuI (21 mg, 0.113 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 4-(but-3-yn-1-yl)morpholine 41 (commercially available from Enamine LTd) (47 mg, 0.395 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 5:95) to afford the desired coupled picolinonitrile 42 as a yellowish solid (62.4 mg, 64%). R.sub.f (100% EtOAc) 0.30; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) ) 7.59-7.48 (m, 2H), 3.69 (m, 4H), 2.69-2.58 (m, 4H), 2.48 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 161.32, *158.62, 141.31, *141.26, 131.93, *131.89, 125.11, *124.92, 122.75, *122.58, 112.29, *112.25, 91.42, 78.69, 66.82, 56.70, 53.23, 17.40 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −118.86; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.15F.sub.1N.sub.3.sup.+ 260.1194 found 260.1196.
3-fluoro-6-((3-hydroxyoxetan-3-yl)ethynyl)picolinonitrile (Compound 43)
(139) ##STR00207##
(140) To a degassed solution of picolinonitrile 6 (51 mg, 0.254 mmol, 1 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (44 mg, 0.038 mmol, 0.15 equiv) and CuI (14.5 mg, 0.076 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1p (25 mg, 0.254 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 7:3) to afford the desired coupled picolinonitrile 43 as a white solid (50 mg, 90%). R.sub.f (80% EtOAc+PE) 0.30; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)) 7.69 (dd, J=4.1, 8.8 Hz, 1H), 7.60 (dd, J=7.6, 8.8 Hz, 1H), 4.93 (dd, J=0.7, 6.8 Hz, 2H), 4.78 (dd, J=0.7, 6.8 Hz, 2H); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −113.76.
6-((1-aminocyclohexyl)ethynyl)-3-fluoropicolinonitrile (Compound 44)
(141) ##STR00208##
(142) To a degassed solution of picolinonitrile 6 (62 mg, 0.309 mmol, 1.0 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (53 mg, 0.046 mmol, 0.15 equiv) and CuI (17.5 mg, 0.092 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1f (40 mg, 0.309 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 95:5) to afford the desired coupled picolinonitrile 44 as a yellowish solid (68 mg, 90%). R.sub.f (10% MeOH+EtOAc) 0.50; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) ) 7.65-7.46 (m, 2H), 1.88 (m, 1H), 1.72-7.10 (m, 10H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 161.29, *158.60, 141.24, *141.19, 132.19, *132.15, 125.05, *124.86, 122.62, *122.46, 112.27, *112.22, 98.18, 79.98, 39.78, 29.56, 25.09, 23.15 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −115.89; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.15F.sub.1N.sub.3.sup.+ 244.1245 found 244.1245.
(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-cyano-5-fluoropyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Compound 45)
(143) ##STR00209##
(144) To a degassed solution of picolinonitrile 6 (50.5 mg, 0.251 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/3 mL), Pd[PPh.sub.3].sub.4 (40 mg, 0.034 mmol, 0.15 equiv) and CuI (13 mg, 0.068 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 1v (85 mg, 0.228 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (checked by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 5:95) to afford the desired coupled picolinonitrile 45 as a yellowish solid (106 mg, 94%). R.sub.f (100% EtOAc) 0.20; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm) ) 8.27-8.14 (2s, 2H), 7.90 (t, J=8.8, 1H), 7.78-7.71 (m, 2H), 6.98 (br s, 2H), 6.35 (d, J=2 Hz, 1H), 5.52 (dd, J=2, 6.1 Hz, 1H), 5.46 (dd, J=2, 6.1 Hz, 1H), 4.66 (d, J=2.0 Hz, 1H), 3.27 (m, 2H), 2.46 (m, 1H), 2.31 (m, 1H), 1.58 (s, 3H), 1.38 (s, 3H); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 170.04, 162.57, *159.91, 157.27, 153.82, 150.07, 141.88, *141.84, 141.44, 133.97, *133.92, 126.71, *126.52, 123.10, *122.93, 120.74, 114.50, 113.60, *113.55, 90.88, 90.62, 87.56, 84.81, 84.33, 79.86, 38.09, 27.31, 25.50, 20.23 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −118.50; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.22F.sub.1N.sub.8O.sub.4.sup.+ 493.1743 found 493.1741.
Amidoxime Derivatives
3-fluoro-N′-hydroxy-6-(pentadec-1-yn-1-yl)picolinimidamide (Compound 46)
(145) ##STR00210##
(146) A solution of coupled picolinonitrile 39 (40 mg, 0.122 mmol, 1 equiv), hydroxylamine hydrochloride (13 mg, 0.183 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (19 g, 0.183 mmol, 1.5 equiv) in dry ethanol (4 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 2:3) to afford the amidoxime 46 as a white solid (40 mg, 91%). R.sub.f (80% EtOAc+PE) 0.60; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.54 (br s, 1H, OH), 7.44-7.32 (m, 2H, Ar), 5.67 (br s, 2H), 2.41 (t, J=7.1 Hz, 2H), 1.61 (quintet, J=7.1, 7.4 Hz, 2H), 1.42 (m, 2H), 1.23 (s, 18H), 0.86 (t, J=6.5 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 157.85, *155.176, 148.85, *148.75, 138.72, *138.67, 136.69, *136.60, 128.58, *128.53, 125.29, *125.07, 91.43, 79.10, 31.91, 29.64, 29.50, 29.34, 29.14, 28.99, 28.30, 22.68, 19.29, 14.11 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CDCl.sub.3) δ (ppm) −116.71; HRMS (ESI.sup.+) m/z calcd for C.sub.21H.sub.33F.sub.1N.sub.3O.sub.1.sup.+ 362.2602 found 362.2605.
6-((4-ethylphenyl)ethynyl)-3-fluoro-N′-hydroxypicolinimidamide (Compound 47)
(147) ##STR00211##
(148) A solution of coupled picolinonitrile 40 (50 mg, 0.20 mmol, 1 equiv), hydroxylamine hydrochloride (21 mg, 0.30 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (32 g, 0.30 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:3) to afford the amidoxime 47 as a white solid (72 mg, 91%). R.sub.f (30% EtOAc+PE) 0.30; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.21 (br s, 1H, OH), 7.83 (dd, J=8.6, 10.5 Hz), 7.74 (dd, J=2.8, 8.6 Hz, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 5.86 (br s, 2H), 2.65 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 157.49, *154.83, 145.66, 137.32, *137.28, 131.73, 131.51, *131.42, 128.79, *128.68, 128.33, 125.77, *125.77, 118.35, 88.78, 87.28, 28.11, 15.19 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −116.08; HRMS (ESI.sup.+) m/z calcd for C.sub.16H.sub.15F.sub.1N.sub.3O.sub.1.sup.+ 284.1194 found 284.1197.
3-fluoro-N′-hydroxy-6-(4-morpholinobut-1-yn-1-yl)picolinimidamide (Compound 48)
(149) ##STR00212##
(150) A solution of coupled picolinonitrile 42 (55 mg, 0.212 mmol, 1 equiv), hydroxylamine hydrochloride (22 mg, 0.318 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (34 g, 0.318 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 5:95) to afford the amidoxime 48 as a white solid (38 mg, 61%). R.sub.f (5% MeOH+EtOAc) 0.30; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm)) 10.17 (s, 1H), 7.75 (dd, J=8.6, 10.5 Hz, 1H), 7.54 (dd, J=3.4, 8.6 Hz, 1H), 5.78 (br s, 2H), 3.58 (br t, J=4.5 Hz, 4H), 2.68-2.56 (m, 4H), 2.47-2.40 (m, 4H); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.99, *154.87, 147.88, *147.81, 138.68, *138.59, 137.70, *137.66, 128.21, *128.47, 125.85, *125.68, 89.33, 79.85, 66.11, 56.45, 52.85, 16.61 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, DMSO-d6) δ (ppm) −116.87; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.18F.sub.1N.sub.4O.sub.2.sup.+ 293.1408 found 293.1409.
3-fluoro-N′-hydroxy-6-((3-hydroxyoxetan-3-yl)ethynyl)picolinimidamide (Compound 49)
(151) ##STR00213##
(152) A solution of coupled picolinonitrile 43 (30 mg, 0.137 mmol, 1 equiv), hydroxylamine hydrochloride (14 mg, 0.206 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (22 g, 0.206 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 4:1) to afford the amidoxime 49 as a white solid (27.6 mg, 88%). R.sub.f (100% EtOAc) 0.30; .sup.1H NMR (400 MHz, Acetone-d6) δ (ppm)) 9.49 (s, 1H), 7.69 (dd, J=8.5, 10.4 Hz, 1H), 7.62 (dd, J=3.5, 8.5 Hz, 1H), 5.72 (br s, 2H), 4.84 (dd, J=0.6, 6.4 Hz, 2H), 4.70 (dd, J=0.6, 6.4 Hz, 2H); .sup.13C NMR (100 MHz, Acetone-d6) δ (ppm) 159.14, *156.46, 149.41, *149.32, 139.75, *139.65, 138.09, *138.04, 129.78, *129.73, 126.64, *126.43, 89.83, 84.92, 83.87, 67.54 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, Acetone-d6) δ (ppm) −115.44; HRMS (ESI.sup.+) m/z calcd for C.sub.11H.sub.11F.sub.1N.sub.3O.sub.3 252.0779 found 252.0781.
6-((1-aminocyclohexyl)ethynyl)-3-fluoro-N′-hydroxypicolinimidamide (Compound 50)
(153) ##STR00214##
(154) A solution of coupled picolinonitrile 44 (60 mg, 0.247 mmol, 1 equiv), hydroxylamine hydrochloride (26 mg, 0.370 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (39 mg, 0.370 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 1:9) to afford the amidoxime 50 as a white solid (54 mg, 79%). R.sub.f (10% MeOH+EtOAc) 0.20; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) ) 7.62 (dd, J=8.7, 10.1 Hz, 1H), 7.54 (dd, J=3.5, 8.7 Hz, 1H), 2.02-1.94 (m, 2H), 1.76-1.64 (m, 5H), 1.54-1.45 (m, 2H), 1.32-1.26 (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 159.50, *156.84, 150.87, *150.76, 139.99, *139.87, 139.81, *139.76, 130.42, *130.38, 126.91, *126.70, 95.25, 83.13, 51.49, 40.63, 26.48, 24.60 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −118.88; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.18F.sub.1N.sub.4O.sup.+ 277.1459 found 277.1460.
(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-fluoro-6-((E)-N′-hydroxycarbam-imidoyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-di methyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Compound 51)
(155) ##STR00215##
(156) A solution of coupled picolinonitrile 45 (85 mg, 0.173 mmol, 1 equiv), hydroxylamine hydrochloride (18 mg, 0.256 mmol, 1.5 equiv), and Na.sub.2CO.sub.3 (27 mg, 0.256 mmol, 1.5 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After completion (checked by TLC), the reaction mixture was filtered through a small celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 1:9) to afford the amidoxime 51 as a white solid (70.5 mg, 78%). R.sub.f (5% MeOH+EtOAc) 0.30; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) ) 8.11 (s, 1H), 8.08 (s, 1H), 7.44 (dd, J=8.6, 10.2 Hz, 1H), 7.25 (dd, J=3.5, 8.6 Hz, 1H), 6.23 (d, J=1.3 Hz, 1H), 5.48 (dd, J=2.0, 6.1 Hz, 1H), 5.31 (dd, J=2.0, 6.1 Hz, 1H), 4.59 (d, J=2.0 Hz, 1H), 3.13 (m, 1H), 3.02 (m, 1H), 2.22 (m, 1H), 2.05 (m, 1H), 1.27 (s, 3H), 1.17 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 172.12, 159.31, *156.66, 157.40, 124.06, 150.30, 142.52, 139.64, *139.55, 130.21, *130.16, 126.82, *126.61, 120.58, 115.23, 92.61, 88.64, 88.60, 85.29, 81.13, 38.71, 27.30, 25.53, 20.38 (* doubling of the peaks were observed due to the coupling of carbons with fluorine atom); .sup.19F NMR (400 MHz, CD.sub.3OD) δ (ppm) −118.89; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.25F.sub.1N.sub.9O.sub.5.sup.+ 526.1957 found 526.1970.
Example 2: In Vitro Reactivation of Human Acetylcholinesterase (hAChE) by Compound 30
Compound 30 above, i.e. 3-(2-(5-fluoro-6-((hydroxyimino)methyl)pyridin-2-yl)ethyl)pyridin-1-ium-chloride
(157) ##STR00216##
was tested for its reactivation properties of hAChE inhibited by O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun or sarin. 2-PAM (pralidoxime or 2-[(E)-(hydroxyimino)methyl]-1-methylpyridinium) and H16 (asoxime chloride or [1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl-oxoazanium dichloride) were used as comparative compounds.
(158) The protocol was as follows:
(159) Materials and methods are already described in WO2017021319, in European Journal of Medicinal Chemistry 2014, 78, 455-467, and in J. Med. Chem. 2018, 61, 7630-7639.
(160) IC.sub.50 measurements. Recombinant hAChE was produced and purified as previously described (Carletti et al 2008 J Am Chem Soc 130(47): 1601 1-20). Oximes were dissolved in MeOH to make 5 mM or 10 mM stock solution and further diluted in phosphate buffer (sodium phosphate 0.1 M, pH 7.4). Recombinant hAChE activity was measured spectrophotometrically (absorbance at 412 nm) in the presence of various concentrations of oximes in 1 mL Ellman's buffer (sodium phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25° C.). Measurements were performed at least in duplicate for each concentration tested. The concentration of oxime producing 50% of enzyme inhibition was determined by non-linear fitting using ProFit (Quantumsoft) using the standard IC.sub.50 equation:
% Activity=100*IC.sub.50/(IC.sub.50+[Ox]).
(161) Inhibition of hAChE by OPNAs. Recombinant hAChE was produced and purified as previously described (see reference: http://www.ncbi.nlm.nih.gov/pubmed/18975951). VX and tabun were from DGA maitrise NRBC (Vert le Petit, France). Stock solution of VX, sarin and tabun were 5 mM in isopropanol. The inhibition of 120 μM hAChE was carried out with a 5-fold excess of OPNAs and was performed in tris buffer (20 mM, pH 7.4, 0.1% BSA) at 25° C. After a 20-minute incubation, inhibited hAChE was desalted on PD-10 column (GE Healthcare).
(162) Reactivation of hAChE inhibited by OPNAs. OPNA-inhibited hAChE was incubated at 37° C. with at least 4 or 5 concentrations of oxime in phosphate buffer (0.1 M, pH 7.4, 0.1% BSA). The final concentration of MeOH in the incubation mix was below 2% and had no influence on the enzyme stability. At time intervals ranging from 1 to 10 minutes depending on the reactivation rate, 10 aliquots of each solution containing the different concentrations of oxime were transferred to cuvettes containing 1 mM acetylthiocholine in 1 mL Ellman's buffer (phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25° C.) for measurement of hAChE activity.
(163) The enzyme activity in the control remained constant during the experiment. The percentage of reactivated enzyme (% E.sub.react) was calculated as the ratio of the recovered enzyme activity and activity in the control. The apparent reactivation rate kobs for each oxime concentration, the dissociation constant KO of inhibited enzyme-oxime complex (E-POx) and the maximal reactivation rate constant ki, were calculated by non-linear fit with ProFit (Quantumsoft) using the standard oxime concentration-dependent reactivation equation derived from the following scheme:
(164) ##STR00217##
(165) The results are as follows (Table 1):
(166) TABLE-US-00001 TABLE 1 Reactivation of OP-inhibited human hAChE by oximes 2-PAM, HI6 and 30 OP Oxime (μM) k.sub.r (min.sup.−1) K.sub.D (μM) kr.sub.2 (mM.sup.−1 min.sup.−1) VX 2-PAM 0.19 ± 0.013 26 ± 7 7.3 HI6 0.38 ± 0.02 19 ± 4 20 30.HCl 0.04 ± 0.001 8.2 ± 1.6 4.8 Sarin 2-PAM 0.27 ± 0.02 24.8 ± 7.12 10.8 HI6 0.76 ± 0.06 57 ± 11 13.3 30.HCl 0.15 ± 0.006 1.8 ± 0.4 82.6 Tabun 2-PAM 0.47 ± 0.19 211 ± 113 2.24 HI6 0 0 0 30.HCl 0 0 0 IC.sub.50 of 30: 628 +/− 124 μM
(167) They showed that the compound 30 of the invention has the best affinity for the various OP agents, and specifically for VX and Sarin.