THIOPHENOXIME AND FURANOXIME SCAFFOLDS

Abstract

The present invention relates to a compound of formula (I). It also relates to a pharmaceutical composition comprising at least one compound of formula (I) 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.

Claims

1. Compound chosen from compounds of formula (I) and their pharmaceutically acceptable salts: ##STR00098## wherein: X is S or O; Y is —CH.sub.2—CH.sub.2—, —C═C— or —CH═CH—; Z is —CH.sub.2—; n is an integer from 0 to 3; and R is an alkyl group, a heteroalkyl, an aryl, a heteroaryl, a heterocycloalkyl, a biomolecule, a carboxyl group, a hydroxyl group, a cyano, an oxime, an hydroxamic group, a ketone, a thiol or thioether or thioester group, a phosphate, a phosphonate, phosphinate, phosphonium, sulfone, sulfonium, sulfate group, a fluorescent probe, or a group —N(R1)(R2), wherein R1 and R2 are each independently H, an alkyl group, an aryl, a heteroaryl or a group ##STR00099## or R1 and R2 form together with the nitrogen atom a dioxoindolinyl group.

2. Compound according to claim 1, which is a salt of a compound of formula (I) with an acid or a base, preferably a chlorhydrate salt.

3. Compound according to claim 1, wherein R is a heteroaryl, preferably a pyridine group such as 2-, 3- or 4-pyridino, preferably 3-pyridino, or a 5-imidazolyl which is preferably substituted by an alkyl group, preferably methyl, or a 3-oxetanyl group preferably substituted by a hydroxyl group; or an aryl; or R is a group —N(R1)(R2), wherein R1 and R2 are each independently H, a heteroaryl or a group ##STR00100## or R1 and R2 form together with the nitrogen atom a dioxoindolinyl group.

4. Compound according to claim 1, wherein the —Y—(Z)n—R group is in position 5 or 4, and/or the oxime group is in position 2.

5. Compound according to claim 1, wherein it is chosen from: compounds of formula (II) and their pharmaceutically acceptable salts: ##STR00101## wherein Y, Z, n and R are as in claim 1 ;; compounds of formula (III) and their pharmaceutically acceptable salts: ##STR00102## wherein Y, Z, n and R are as in claim 1; and compounds of formula (IV) and their pharmaceutically acceptable salts: ##STR00103## wherein Y, Z, n and R are as in claim 1.

6. Compound according to claim 5, wherein it is chosen from: compounds of formula (II) and their pharmaceutically acceptable salts, wherein : Y is —CH.sub.2—CH.sub.2— or —C═C—, n is 0, 1 or 2, preferably n is 0 or 2; and R is a heteroaryl, preferably said heteroaryl is not substituted and is a pyridine group such as 2-, 3- or 4-pyridino, preferably 3-pyridino, or R1 and R2 form together with the nitrogen atom a dioxoindolinyl group; compounds of formula (III) and their pharmaceutically acceptable salts, wherein : Y is —CH.sub.2—CH.sub.2— or —C═C—, n is 0, 1 or 2, preferably n is 0 or 2; and R is a heteroaryl or a group —N(R1)(R2), preferably R is a pyridine group such as 2-, 3- or 4-pyridino, preferably 3-pyridino, a 5-imidazolyl substituted by an alkyl group preferably methyl or a 3-oxetanyl group preferably substituted by a hydroxyl group, or preferably R is a group —N(R1)(R2), wherein R1 is H, and R2 is a heteroaryl, preferably a quinoline group such as a 4-quinolinyl, or a group ##STR00104## or R1 and R2 form together with the nitrogen atom a dioxoindolinyl group; and compounds of formula (IV) and their pharmaceutically acceptable salts, wherein : Y is —CH.sub.2—CH.sub.2— or —C═C—, n is 0, 1, 2 or 3, preferably n is 0 or 3; and R is an aryl or a heteroaryl, preferably said aryl or said heteroaryl is not substituted and is a phenyl or a pyridine group such as 2-, 3- or 4-pyridino, preferably 3-pyridino.

7. Compound according to claim 1, wherein R is 3-pyridino, a 5-imidazolyl which is substituted by a methyl, a 3-oxetanyl group substituted by a hydroxyl group or a phenyl; or R is a group —N(R1)(R2), wherein R1 and R2 are each independently H, a heteroaryl or a group ##STR00105## or R1 and R2 form together with the nitrogen atom a dioxoindolinyl group.

8. Compound according to claim 1, wherein it is chosen from: (E/Z)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime 4: ##STR00106## (E/Z)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime hydrochloride NM-27: ##STR00107## (E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime 5: ##STR00108## (E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime hydrochloride NM-29: ##STR00109## (E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 8: ##STR00110## (E/Z)-5-(2-(pyridin-3-yl)ethynyl)furan-2-carbaldehyde oxime hydrochloride NM-28: ##STR00111## (E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime 9: ##STR00112## (E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime hydrochloride NM-34: ##STR00113## (E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime 11: ##STR00114## (E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime hydrochloride NM-53: ##STR00115## (E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime 14: ##STR00116## (E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime hydrochloride NM-80: ##STR00117## (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)thiophene-2-carbaldehyde oxime CV-65: ##STR00118## (Z/E)-5-((1-methyl-1H-imidazol-5-yl)ethynyl)furan-2-carbaldehyde oxime 5: ##STR00119## (E/Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime 6: ##STR00120## (Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime hydrochloride FR-152 : ##STR00121## (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-((2)-(hydroxyimino)methyl)furan-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide FR-151: ##STR00122## (Z/E)-5-((3-hydroxyoxetan-3-yl)ethynyl)furan-2-carbaldehyde oxime FR-99: ##STR00123## (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)furan-2-carbaldehyde oxime CV-59: ##STR00124## (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)butyl)furan-2-carbaldehyde oxime CV-60 : ##STR00125## (E/Z)-4-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 3 : ##STR00126## (E/Z)-4-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime FR-82: ##STR00127## and (Z/E)-4-(5-phenylpent-1-yn-1-yl)furan-2-carbaldehyde oxime FR-66 : ##STR00128## .

9. A process for preparing a compound according to claim 1, which comprises the following steps: a Sonogashira coupling reaction between a terminal alkyne ##STR00129## and an isomer of unprotected bromo-thiophenoxime or an isomer of unprotected bromo-furanoxime, preferably under palladium catalysis, to obtain the conjugate ##STR00130## of formula (I), wherein G is X; optionally, said conjugate is then submitted to hydrogenation, preferably with Pd/C catalyst in heterogeneous conditions, to provide the corresponding alkene, and finally the hybrid reactivator ##STR00131## of formula (I), wherein G is X.

10. A pharmaceutical composition comprising at least one compound according to claim 1, and at least one pharmaceutically acceptable support.

11. A method for treating a subject in need thereof, comprising administering at least one compound according to claim 1 4 to said subject.

12. A method for treating a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent, by virtue of their reactivation potency of organophosphorous inhibited cholinesterases, including acetylcholinesterase and butyrylcholinesterase, in a subject in need thereof, comprising administering at least one compound according to claim 1 to said subject .

13. A method for treating a neurological disease such as Alzheimers disease in a subject in need thereof, comprising administering at least one compound according to claim 1 to said subject .

14. A method for treating cancer in a subject in need thereof, comprising administering at least one compound according to claim 1 to said subject .

Description

PREPARATION OF THE COMPOUNDS OF FORMULA (I)

[0137] A compound of formula (I) according to the invention may be synthesized by any appropriate method. For example, when n is 0, the compounds of formula (I) may be prepared according to the following scheme:

##STR00060##

[0138] In the above scheme, G is X.

[0139] Such methods and others are exemplified in the following examples.

[0140] Preferably, the compounds of formula (I) are synthetized as described below. Such a process is chemoselective. Particularly, it does not necessitate any previous protection step of the oxime. Said process comprises a minimal number of steps (one or two), is quickly performed, at ambient temperature.

[0141] The main steps are as follows:

[0142] As shown in the above scheme, commercially available bromo-aldehyde 1 is first converted to the oxime upon treatment with hydroxylamine hydrochloride affording 2. Subsequent late stage Sonogashira cross-coupling of 2 with alkyne 3, yield the unsaturated reactivator 4 (which is of formula (I)). Selective atmospheric pressure hydrogenation of the triple bond of 4 under Pd/C catalysis with hydrogen, afford reactivator 6 (which is of formula (I)), that can be converted to the hydrochloric salt, after reaction with aqueous HCl leading to compounds of formula (II) 7. 4 is converted to hydrochloride upon treatment with aqueous HCl to yield 5 (which is of formula (I)).

[0143] Compounds 4 to 7 are all according to the invention.

[0144] When n is 1, 2 or 3, then the above process is also applicable.

[0145] Thus, the present invention also relates to a process for preparing a compound of formula (I), which comprises the following steps: [0146] a Sonogashira coupling reaction between a terminal alkyne and an isomer of unprotected bromo-thiophenoxime or an isomer of unprotected bromo-furanoxime, preferably under palladium catalysis, to obtain the conjugate (which is of formula (I); G is X); [0147] optionally, said conjugate is then submitted to hydrogenation, preferably with Pd/C catalyst in heterogeneous conditions, to provide the corresponding alkene, and finally the hybrid reactivator (which is of formula (I); G is X).

Pharmaceutical Uses of the Compounds of the Invention

[0148] The compounds of this invention may be used in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent which may preferably be selected from warfare agents such as O-ethyl S—[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun, sarin, cyclosarin and soman and pesticides such as paraoxon, parathion and tetraethyl pyrophosphate (TEPP). The compounds of the invention may be used in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent, by virtue of their reactivation potency of organophosphorous inhibited cholinesterases, including acetylcholinesterase and butyrylcholinesterase. These compounds may alternatively be used in the treatment of diseases, which involve a reduced production of acetylcholine that may be overcome by the administration of acetylcholinesterase inhibitors. Examples of such diseases include in particular neurological diseases such as Alzheimer’s disease.

[0149] These compounds may alternatively be used in the treatment of cancer, thanks to their action as inhibitors of histone deacetylases (HDAC).

[0150] The compound of this invention is usually included in a pharmaceutical composition comprising at least one compound according to the invention and a pharmaceutically acceptable support.

[0151] The amount of compound of formula (I) in the composition according to the invention may vary in a broad range depending upon the patient, the mode of administration and the expected effect.

[0152] The compound or composition according to the invention can be administered orally or non-orally, for instance via topical, parenteral, intramuscular, intravenous, cutaneous, nasal or rectal route.

[0153] The pharmaceutical composition of the invention can present different forms including granules, powders, tablets, capsules, syrups, emulsions, suspensions, and forms used for non-oral administration, for instance injections, sprays, transdermal patches or suppositories. These pharmaceutical forms can be prepared via known conventional techniques.

[0154] The preparation of an orally administered solid pharmaceutical form can be for instance performed by the following process: an excipient (for example lactose, sucrose, starch or mannitol), a desintegrant (for example calcium carbonate, calcium carboxymethylcellulose, alginic acid, sodium carboxymethylcellulose, colloidal silicon dioxide, sodium croscarmellose, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, cellulose powder, pregelatinised starch, sodium alginate or starch glycolate), a binder (for example alpha-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, alginic acid, carbomer, dextrin, ethylcellulose, sodium alginate, maltodextrin, liquid glucose, magnesium aluminium silicate, hydroxyethylcellulose, methylcellulose or guar gum) and a lubricant (for example talc, magnesium stearate or polyethylene 6000) are added to the active principle and the mixture obtained is then tabletted. If necessary, the tablet can be coated via the known techniques, in order to mask the taste (for example with cocoa powder, mint, borneol or cinnamon powder) or to allow enteric dissolution or sustained release of the active principles. Coating products that can be used are, for example, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropylmethylcellulose phthalate and Eudragit® (methacrylic acid-acrylic acid copolymer), Opadry® (hydroxypropylmethylcellulose + macrogol + titanium oxide + lactose monohydrate). Pharmaceutically acceptable colorants may be added (for example yellow iron oxide, red iron oxide or quinoline yellow lake).

[0155] Liquid pharmaceutical forms for oral administration include solutions, suspensions and emulsions. The aqueous solutions can be obtained by dissolving the active principle in water, followed by addition of flavourings, colorants, stabilisers and/or thickeners, if necessary. In order to improve the solubility, it is possible to add ethanol, propylene glycol or any other pharmaceutically acceptable non-aqueous solvent. The aqueous suspensions for oral use can be obtained by dispersing the finely divided active principle in water with a viscous product, such as a natural or synthetic gum or resin, methylcellulose or sodium carboxymethylcellulose.

[0156] The pharmaceutical forms for injection can be obtained, for example, by the following process. The active principle is dissolved, suspended or emulsified either in an aqueous medium (for example distilled water, physiological saline or Ringer’s solution) or in an oily medium (for example olive oil, sesame seed oil, cottonseed oil, corn oil or propylene glycol), with a dispersant (for example Tween® 80, HCO® 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose or sodium alginate), a preserving agent (for example methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol or phenol), an isotonicity agent (for example sodium chloride, glycerol, sorbitol or glucose) and optionally other additives, such as, if desired, a solubilizing agent (for example sodium salicylate or sodium acetate) or a stabilizer (for example human serum albumin).

[0157] Pharmaceutical forms for external use (topical use) can be obtained from a solid, semi-solid or liquid composition containing the active principle. For example, to obtain a solid form, the active principle can be treated with excipients (for example lactose, mannitol, starch, microcrystalline cellulose or sucrose) and a thickener (for example natural gums, cellulose derivatives or acrylic polymers) so as to convert them into powder. The liquid pharmaceutical compositions are prepared in substantially the same way as the forms for injection, as indicated previously. The semi-solid pharmaceutical forms are preferably in the form of aqueous or oily gels or in the form of pomades. These compositions may optionally contain a pH regulator (for example carbonic acid, phosphoric acid, citric acid, hydrochloric acid or sodium hydroxide) and a preserving agent (for example a p-hydroxybenzoic acid ester, chlorobutanol or benzalkonium chloride).

[0158] A method for the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent, comprising administering at least one compound according to the invention is also described herein.

[0159] A method for the treatment of a neurological disease such as Alzheimer’s disease, comprising administering at least one compound according to the invention is also described herein.

[0160] A method for the treatment of a cancer, comprising administering at least one compound according to the invention is also described herein.

[0161] A method for the treatment of a virus, comprising administering at least one compound according to the invention is also described herein.

[0162] Within the context of the invention, the term treatment denotes curative, symptomatic, and/or preventive treatments. In particular, it can refer to reducing the progression of the disease, reducing or suppressing at least one of its symptoms or complications, or improving in any way the state of health of patients.

[0163] The administration of the compounds or of the composition according to the invention may be performed before, during or after the exposition of the subject to the organophosphorous nerve agent.

[0164] In the present invention, the terms “subject” and “patient” are used indifferently and designate a human subject.

[0165] The amount of compound according to the invention to be administered according to the invention may vary in a broad range depending upon the patient, the mode of administration and the expected effect. In particular, the amount of compound according to the invention may be comprised between 200 mg and 4000 mg, with up to 3 daily intakes.

[0166] The compound or composition according to the invention may be co-administered with at least one other active agent, such as an antimuscarinic agent, in particular atropine, an anticonvulsant, in particular diazepam or one of its prodrugs, such as avizafone, and/or a bioscavenger able to capture and/or degrade OPNAs in blood, such as human butyrylcholinesterase.

[0167] The term co-administered means that the administration of the compound or composition according to the invention and that of the other active agent can be simultaneous, sequential and/or separate.

Other Uses of the Compounds of the Invention

[0168] The compounds of this invention may further be used as tools for in vivo and/or in vitro biological studies. In this application, the compounds according to the invention may include one or more isotopes, which will allow for their detection.

[0169] The following examples are provided as illustrative, and not limitative, of the present invention.

EXAMPLES

Example 1: Synthesis of Compounds of the Invention

General Methods

[0170] 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 .Math.m). 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.

Experimental Procedures

(E/Z)(pyridin-3-ylethynyl)thiophene-2-carbaldehyde Oxime Hydrochloride NM-27:

(E/Z)(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde Oxime Hydrochloride NM-29:

##STR00064##

(E)bromothiophene-2-carbaldehyde Oxime 2:

[0171] ##STR00065##

[0172] A solution of commercially available 5-bromothiophene-2-carbaldehyde 1 (1 g, 5.23 mmol, 1 equiv), hydroxylamine hydrochloride (727 mg, 10.46 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (1.28 g, 15.70 mmol, 3 equiv) in dry ethanol (10 mL) was stirred at room temperature for 16 h. Upon completion, 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 pure (E)-5-bromothiophene-2-carbaldehyde oxime 2 as a white solid (850 mg, 79.4%); R.sub.f (10% EtOAc/PE) 0.3; .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.45 (brs, 1H, OH), 7.63 (s, 1H), 7.12 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 4.0 Hz, 1H).

(E/Z)(pyridin-3-ylethynyl)thiophene-2-carbaldehyde Oxime 4:

[0173] ##STR00066##

[0174] To a degassed solution of (E)-5-bromothiophene-2-carbaldehyde oxime 2 (110 mg, 0.533 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (84.2 mg, 0.072 mmol, 0.15equiv) and Cul (27.7 mg, 0.145 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine 3 (50 mg, 0.485 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE, 1:1) to afford (E)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oximeas a white solid (65 mg, 58.7%);R.sub.f (50% EtOAc/PE) 0.25;IR(neat):v.sub.max3058, 2790, 1493, 1229, 1193, 1049, 924, 797, 698, 567 cm.sup.-1;HRMS (ESI.sup.+): m/z calcd for C.sub.12H.sub.8N.sub.2OS.sup.+229.0430 found 229.0433. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δppm 12.32 (s, 1H), 8.76 (s, 1H), 8.60 (d, J = 3.8 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.47 (bs, 3H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δppm 151.41, 149.25, 139.56, 138.40, 132.59, 132.18, 131.22, 124.93, 123.66, 118.94, 91.72, 85.62.

(E/Z)(pyridin-3-ylethynyl)thiophene-2-carbaldehyde Oxime Hydrochloride NM-27:

[0175] ##STR00067##

[0176] To a solution of (E)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime 4 (20 mg, 0.087 mmol) in water (3 ml) was added 2N HCl (1 mL) at room temperature and stirred for 20 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2 × 3 mL). The solid was dried under vacuum to give cis-trans isomers (1:0.2 ratio) of (E/Z) 5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime hydrochloride NM-27 as a pale yellow solid (21.5 mg, 93.4%); IR(neat): v.sub.max3051, 2924, 2585, 2358, 2216, 1442, 1425, 1254, 985, 798, 672, 546 cm.sup.-1; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 9.12 (bs, 1.2H), 8.86 (bs, 1.2H), 8.78-8.69 (m, 1.2H), 8.24 (s, 0.2H), 8.14 (s, 1.2H), 7.81 (s, 1H), 7.48 (d, J = 3.9 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 3.7 Hz, 0.2H), 7.09 (d, J = 3.6 Hz, 0.2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 156.55, 149.25, 144.93, 144.17, 142.48, 141.83, 136.03, 135.71, 134.63, 132.20, 130.04, 128.90, 127.17, 125.75, 121.93, 100.87, 91.49, 91.33, 88.47.

(E/Z)(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde Oxime 5:

[0177] ##STR00068##

[0178] To a solution of (E)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime 4 (25 mg, 0.109 mmol) in 4:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (10 mg) at room temperature under Argon atmosphere and stirred the mixture for 3 h. Upon completion, the mixture was filtered using small celite pad and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc/PE, 60:40) to afford cis-trans isomers (1:0.1) of (E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime 5 as a white solid (23 mg, 90%); R.sub.f (50% EtOA/PE) 0.20; IR (neat): v.sub.max2921, 2851, 2719, 1474, 1429, 1042, 917, 794, 707, 640, 591, 569 cm.sup.-1; HRMS (ESI.sup.+): m/z calcd for C.sub.12H.sub.13N.sub.2OS.sup.+ 233.0769 found 233.0743; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.48 (bs, 2H), 7.64 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.23 (dd, J = 7.4, 5.0 Hz, 1H), 7.18 (d, J = 3.7 Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H), 3.17 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 149.56, 149.41, 147.44, 144.76, 136.25, 131.45, 129.37, 125.13, 124.30, 123.49, 34.59, 31.26.

(E/Z)(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde Oxime Hydrochloride NM-29:

[0179] ##STR00069##

[0180] To a solution of (E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime 5 (20 mg, 0.087 mmol) in water (3 ml) was added 2N HCl (1 mL) at room temperature and stirred for 20 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2 × 5 mL). The solid was dried under vacuum to give cis-trans isomers (75:25 ratio)of (E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime hydrochloride NM-29 as a white solid (22 mg, 95% yield); IR(neat): v.sub.max3050, 2924, 2359, 2340, 1526, 1254, 1008, 987, 804, 674, 547 cm.sup.-1; HRMS (ESI.sup.+): m/z calcd for C.sub.12H.sub.13N.sub.2OS.sup.+ 233.0744 found 233.0743;.sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 9.06-8.42 (m, 3H), 8.25-7.87 (m, 2H), 7.69-7.37 (s, 0.75H), 7.18-6.89 (bs, 1H), 6.84-6.65 (s, 0.25H), 3.60-3.05 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 153.64, 148.90, 148.79, 145.08, 144.89, 142.98, 142.89, 142.81, 142.75, 141.10, 140.97, 137.13, 136.36, 130.39, 128.83, 128.71, 127.56, 127.28, 35.34, 31.76, 31.72.

(E/Z)(2-(pyridin-3-yl)ethynyl)furan-2-carbaldehyde Oxime Hydrochloride NM-28:

(E/Z)(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde Oxime Hydrochloride NM-34:

[0181] ##STR00070##

(E/Z)bromofuran-2-carbaldehyde Oxime 7:

[0182] ##STR00071##

[0183] A solution of commercially available 5-bromofuran-2-carbaldehyde 6 (2.5 g, 14.28 mmol, 1 equiv), hydroxylamine hydrochloride (1.98 mg, 28.48 mmol, 2 equiv), and Na.sub.2CO.sub.3 (4.54 g, 42.83 mmol, 3 equiv) in 1:1 ratio of MeOH/H.sub.2O (10 mL) was stirred at room temperature for 2 h. Upon completion, the reaction mixture was concentrated, extracted with EtOAc (3× 30 mL) dried over anhydrous Na.sub.2SO.sub.4 and concentrated by vacuo. The crude was purified by column chromatography (EtOAc/PE 1:9) to afford cis-trans isomers (1:0.55 ratio) of (E/Z)-5-bromofuran-2-carbaldehyde oxime 7 as a white solid (2.5 g, 92.2%); R.sub.f (10% EtOAc/PE) 0.55; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.92 (s, 0.55H), 7.45 (s, 1H), 7.27 (d, J = 3.5 Hz, 1H), 6.58 (d, J = 3.4 Hz, 0.55H), 6.47 (dd, J = 3.5, 0.5 Hz, 1H), 6.40 (d, J = 3.5 Hz, 0.55H).

(E/Z)(pyridin-3-ylethynyl)furan-2-carbaldehyde Oxime 8:

[0184] ##STR00072##

[0185] To a degassed solution of (E/Z)-5-bromofuran-2-carbaldehyde oxime 7 (101 mg, 0.531 mmol, 1.1 equiv) in THF/Et.sub.3N (4 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (84.2 mg, 0.072 mmol, 0.15equiv) and Cul (27.7 mg, 0.145 mmol, 0.3equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine (50 mg, 0.485 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to afford cis-trans isomers (1:0.8 ratio) of (E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 8 as a light yellow solid (72 mg, 70%); IR(neat): v.sub.max2808, 2360, 1479, 1407, 1019, 986, 955, 791, 695, 518 cm.sup.-1; R.sub.f (30% EtOAc/PE) 0.30; HRMS (ESI.sup.+): m/z calcd for C.sub.12H.sub.9N.sub.2O.sub.2.sup.+ 213.0662found 213.0658; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.13 (s, 0.8H), 11.57 (s, 1H), 8.80 (s, 1.8H), 8.65 (s, 1.8H), 8.06 (s, 1H), 8.05-8.00 (m, 1.8H), 7.61 (s, 0.8H), 7.54-7.46 (m, 1.8H), 7.29 (d, J = 3.6 Hz, 0.8H), 7.11 (dd, J = 3.6, 0.5 Hz, 0.8H), 7.06 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 3.6 Hz, 1H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 151.50, 149.67, 149.55, 146.58, 138.53, 135.77, 134.75, 134.73, 132.05, 132.02, 131.53, 131.43, 128.81, 128.70, 118.91, 118.57, 117.59, 112.85, 91.60, 91.49, 82.24, 82.11.

(E/Z)(pyridin-3-ylethynyl)furan-2-carbaldehyde Oxime Hydrochloride NM-28:

[0186] ##STR00073##

[0187] To a solution of (E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 8 (30 mg, 0.141 mmol) in water (3 ml) was added 2N HCl (1 mL) at room temperature and stirred for 30 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2 × 3 mL). The solid was dried under vacuum to give trans-cis isomers (55:45 ratio) isomers of(E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime hydrochloride NM-28 as a white solid (30 mg, 92%); IR (neat): v.sub.max3104, 3024, 2850, 2215, 1540, 1146, 982, 923, 795, 741, 672, 620 cm.sup.-1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 9.18 (bs, 1H), 8.94 (bs, 1H), 8.82-8.68 (m, 1H), 8.17 (s, 1H), 8.01 (s, 0.45H), 7.48 (s, 0.55H), 7.38 (d, J = 3.3 Hz, 0.55H), 7.10 (d, J = 3.4 Hz, 0.55H), 7.05 (d, J = 3.4 Hz, 0.45H), 6.80 (d, J = 3.3 Hz, 0.45H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 152.16, 149.03, 148.93, 145.14, 144.99, 142.40, 142.35, 142.26, 142.24, 139.83, 136.91, 135.81, 121.67, 121.30, 119.00, 113.49, 88.69, 88.46, 87.41, 87.34.

(E/Z)(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde Oxime 9:

[0188] ##STR00074##

[0189] To a solution of (E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 8 (30 mg, 0.141 mmol) in EtOAc (5 mL) was added 10% Pd/C (10 mg) at room temperature under Argon atmosphere and stirred the mixture for 2.5 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered using celite pad and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc/PE, 40:60) to afford cis-trans isomers (60:40 ratio) of (E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime as white solid (27 mg, 88%); R.sub.f (30%EtOAc/PE) 0.20; IR(neat): v.sub.max 2850, 2289, 2161, 1579, 1524, 1460, 1425, 1020, 967, 913, 800, 706, 640 cm.sup.-1;HRMS (ESI.sup.+):m/z calcd for C.sub.12H.sub.13N.sub.2O.sub.2.sup.+ 217.0957 found 217.0971; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.40-8.27 (m, 2 H), 7.90 (s, 0.4 H), 7.70-7.61 (m, 1 H), 7.37-7.29 (m, 1.6H), 7.14 (d, J = 3.3 Hz, 0.6H), 6.51 (d, J = 3.3 Hz, 0.40H), 6.15 (dd, J = 3.3, 0.5 Hz, 0.6H), 6.08 (d, J = 3.3 Hz, 0.40H), 3.06-2.95 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD):δ ppm 157.60, 156.67, 150.10, 150.08, 148.09, 147.82, 147.79, 147.51, 145.99, 140.68, 138.58, 138.56, 138.32, 138.20, 137.10, 125.09, 119.31, 114.06, 109.85, 109.22, 32.08, 32.07, 30.36, 30.26.

(E/Z)(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde Oxime Hydrochloride NM-34:

[0190] ##STR00075##

[0191] To a solution of (E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime 9 (20 mg, 0.092 mmol) in CH.sub.2Cl.sub.2 (3 ml) was added 2N HCl (1 mL) at room temperature and stirred for 30 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2 × 3 mL). The solid was dried under vacuum to give cis-trans isomers (60:40 ratio) of (E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime hydrochloride NM-34 as a light brown solid (22 mg, 94%); IR (neat): v.sub.max3155, 3051, 3004, 2627, 2083, 1558, 1520, 1470, 1024, 1011, 807, 682 cm.sup.-1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.86-8.70 (m, 2H), 8.55 (t, J = 7.9 Hz, 1H), 8.11-8.00 (m, 1H), 7.99 (s, 0.4H), 7.74 (s, 0.6H), 7.39 (d, J = 2.6 Hz, 0.6H), 6.63 (d, J = 2.8 Hz, 0.4H), 6.41 (d, J = 2.8 Hz, 0.6H), 6.23 (d, J = 2.8 Hz, 0.4H), 3.32 (m, 2H), 3.17 (m, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD):δppm 157.38, 155.84, 147.14, 147.12, 146.53, 141.76, 141.59, 141.08, 141.05, 139.41, 139.31, 127.12, 127.06, 121.60, 114.07, 110.20, 108.81, 30.43, 30.24, 28.10, 28.08.

(E/Z)(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde Oxime hydrochloride NM-53:

[0192] ##STR00076##

(E/Z)(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde Oxime 11:

[0193] ##STR00077##

[0194] To a degassed solution of (E/Z)-5-bromofuran-2-carbaldehyde oxime 7 (32 mg, 0.168 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (26.5 mg, 0.022 mmol, 0.15 equiv) and Cul (8.7 mg, 0.045 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, N-(but-3-yn-1-yl)quinolin-4-amine 10 (30 mg, 0.152 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (100% EtOAc to MeOH/EtOAc 5:95) to afford trans-cis isomers (1:0.5 ratio) of (E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime 11 as an off white solid (18 mg, 36%); R.sub.f (10% MeOH/EtOAc) 0.20; IR(neat):v.sub.max3050, 2924, 2567, 2357, 1550, 1442, 1172, 1172, 986, 804, 763, 582, 486 cm.sup.-1;HRMS (ESI.sup.+):m/z calcd for C.sub.18H.sub.16N.sub.3O.sub.2.sup.+ 306.122218 found 306.123703; .sup.1H NMR (400 MHz, DMSO-d.sub.6):b ppm 11.98 (s, 0.67H), 11.42 (s, 0.33H), 8.42 (d, J = 5.4 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.97 (s, 0.33H), 7.79 (d, J = 7.7 Hz, 1H), 7.67-7.57 (m, 1H), 7.49 (s, 0.67H), 7.47-7.42 (m, 2H), 7.17 (d, J = 3.5 Hz, 0.67H), 6.78 (d, J = 3.5 Hz, 0.67H), 6.72 (dd, J = 9.0, 3.5 Hz, 0.67H), 6.58 (d, J = 5.4 Hz, 1H), 3.58 (dd, J = 12.8, 6.8 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 150.38, 149.69, 148.20, 147.88, 145.47, 138.53, 136.83, 135.80, 134.78, 128.98, 128.72, 124.11, 124.09, 121.63, 118.71, 117.35, 117.33, 116.76, 116.37, 112.57, 98.49, 94.67, 71.72, 41.01, 40.96, 21.15, 18.86, 18.85.

(E/Z)(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde Oxime Hydrochloride NM-53:

[0195] ##STR00078##

[0196] To a solution of (E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime 11 (8.5 mg, 0.027 mmol) in THF (3 ml) was added 2N HCl (0.1 mL) at room temperature and stirred for 20 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether. The solid was dried under vacuum to give cis-trans isomers (8:2 ratio) of (E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime hydrochloride NM-53 as a pale yellow solid (8 mg, 84% yield); IR(neat): v.sub.max3173, 2807, 2220, 1591, 1570, 786, 750 cm.sup.-1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.44-8.41 (m, 2H), 8.01-7.96 (m, 1H), 7.90-7.88 (m, 1.8H), 7.78-7.73 (m, 1H), 7.30 (s, 0.2H), 7.22 (d, J = 3.5 Hz, 0.2H), 7.06 (d, J = 7.1 Hz, 1H), 6.62 (d, J = 3.5 Hz, 0.8H), 6.60 (d, J = 3.6 Hz, 0.2H), 6.55 (d, J = 3.5 Hz, 0.8H), 3.93 (t, J = 6.7 Hz, 2H), 3.07-2.95 (m, 2H); .sup.1H NMR (101 MHz, CD.sub.3OD): δ ppm 157.99, 149.77, 143.21, 144.04, 139.35, 139.01, 136.24, 135.03, 135.00, 128.34, 123.75, 121.16, 118.80, 118.37, 117.68, 117.21, 113.35, 99.67, 93.45, 93.29, 73.69, 73.67, 42.97, 42.94, 20.28, 20.21.

(E/Z)(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde Oxime Hydrochloride NM-80:

[0197] ##STR00079##

5-(Quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde 12:

[0198] ##STR00080##

[0199] To a degassed solution of 5-bromofuran-2-carbaldehyde 6 (110 mg, 0.575 mmol, 1.2equiv) in THF/Et.sub.3N (6 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (83.4 mg, 0.024 mmol, 0.15 equiv) and Cul (27.47 mg, 190.47 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, N-(but-3-yn-1-yl)quinolin-4-amine 10 (100 mg, 0.480 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc to MeOH/CH.sub.2Cl.sub.2 5:95) to afford the 5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde 12 as an off white solid (115 mg, 81%); R.sub.f (10% MeOH/CH.sub.2Cl.sub.2) 0.25; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 9.56 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 6.3 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.76-7.66 (m, 1H), 7.53-7.48 (m, 1H), 7.19 (d, J = 3.7 Hz, 1H), 6.66-6.57 (m, 2H), 3.84 (q, J = 6.5 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 177.09, 152.10, 151.66, 147.35, 144.62, 144.28, 141.60, 130.79, 126.37, 125.76, 121.71, 121.24, 118.28, 116.70, 98.43, 94.80, 41.39, 19.95.

5-(Quinolin-4-ylamino)butyl)furan-2-carbaldehyde 13:

[0200] ##STR00081##

[0201] To a solution of 5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde 12 (25 mg, 0.0861 mmol) in 3:1 ratio of EtOAc/MeOH (4 mL) was added 10% Pd/C (10 mg) at room temperature under Argon atmosphere and stirred the mixture for 2.5 h under H.sub.2 using balloon pressure. Upon completion, the mixture was filtered using celite pad, concentrated under reduced pressure and the crude was purified by column chromatography (EtOAc to MeOH/CH.sub.2Cl.sub.2 10:90) to afford 5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde 13 as pale yellow solid (22 mg, 87%);R.sub.f(10% MeOH/CH.sub.2Cl.sub.2) 0.20; IR (neat): v.sub.max2926, 1666, 1579, 1514, 1339, 1119, 1021, 759, 538 cm.sup.-1; HRMS (ESI.sup.+): m/z calcd for C.sub.18H.sub.19N.sub.2O.sub.2.sup.+295.144300 found 295.144104; .sup.1H NMR (400 MHz, CD.sub.3OD):δ ppm 9.42 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.65-7.62 (m, 1H), 7.58-7.51 (m, 1H), 7.46-7.41 (m, 1H), 7.33 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 5.7 Hz, 1H), 6.38 (dd, J = 3.6, 0.8 Hz, 1H), 3.40 (t, J = 6.8 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H), 1.91-1.74 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 177.38, 163.77, 151.99, 151.56, 132.36, 131.72, 131.62, 129.36, 128.64, 128.52, 126.83, 124.36, 120.91, 108.88, 42.16, 27.41, 27.36, 24.85.

(E/Z)(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde Oxime 14:

[0202] ##STR00082##

[0203] To a solution of 5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde 13 (40 mg, 0.135 mmol) in EtOH (4 mL) was added TEA (54.9 mg, 0.543 mmol), hydroxylamine hydrochloride (18.89 mg, 0.271 mmol), and stirred at room temperature for 12 h. Upon completion, cooled to room temperature and distilled off under reduced pressure. The crude mixture was purified by column chromatography (MeOH/CH.sub.2Cl.sub.2, 1:9) to give cis-trans isomers of (1:0.4 ratio) of (E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime 14 as light brown solid (22 mg, 42%); R.sub.f (10%MeOH/CH.sub.2Cl.sub.2) 0.20; IR (neat): v.sub.max 3189, 3108, 2939, 2360, 2341, 1591, 1447, 1219, 976, 758 cm.sup.-1;HRMS (ESI.sup.+):m/z calcd for C.sub.18H.sub.20N.sub.3O.sub.2.sup.+ 310.153453 found 310.155003; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.39 (t, J = 8.3 Hz, 2H), 8.00-7.80 (m, 2.7H), 7.71 (t, J = 7.5 Hz, 1H), 7.27 (s, 0.3 H), 7.15 (d, J= 4.2 Hz, 0.3H), 6.86 (d, J = 6.6 Hz, 1H), 6.55 (d, J = 3.2 Hz, 0.7H), 6.25(d, J = 4.2 Hz, 0.3H), 6.19 (d, J = 3.2 Hz, 0.7H), 3.62 (m, 2H), 2.78 (m, 2H), 1.86 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD):δppm 158.95, 157.64, 147.87, 143.05, 140.73, 139.29, 137.10, 134.82, 128.13, 123.81, 121.09, 119.40, 118.33, 114.34, 109.30, 108.67, 99.19, 44.41, 28.43, 28.39, 26.38, 26.27.

(E/Z)(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde Oxime Hydrochloride NM-80:

[0204] ##STR00083##

[0205] To a solution of (E/Z)-6-(2-(pyridin-3-yl)ethyl)pyridazine-3-carbaldehyde oxime 14 (20 mg, 0.064 mmol) in H.sub.2O (2 mL) was added 2N HCl (0.5 mL) at room temperature and stirred for 30 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2× 4 mL). The solid was dried under vacuum to give cis-trans isomers (60:40 ratio) of (E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime hydrochloride NM-80 as a light brown solid (18 mg, 80%); IR (neat): v.sub.max 2945, 2360, 1615, 1566, 1447, 1219, 758 cm.sup.-1; .sup.1H NMR(400 MHz, CD.sub.3OD): δ ppm 8.45-8.30 (m, 2.4H), 8.03-7.81 (m, 2.6H), 7.71 (t, J = 6.8 Hz, 1H), 7.22 (s, 0.6H), 6.86 (s, 1H), 6.56(d, J =2.8 Hz, 0.4H), 6.28 (d, J= 7.6 Hz, 0.6H), 6.19 (d, J = 2.6 Hz, 0.4H), 3.64 (s, 2H), 2.78 (s, 2H), 1.87 (s, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 159.06, 158.52, 157.65, 143.07, 139.23, 134.87, 128.16, 123.82, 121.07, 120.07, 118.32, 114.56, 109.67, 108.75, 99.25, 44.46, 28.50, 28.46, 28.43, 28.40, 26.38, 26.22.

(E/Z)(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde Oxime FR-82 :

[0206] ##STR00084##

(E/Z)(pyridin-3-ylethynyl)furan-2-carbaldehyde Oxime 3 :

[0207] ##STR00085##

[0208] To a degassed solution of (E/Z)-4-bromofuran-2-carbaldehyde oxime 1 (80 mg, 0.421 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (97.31 mg, 0.084 mmol, 0.2 equiv) and Cul (32.08 mg, 0.168 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne (3-ethynylpyridine, 0.505 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 hour at 100° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/P 2:3) to afford the desired coupled (E/Z)-4-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 3 as a yellow solid (55 mg, 62%). R.sub.f (50% EA+P) 0.3; .sup.1H NMR (400 MHz, DMF-d.sub.7) δ 12.39 (s, 0.6H), 11.75 (s, 0.4H), 8.77 (ddd, J = 9.4, 2.3, 0.9 Hz, 1H), 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 8.27 (dd, J = 7.6, 0.8 Hz, 1H), 8.12 (s, 0.4H), 7.99 (tt, J = 8.6, 1.9 Hz, 1H), 7.60 (s, 0.6H), 7.52 - 7.47 (m, 1H), 7.42 (d, J = 0.8 Hz, 0.6H), 6.97 (d, J = 0.8 Hz, 0.4H). .sup.13C NMR (101 MHz, DMF) δ 152.86, 152.83, 150.43, 150.26, 148.87, 147.94, 147.38, 139.57, 139.51, 139.49, 136.03, 124.70, 120.84, 119.03, 113.99, 110.01, 109.63, 89.26, 89.19, 84.21.

(E/Z)(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde Oxime FR-82 :

[0209] ##STR00086##

[0210] To a degassed solution of (E/Z)-4-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime (40 mg, 0.131 mmol, 1 equiv) in EtOAc/MeOH (3 mL/ 1 mL), Pd/C (14 mg (10%w), 0.013 mmol, 0.1 equiv) was added. After degassing the reaction mixture for 5 min at room temperature, the mixture is stirred under H.sub.2 pressure for 1h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative chromatography (EtOAc/P 1:1) to afford the desired hydrogenated (E/Z)-4-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime FR-82 as a white solid (15 mg, 50%). R.sub.f (50 % EA+P) 0.2 ; .sup.1H NMR (400 MHz, DMF-d.sub.7) δ 11.99 (s, 0.67H), 11.43 (s, 0.33H), 8.48 (d, J = 30.9 Hz, 2H), 8.02 (s, 0.33), 7.71 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 0.8 Hz, 0.67H), 7.53 - 7.50 (m, 0.34H), 7.45 (s, 0.67H), 7.33 (dd, J = 7.4, 4.7 Hz, 1H), 7.25 (s, 0.67H), 6.70 (s, 0.33H), 2.95 (dd, J = 8.8, 6.8 Hz, 2H), 2.86 - 2.77 (m, 2H). .sup.13C NMR (101 MHz, DMF) δ 147.67, 146.12, 141.01, 140.26, 136.05, 135.93, 126.94, 118.03, 33.04, 29.06, 26.23.

(Z)(2-(1-methyl-1H-imidazolyl)ethyl)furan-2-carbaldehyde Oxime Hydrochloride FR-152:

[0211] ##STR00087##

(Z/E)((1-methyl-1H-imidazolyl)ethynyl)furan-2-carbaldehyde Oxime 5:

[0212] ##STR00088##

[0213] To a degassed solution of 5-bromofuran-2-carbaldehyde oxime 1 (100 mg, 0.526 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (121.64 mg, 0.105 mmol, 0.2 equiv) and Cul (40.10 mg, 0.210 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 5-ethynyl-1-methyl-1H-imidazole (64.14 .Math.L, 0.631 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 hour at 100° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 5%) to afford the desired coupled (Z/E)-5-((1-methyl-1H-imidazol-5-yl)ethynyl)furan-2-carbaldehyde oxime 5 as a yellow solid (70 mg, 62%). R.sub.f (5 % MeOH + EtOAc) 0.2; .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97 (s, 0H), 7.75 (s, 1H), 7.41 (s, 1H), 7.37 - 7.32 (m, 1H), 7.32 (d, J = 3.6 Hz, 1H), 6.89 (dd, J = 3.6, 0.6 Hz, 1H), 6.83 (d, J = 3.6 Hz, 0H), 6.72 (d, J = 3.6 Hz, 0H), 3.76 (d, J = 1.9 Hz, 3H). .sup.13C NMR (101 MHz, MeOD) δ 150.73, 147.87, 139.82, 138.05, 136.96, 136.05, 135.15, 135.06, 133.57, 132.92, 132.81, 129.83, 129.70, 124.31, 119.16, 118.83, 118.79, 117.68, 113.28, 86.81, 86.77, 82.48, 82.35, 49.43, 49.21, 49.00, 48.79, 48.58, 48.36, 48.15, 32.47, 32.38. HRMS (ESI.sup.+) m/z calcd 216.07728 for C.sub.11H.sub.10N.sub.3O.sub.2.sup.+ found 216.076753.

(E/Z)(2-(1-methyl-1H-imidazolyl)ethyl)furan-2-carbaldehyde Oxime 6:

[0214] ##STR00089##

[0215] To a degassed solution of (Z/E)-5-((1-methyl-1H-imidazol-5-yl)ethynyl)furan-2-carbaldehyde oxime (20 mg, 0.092 mmol, 1 equiv) in EtOAc/MeOH (2 mL/ 2 mL), Pd/C (4.94 mg (10%w), 0.005 mmol, 0.05 equiv) was added. After degassing the reaction mixture for 5 min at room temperature, the mixture is stirred under H.sub.2 pressure for 6h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative chromatography (MeOH/EtOAc 5%); to afford the desired hydrogenated (E/Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime 6 as a white solid (13 mg, 64%). R.sub.f (5% MeOH+ EA) {0.16 ; 0.22}; .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (s, 0H), 7.53 (s, 1H), 7.34 (s, 1H), 7.16 (d, J = 3.3 Hz, 1H), 6.72 (s, 1H), 6.55 (d, J = 3.3 Hz, 0H), 6.24 (dd, J = 3.3, 0.7 Hz, 1H), 6.17 (d, J = 3.4 Hz, 0H), 3.58 (d, J = 2.8 Hz, 3H), 3.02 - 2.96 (m, 4H). .sup.13C NMR (101 MHz, MeOD) δ 156.38, 155.44, 144.61, 139.30, 137.38, 135.71, 124.64, 118.01, 112.82, 108.27, 107.66, 30.10, 26.76, 21.74.

(Z)(2-(1-methyl-1H-imidazolyl)ethyl)furan-2-carbaldehyde Oxime hydrochloride FR-152 :

[0216] ##STR00090##

[0217] To a solution of (E/Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime (25 mg, 0.06 mmol) in MeOH (3 mL) was added 0.5N HCl (1 mL) at room temperature and stirred for 5 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulting solid was washed with diethyl ether (2 × 3 mL). The solid was dried under vacuum to give cis/trans isomer (6.5/3.5 ratio) of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride FR-152 as a light brown solid (20 mg, 71%); .sup.1H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J= 5.5 Hz, 1 H), 7.87 (d, J= 3.6 Hz, 0.35H), 7.50 (q, J= 2.3 Hz, 0.65H), 7.24 (dt, J= 9.3, 3.4 Hz, 1.65H), 6.53 (d, J = 3.4 Hz, 0.35H), 6.34 (q, J= 3.5, 3.0 Hz, 0.65H), 6.20 (d, J= 3.3 Hz, 0.35H), 3.76 (dd, J = 4.0, 2.2 Hz, 3H), 3.05 (dd, J = 10.6, 3.8 Hz, 4H). .sup.13C NMR (400 MHz, Methanol-d.sub.4) δ 157.50, 156.88, 148.16, 145.69, 140.67, 137.21, 136.60, 135.75, 121.54, 117.85, 114.89, 110.82, 109.75, 33.75, 27.01, 26.94, 22.76, 22.65.

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-((Z)-(hydroxyimino)methyl)furan-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide FR-151:

[0218] ##STR00091##

[0219] To a degassed solution of (E/Z)-5-bromofuran-2-carbaldehyde oxime 1 (75 mg, 0.394 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (22.81 mg, 0.019 mmol, 0.05 equiv) and Cul (3.76 mg, 0.019 mmol, 0.05 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne ((3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 7, 0.505 mmol, 1.1 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 15 min at 120° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 2%) to afford the desired coupled oxime FR-151 (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-((Z)-(hydroxyimino)methyl)furan-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide as a yellow solid (94 mg, 49%). R.sub.f (5 % MeOH+ EA) 0.25; .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 11.19 (d, J= 159.7 Hz, 1H), 8.26-8.16 (m, 2H), 7.70 (dt, J= 36.8, 6.2 Hz, 1H), 6.94 (d, J = 23.2 Hz, 2H), 6.65 (dd, J= 6.1, 3.5 Hz, 1H), 6.36-6.31 (m, 1H), 5.50 (dd, J= 6.3, 2.1 Hz, 1H), 5.46 (dt, J= 6.1, 2.0 Hz, 1H), 4.63 (t, J= 1.8 Hz, 1H), 3.27 - 3.15 (m, 2H), 2.50 -2.20 (m, 2H), 1.57 (d, J = 3.0 Hz, 3H), 1.36 (d, J = 1.7 Hz, 3H)..sup.13C NMR (101 MHz, Acetone) δ 169.15, 169.12, 156.38, 152.87, 149.18, 148.42, 145.64, 140.54, 138.71, 137.71, 136.59, 135.19, 117.59, 116.49, 116.05, 113.58, 113.53, 112.19, 93.20, 91.01, 90.99, 90.94, 90.89, 86.72, 86.60, 83.92, 83.43, 83.36, 71.53, 71.49, 37.31, 37.25, 26.38, 26.35, 24.55, 19.47, 19.45.

(Z/E)((3-hydroxyoxetan-3-yl)ethynyl)furan-2-carbaldehyde Oxime FR-99:

[0220] ##STR00092##

[0221] To a degassed solution of (E/Z)-5-bromofuran-2-carbaldehyde oxime 1 (80 mg, 0.421 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (97.31 mg, 0.084 mmol, 0.2 equiv) and Cul (32.08 mg, 0.168 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne (3-ethynyloxetan-3-ol 8, 0.505 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 hour at 100° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/P 2:3) to afford the desired coupled oxime a(Z/E)-5-((3-hydroxyoxetan-3-yl)ethynyl)furan-2-carbaldehyde oxime FR-99 as a white solid (70 mg, 80%). IR (neat) V.sub.max 753.11, 984.85, 1036.93, 1209.37, 1429.67, 2359.92, 3095.68. R.sub.f (50 % EA+P) 0.30. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97 (s, 1H), 7.41 (s, 0.3H), 7.30 (d, J= 3.6 Hz, 0.27H), 6.82 (d, J= 3.7 Hz, 0.27H), 6.76 (d, J= 3.6 Hz, 1H), 6.70 (d, J= 3.6 Hz, 1H), 4.91 - 4.87 (m, 2.7H), 4.76-4.70 (m, 2.7H). .sup.13C NMR (101 MHz, MeOD) δ 149.11, 146.35, 138.73, 136.81, 135.75, 117.55, 117.14, 112.01, 93.94, 93.82, 84.23, 84.21, 74.73, 66.50, 48.29, 48.08, 47.87, 47.66, 47.44, 47.23, 47.02. HRMS (ESI.sup.+) m/z calcd 208.06096 for C.sub.10H.sub.11NO.sub.4.sup.+found 208.060434.

(Z/E)(5-phenylpent-1-yn-1-yl)furan-2-carbaldehyde Oxime FR-66:

[0222] ##STR00093##

[0223] To a degassed solution of (E/Z)-4-bromofuran-2-carbaldehyde oxime 1 (100 mg, 0.526 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (121.64 mg, 0.105 mmol, 0.2 equiv) and Cul (40.1 mg, 0.210 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne (pent-4-yn-1-ylbenzene 9, 0.578 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 hour at 100° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/P 10%) to afford the desired coupled (Z/E)-4-(5-phenylpent-1-yn-1-yl)furan-2-carbaldehyde oxime FR-66 as a white solid (80 mg, 60%). R.sub.f (10% EA+P) 0.25; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 0.6H), 7.59 (d, J= 3.5 Hz, 1H), 7.42 -7.27 (m, 2H), 7.26-7.11 (m, 3H), 6.64 (s, 1H), 2.78 (td, J= 7.5, 2.7 Hz, 2H), 2.40 (td, J = 7.1, 2.2 Hz, 2H), 1.92 (p, J= 7.3 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 147.09, 146.48, 145.52, 141.61, 141.58, 139.86, 128.66, 128.65, 128.51, 126.08, 126.07, 120.82, 115.17, 110.84, 110.17, 92.60, 92.44, 77.48, 77.16, 76.84, 71.22, 70.98, 34.96, 34.95, 30.24, 30.21, 18.95.

(Z/E)(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)furan-2-carbaldehyde Oxime CV-59:

[0224] ##STR00094##

[0225] To a degassed solution of (Z/E)-5-bromofuran-2-carbaldehyde oxime (50 mg, 0.263 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/ 2 mL), Pd[PPh.sub.3].sub.4 (61 mg, 0.053 mmol, 0.20 equiv) and Cul (20 mg, 0.105 mmol, 0.40 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 2-(but-3-yn-1-yl)isoindoline-1,3-dione (63 mg, 0.316 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 h at 100° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 30%) to afford the desired coupled oxime (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)furan-2-carbaldehyde oxime CV-59 as a yellow solid (41 mg, 51%). Rf(50 % EA+PE) 0.63; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (s, 0.5H), 7.86 (tt, J = 5.4, 2.6 Hz, 2H), 7.76-7.69 (m, 2H), 7.42 (s, 0.5H), 7.35 (s, 0.5H), 6.57 (d, J= 3.5 Hz, 0.5H), 6.55 (d, J= 3.5 Hz, 0.5H), 6.49 (d, J= 3.5 Hz, 0.5H), 3.96 (q, J= 7.0 Hz, 2H), 2.87 (q, J= 7.0 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.13, 147.25, 139.96, 134.29, 134.27, 132.08, 123.58, 119.59, 117.17, 116.38, 113.23, 92.48, 92.39, 72.58, 72.53, 36.35, 19.67.

(Z/E)(4-(1,3-dioxoisoindolin-2-yl)butyl)furan-2-carbaldehyde Oxime CV-60:

[0226] ##STR00095##

[0227] To a degassed solution of (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)furan-2-carbaldehyde oxime CV-59 (29 mg, 0.094 mmol, 1 equiv) in EtOAc/MeOH (4 mL/ 2 mL), Pd/C (12 mg (10%w), 0.0094 mmol, 0.10 equiv) was added. After degassing the reaction mixture for 5 min at room temperature, the mixture is stirred under H.sub.2 pressure for 2h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative chromatography (EtOAc/PE 50%); to afford the desired hydrogenated (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)butyl)furan-2-carbaldehyde oxime CV-60 as a white solid (26 mg, 90%). R.sub.f (50% EA+PE) 0.63; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (s, 1H), 7.84 (dd, J = 5.7, 2.8 Hz, 2H), 7.71 (d, J= 2.8 Hz, 2.5H), 7.37 -7.32 (m, 0.5H), 6.49 (d, J= 3.3 Hz, 0.5H), 6.18 (s, 0.5H), 6.08 (d, J= 3.3 Hz, 0.5H), 3.77 -3.67 (m, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.78 -1.66 (m, 4H)..sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.58, 158.31, 145.67, 134.09, 134.05, 132.21, 123.38, 123.36, 114.35, 107.62, 37.66, 28.12, 27.75, 25.25.

(Z/E)(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)thiophene-2-carbaldehyde oxime CV-65:

[0228] ##STR00096##

[0229] To a degassed solution of (Z/E)-5-bromothiophene-2-carbaldehyde oxime (50 mg, 0.243 mmol, 1 equiv) in DM (8 mL) Pd[PPh.sub.3].sub.4 (14 mg, 0.012 mmol, 0.05 equiv), Cul (2 mg, 0.012 mmol, 0.05 equiv) and Et.sub.3N (101 .Math.L, 0.728 mmol, 3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 2-(but-3-yn-1-yl)isoindoline-1,3-dione (58 mg, 0.291 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 15 min at 120° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 15%) to afford the desired coupled oxime (Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)thiophene-2-carbaldehyde oxime CV-65 as a yellow solid (58 mg, 74%). R.sub.f (50 % EA+PE) 0.57; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (ddd, J = 5.4, 3.2, 1.0 Hz, 2H), 7.77 -7.68 (m, 3H), 7.35 (d, J = 4.2 Hz, 0.5H), 7.21 (d, J = 3.9 Hz, 0.5H), 7.05 (d, J = 3.8 Hz, 1H), 6.98 (s, 0.5H), 3.96 (td, J = 7.1, 4.7 Hz, 2H), 2.86 (q, J = 7.2 Hz, 2H.sup.13C NMR (101 MHz, CDCl.sub.3) δ 168.19, 144.69, 136.08, 134.26, 132.11, 129.30, 123.57, 123.55, 93.31, 92.23, 75.67, 36.56, 31.07, 19.95.

Example 2: In Vitro Reactivation of Human Acetylcholinesterase (hAChE) by Compounds of the Invention

[0230] Compounds NM-27, 28, 29 and 34 and FR-152 of the invention were tested for their reactivation properties of hAChE inhibited by O-ethyl S—[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun, sarin or paraoxon. 2-PAM (pralidoxime or 2-[(E)-(hydroxyimino)methyl]-1-methylpyridinium) and Hl6 (asoxime chloride or [1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl-oxoazanium dichloride) were used as comparative compounds.

[0231] Inhibition of hAChE by OPNAs. Recombinant hAChE was produced and purified as previously described (see reference https://www.ncbi.nlm.nih.gov/pubmed/31132435). VX, sarin and tabun have been supplied by DGA maîtrise NRBC (Vert le Petit, France). Stock solutions of OPNA at 5 mM in isopropanol were used to inhibit the purified hAChE as previously described [Carletti, E. et al. 2008]. Briefly, a ten-fold excess of OPNA was used to perform the inhibition of hAChE in a sodium phosphate buffer (100 mM, pH 7.4, 0.1% BSA) at 25° C. Complete inhibition of hAChE was monitored by measuring the residual activity with a modified Ellman assay as previously described [Ellman, G.L., et al. 1961] and excess of OPNA were removed by using a desalting PD-10 column (GE Healthcare).

[0232] IC.sub.50 measurements. Compounds were dissolved in water to make 40 mM stock solutions. Recombinant hAChE activity was measured spectrophotometrically at 25° C., monitoring the absorbance at 412 nm, in 1 mL of Ellman’s buffer (0.5 mM DTNB, 0.1% BSA, 0.1 M phosphate, pH 7.4), in the presence of appropriate oxime concentrations. Measurements were performed at least in duplicate for each concentration tested. The oxime concentration producing 50% inhibition was determined by nonlinear fitting with ProFit (Quantumsoft) using the standard IC 50 equation: % activity = 100×lC50/ (IC50+ [Ox]).

[0233] Reactivation of hAChE inhibited by OPNAs. The ability of the compounds to reactivate OP-inhibited hAChE were assessed with a modified Ellman assay using a microplate reader (SPARK 10 M, Tecan) and a continuous method described previously [ Kitz, R.J., et al. 1965, Worek, F., et al., 2004] with minor modifications. Briefly, the desired oximes concentrations to be tested were dispensed in a 96-well flat-bottomed polystyrene microplate containing 0.1% BSA phosphate buffer and DTNB. At t=0, OP-inhibited hAChE and acetylthiocholine (ATCh) diluted in 0.1% BSA phosphate buffer were injected in each well containing oximes using the built-in injectors of the microplate reader to a final volume of 200 pL. ATCh hydrolysis was continuously monitored over 30 minutes and the increase of absorbance at 412 nm recorded every 10 seconds at 25° C. Activities were individually corrected for oxime-induced hydrolysis of ATCh. Reactivation of OP-inhibited hAChE by oximes proceeds according to scheme 1 and kinetics of oximes reactivation were determined as previously described [ Worek, F., et al., 2004]. For each oxime concentration, the apparent reactivation rate, k.sub.obs, the dissociation constant, K.sub.D and the reactivation rate constant, k.sub.r, were calculated by nonlinear fitting with ProFit (Quantumsoft) using the standard oxime-concentration-dependent reactivation equation (1):

##STR00097##

[00001]$\begin{array}{cc}{k}_{obs}=\frac{k_r\left[OX\right]}{K_D+\left[OX\right]}& \text{­­­Eq (1):}\end{array}$

[0234] When [OX] << K.sub.D, Eq (1) simplifies to Eq (2):

[00002]$\begin{array}{cc}{k}_{obs}=\left(\frac{k_r}{K_D}\right)\left[OX\right]& \text{­­­Eq (2) :}\end{array}$

[0235] The second order reactivation rate constant k.sub.r2, describing the specific reactivity can be derived from Eq (2).

[00003]$\begin{array}{cc}{k}_{r2}=\frac{k_r}{K_D}& \text{­­­Eq (3):}\end{array}$

[0236] For the continuous method of recording OP-inhibited hAChE reactivation by oximes, the velocity of substrate hydrolysis (v) is proportional to the concentration of the reactivated hAChE and is expressed and derived as equation 4 and 5 respectively. v.sub.t is the velocity at time t and v.sub.0 represents the maximum velocity. Equation 5 was used to determine the k.sub.obs by non-linear regression analysis for each individual oxime concentration with ProFit (Quantumsoft).

[00004]$\begin{array}{cc}{v}_t=v_0\left(1-e^{-k_{obs}t}\right)& \text{­­­Eq (4) :}\end{array}$

[00005]$\begin{array}{cc}-d\left[S\right]={\displaystyle {\int }_0^{t}vdt=v_{0}t+\frac{v_0}{k_{obs}}}\left(e^{-k_{obs}t}-1\right)& \text{­­­Eq (5) :}\end{array}$

[0237] The results are as follows:

TABLE-US-00001 Reactivation of OP-inhibited human hAChE by oximes 2-PAM, Hl-6, NMs and FR-152 OP Oximes k.sub.r (min.sup.-1) K.sub.D (.Math.M) k.sub.r2 (mM.sup.-1.min.sup.-1) VX 2-PAM 0.2 ± 0.01 26 ± 7 7 Hl-6 0.4 ± 0.02 19 ± 4 20 NM27 0 0 0 NM28 0 0 0 NM29 0.08 ± 0.002 8 ± 0.6 10 NM34 0.09 ± 0.002 20 ± 2 4 FR-152 0.14 ± 0.003 7 ± 0.8 18 Sarin 2-PAM 0.3 ± 0.02 25 ± 7 11 Hl-6 0.8 ± 0.06 57 ± 11 13 NM27 0 0 0 NM28 0 0 0 NM29 0.1 ± 0.003 69 ± 26 1.4 NM34 0 0 0 FR-152 0.14 ± 0.005 16 ± 2 8.5 Tabun 2-PAM 0.5 ± 0.2 211 ± 113 2 Hl-6 0 0 0 NM27 0 0 0 NM28 0 0 0 NM29 0 0 0 NM34 0 0 0 FR-152 0 0 0 Paraoxon 2-PAM 0.07 ± 0.02 68 ± 16 1 Hl-6 0.8 ± 0.06 290 ± 70 0.4 NM27 0 0 0 NM28 0 0 0 NM29 0.1 ± 0.04 12 ± 2 8 NM34 0.2 ± 0.034 10 ± 1 20 FR-152 / / 0.09

TABLE-US-00002 IC50 for hAChE of oximes: 2-PAM, Hl-6, NMs and FR-152 Oxime IC50 (.Math.M) 2-PAM 580 ± 28 Hl-6 82 ± 6 NM27 Nd* NM28 Nd* NM29 360 ± 43 NM34 2359 ± 537 FR-152 54 ± 4 *Nd: not determined, due to low solubility when the concentration is higher than 500 .Math.M

[0238] These results showed that the compounds of the invention have a broad spectrum of reactivation of OPNA-inhibited AChE: particularly they show an increased efficacy for VX and paraoxon, and a good potency against sarin.