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THIAZOLOXIME AND OXAZOLOXIME DERIVATIVES AS REACTIVATORS OF ORGANOPHOSPHOROUS NERVE AGENT (OPNA)-INHIBITED HUMAN ACETYLCHOLINESTERASE FOR THE TREATMENT OF NERVOUS AND/OR RESPIRATORY FAILURE AFTER INTOXICATION WITH OPNA

20230203024 · 2023-06-29

    Inventors

    Cpc classification

    International classification

    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 compounds of formula (I) for use in a method of medical treatment, preferably in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organo-phosphorous nerve agent (OPNA); in the treatment of neurological diseases such as Alzheimer's disease; and/or in the treatment of cancer. The compounds act as reactivators of OPNA-inhibited hAChE (human acetylcholinesterase).

    ##STR00001##

    Claims

    1. Compound which is chosen from compounds of formula (I) and their pharmaceutically acceptable salts: ##STR00125## wherein: X is O or S; 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 4; and R is an alkyl group, a hydroxyalkyl group, an alkyl group ended by a radical —C(═O)—O—CH3, an aryl, a heteroaryl, a cycloalkyl, a heterocyclyl, a biomolecule, 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 cycloalkyl.

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

    3. Compound according to claim 1, wherein R is a heteroaryl or a group —N(R1)(R2), wherein R1 and R2 are each independently H or a heteroaryl.

    4. Compound according to claim 1, wherein the heteroaryl group is a pyridine group, or a quinoline group, or a pyrimidine group such.

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

    6. Compound according to claim 1, wherein the compound is chosen from: compounds of formula (II) and their pharmaceutically acceptable salts: ##STR00126## wherein X, Y, Z, n and R1 are as in claim 1; compounds of formula (III) and their pharmaceutically acceptable salts: ##STR00127## wherein X, Y, Z, n and R1 are as in claim 1; compounds of formula (IV) and their pharmaceutically acceptable salts: ##STR00128## wherein X, Y, Z, n and R1 are as in claim 1; and compounds of formula (V) and their pharmaceutically acceptable salts: ##STR00129## wherein X, Y, Z, n and R1 are as in claim 1.

    7. Compound according to claim 6, wherein the compound is chosen from: compounds of formula (II) and their pharmaceutically acceptable salts, wherein: X is S; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2; and R is an alkyl, a hydroxyalkyl group, an alkyl group ended by a radical —C(═O)—O—CH3, an aryl, a heteroaryl or a group —N(R1)(R2), or R1 is H and R2 is a heteroaryl; or X is O; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2; and R is a heteroaryl; compounds of formula (III) and their pharmaceutically acceptable salts, wherein: X is S; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2, and R is a heteroaryl or a group —N(R1)(R2), or R1 is H and R2 is a heteroaryl; or X is O; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2, and R is a heteroaryl; compounds of formula (IV) and their pharmaceutically acceptable salts, wherein X is S; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2, and R is a heteroaryl; and compounds of formula (V) and their pharmaceutically acceptable salts, wherein: X is S; Y is —CH.sub.2—CH.sub.2— or —C≡C—, n is 0, 1 or 2, and R is an aryl or a heteroaryl.

    8. Compound according to claim 1, wherein the compound is chosen from: ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##

    9. Compound according to claim 1, wherein the compound is chosen from ##STR00139## ##STR00140## ##STR00141## ##STR00142##

    10. A process for preparing a compound of formula (I) of claim 1, which comprises the following steps: a Sonogashira coupling reaction between a terminal alkyne ##STR00143##  and an isomer of unprotected bromo-oxime-1,3-thiazole or an isomer of unprotected bromo-oxime-1,3-oxazole to obtain the conjugate ##STR00144##  of formula (I); optionally, said conjugate is then submitted to hydrogenation to provide the corresponding alkene, and finally the hybrid reactivator ##STR00145##  of formula (I).

    11. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1, and at least one pharmaceutically acceptable support.

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

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

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

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

    16. The compound according to claim 2, wherein the salt is a chlorhydrate salt.

    17. The compound according to claim 4, wherein the pyridine group is 2-, 3- or 4-pyridino, the quinoline group is 4-quinolinyl, and the pyrimidine group is a pyrimidin-2-yl.

    18. The method according to claim 14, wherein the neurological disease is Alzheimer's disease.

    Description

    EXAMPLES

    Example 1: Synthesis of Compounds of the Invention

    2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-55

    [0152] ##STR00037##

    2-bromothiazole-4-carbaldehyde oxime (2)

    [0153] ##STR00038##

    [0154] A solution of commercially available 2-bromothiazole-4-carbaldehyde 1 (200 mg, 1.04 mmol, 1 equiv), hydroxylamine hydrochloride (144 mg, 2.04 mmol, 2 equiv), and NaOAc (256 mg, 3.12 mmol, 3 equiv) in EtOH (6 mL) was stirred at room temperature for 12 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 cis/trans isomers (1/0.56 ratio) of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 as off white solid (155 mg, 72%); R.sub.f (20% EtOAc/PE) 0.50; NMR (400 MHz, CDCl.sub.3): δ ppm 8.37 (s, 0.56 H), 8.18 (s, 1H), 7.73 (s, 0.56 H), 7.49 (s, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 148.78, 145.45, 143.45, 140.09, 137.26, 135.63, 129.52, 121.89.

    2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime 4

    [0155] ##STR00039##

    [0156] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (132 mg, 0.637 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.087 mmol, 0.15 equiv) and CuI (33 mg, 0.173 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine 3 (60 mg, 0.582 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at 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 50:50) to afford cis/trans isomers (7.5/2.5 ratio) of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime 4 as a light yellowish solid (30 mg, 30%); IR (neat): v.sub.max 3081, 2784, 1478, 1405, 1281, 1104, 969, 778, 744, 696, 635, 569, 522, 486 cm.sup.−1; R.sub.f (40% EtOAc/PE) 0.30; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.8N.sub.3OS.sup.+ 230.038586 found 230.03829; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.88-8.81 (m, 1H), 8.64 (dt, J=9.0, 4.4 Hz, 1H), 8.52 (s, 0.75H), 8.27 (d, J=8.8 Hz, 0.25H), 7.91 (tt, J=7.7, 1.8 Hz, 1H), 7.81 (s, 0.75H), 7.65 (s, 0.25H), 7.40-7.33 (m, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 152.36, 152.32, 149.81, 149.78, 149.75, 149.36, 148.42, 146.66, 146.08, 140.26, 139.58, 139.07, 139.04, 127.15, 123.31, 119.70, 118.58, 118.53, 90.93, 90.88, 84.95, 84.70.

    2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime hydrochloride NM-46

    [0157] ##STR00040##

    [0158] To a solution of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime 4 (12 mg, 0.052 mmol) in water (2 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 (3/2 ratio) of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime hydrochloride NM-46 as a pale yellow solid (12 mg, 86%); IR (neat): v.sub.max 3075, 2359, 1530, 955, 888, 798, 761, 667 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.9ClN.sub.3OS.sup.+ 266.014937 found 266.013282; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ ppm 12.22 (s, 0.4H), 11.50 (s, 0.6H), 9.22 (s, 1H), 8.79 (s, 1H), 8.74 (s, 0.4H), 8.25 (s, 0.6H), 8.16 (s, 0.6H), 8.13-8.10 (m, 1H), 7.80 (m, 1H), 7.75 (s, 0.4H); .sup.13C NMR (126 MHz, DMSO-d.sub.6): δ ppm 161.94, 160.30, 149.85, 147.73, 145.70, 144.95, 143.28, 139.85, 138.24, 134.07, 131.23, 130.98, 127.63, 125.65, 123.74, 123.56, 121.08.

    2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 5

    [0159] ##STR00041##

    [0160] To a solution of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-4-carbaldehyde oxime 4 (20 mg, 0.087 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 1 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc/PE, 70:30) to afford cis/trans isomers (6/4 ratio) of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 5 as a white solid (17 mg, 83%); R.sub.f(50% EtOAc/PE) 0.20; IR (neat): v.sub.max 2921, 2850, 2360, 1731, 1579, 1421, 1123, 969, 913, 794, 704 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.068309; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.50 (bs, 2H), 8.22 (s, 0.4H), 8.12 (s, 0.6H), 7.74 (s, 0.6H), 7.54 (d, J=7.8 Hz, 1H), 7.37 (s, 0.4H), 7.27-7.18 (m, 1H), 3.40-3.28 (m, 2H), 3.18-3.14 (m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ 170.08, 168.13, 149.73, 149.70, 148.64, 147.83, 147.74, 144.21, 136.23, 135.64, 135.44, 124.16, 123.61, 118.38, 34.63, 34.25, 32.84, 32.71.

    2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-55

    [0161] ##STR00042##

    [0162] To a solution of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 5 (14 mg, 0.06 mmol) in CH.sub.2Cl.sub.2 (3 ml) was added 2N HCl (0.1 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 (6.5/3.5 ratio) of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-55 as a light brown solid (12 mg, 74%); IR (neat): v.sub.max 3056, 2360, 1632, 1556, 1470, 1263, 984, 926, 775, 679 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.94 (s, 0.65H), 8.90 (s, 0.35H), 8.86-8.74 (m, 1H), 8.67 (t, J=9.1 Hz, 1H), 8.55 (s, 0.35H), 8.22 (s, 1.7H), 7.96 (s, 0.65H), 7.65 (s, 0.35H), 3.75-3.59 (m, 2H), 3.48 (t, J=7.3 Hz, 2H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 169.64, 147.20, 141.36, 141.31, 140.73, 140.26, 139.75, 139.59, 136.98, 127.21, 127.13, 125.72, 31.52, 31.35, 31.32.

    2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime hydrogen chloride NM-131

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime hydrogen chloride NM-132

    [0163] ##STR00043##

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime 7

    [0164] ##STR00044##

    [0165] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (104 mg, 0.502 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (79.4 mg, 0.068 mmol, 0.15 equiv) and CuI (26 mg, 0.137 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-(but-3-yn-1-yl)pyridine 6 (60 mg, 0.458 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 70:30) to afford cis/trans isomers (8/2 ratio) of (E)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime 7 as an off white solid (75 mg, 64%); R.sub.f (40% EtOAc/PE) 0.50; IR (neat): v.sub.max 3069, 2689, 2234, 1580, 1447, 1428, 1205, 1032, 969, 798, 772, 709, 643 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.12N.sub.3OS.sup.+ 258.069559 found 258.067414; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.50 (bs, 3H), 7.84 (d, J=7.8 Hz, 1H), 7.72 (s, 0.2H) 7.55 (s, 0.8H), 7.44 (bs, 1H), 3.00 (t, J=6.9 Hz, 2H), 2.86 (t, J=6.9 Hz, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 150.27, 149.12, 148.20, 146.75, 140.21, 138.48, 127.49, 96.98, 96.75, 75.45, 32.10, 21.79.

    [0166] As a note, 3-(but-3-yn-1-yl)pyridine 6 may be described as in Galli et al, Chem Med Chem 2008, 3, 771-779; or Joseph et al, J. Org. Chem. 2013, 78, 1670-1676.

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime hydrochloride NM-131

    [0167] ##STR00045##

    [0168] To a solution of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime 7 (16 mg, 0.062 mmol) was added 2N HCl (2 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 (2×4 mL). The solid was dried under vacuum to give cis/trans mixture (6.5/3.5 ratio) of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime hydrochloride NM-131 as a light brown solid (18 mg, 98%); IR (neat): v.sub.max 3037, 2361, 1632, 1544, 1463, 979, 912, 792, 771, 678, 618 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.13ClN.sub.3OS.sup.+ 294.046237 found 294.04566; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.91-8.61 (m, 4H), 8.08 (s, 1H), 7.64-7.56 (m, 0.35H), 7.23-6.91 (m, 0.65H), 3.32-3.02 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 162.40, 149.17, 148.96, 143.42, 143.13, 142.22, 142.13, 141.53, 141.35, 140.90, 129.11, 128.90, 127.12, 122.27, 42.42, 41.89, 31.74, 31.65.

    2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime 8

    [0169] ##STR00046##

    [0170] To a solution of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-4-carbaldehyde oxime 7 (20 mg, 0.077 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 2 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad and concentrated under reduced pressure. The crude was purified by preparative TLC (EtOAc/PE, 1:1) to afford cis/trans isomers (1/1 ratio) of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime 8 as white solid (17.6 mg, 83%); R.sub.f(60% EtOAc/PE) 0.20; IR (neat): v.sub.max 3063, 2922, 2854, 2360, 2340, 1579, 1462, 1424, 1098, 967, 924, 796, 781, 706, 642 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 262.100860 found 260.100806; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.34-8.22 (m, 2.5H), 8.02 (s, 0.5H) 7.60 (d, J=7.8 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.25 (dd, J=7.4, 4.9 Hz, 1H), 2.96 (t, J=7.4 Hz, 2H), 2.62 (t, J=6.7 Hz, 2H), 1.80-1.50 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 173.92, 171.67, 150.04, 147.55, 146.20, 144.27, 140.67, 139.78, 138.28, 125.88, 125.21, 119.08, 33.57, 33.33, 33.30, 33.28, 31.44, 30.49, 30.44.

    2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime hydrochloride NM-132

    [0171] ##STR00047##

    [0172] To a solution of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime 8 (10 mg, 0.06 mmol) was added 2N HCl (2 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 mixture (7.5/2.5 ratio) of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime hydrochloride NM-132 as a light brown solid (11 mg, 97.3%); IR (neat): v.sub.max 3049, 1629, 1612, 1552, 1466, 1381, 1261, 991, 793, 680 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 262.100860 found 260.1004291; .sup.1H NMR (500 MHz, CD.sub.3OD): δ ppm 9.02-8.50 (m, 3.5H), 8.37-78.94 (m, J=2.25 H), 7.67 (s, 0.25H) 3.37 (s, 2H), 3.03 (s, 2H), 2.18-1.76 (m, 4H); .sup.13C NMR (126 MHz, CD.sub.3OD): δ ppm 173.92, 171.67, 150.04, 147.55, 146.20, 144.27, 140.67, 139.78, 138.28, 125.88, 125.21, 119.08, 33.57, 33.33, 33.30, 33.28, 31.44, 30.49, 30.44.

    2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-109

    [0173] ##STR00048##

    2-(pyridin-2-ylethynyl)thiazole-4-carbaldehyde oxime 10

    [0174] ##STR00049##

    [0175] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (132 mg, 0.637 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.087 mmol, 0.15 equiv) and CuI (33 mg, 0.173 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 2-ethynylpyridine 9 (60 mg, 0.582 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 50:50) to afford (E)-2-(pyridin-2-ylethynyl)thiazole-4-carbaldehyde oxime 10 as an off white solid (40.5 mg, 35.7%); R.sub.f(40% EtOAc/PE) 0.25; IR (neat): v.sub.max 3055, 2850, 1581, 1465, 1435, 1275, 1110, 996, 979, 769, 720, 692, 537 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.8N.sub.3OS.sup.+ 230.038259 found 230.038791; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.71 (s, 1H), 8.66-8.63 (m, 1H), 7.95 (td, J=7.8, 1.7 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.53 (ddd, J=7.7, 5.0, 1.1 Hz, 1H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 151.25, 147.71, 147.57, 142.28, 140.18, 138.79, 129.43, 128.97, 125.97, 93.08, 81.94.

    2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime 11

    [0176] ##STR00050##

    [0177] To a solution of (E)-2-(pyridin-2-ylethynyl)thiazole-4-carbaldehyde oxime 10 (40 mg, 0.087 mmol) in 4:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (20 mg) at room temperature under Argon atmosphere and stirred the mixture for 2 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, 70:30) to afford trans-cis isomers (6/4 ratio) of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime 11 as pale yellow solid (35 mg, 86.2%); R.sub.f (50% EtOAc/PE) 0.20; IR (neat): v.sub.max 2920, 2851, 1592, 1569, 1476, 1435, 1174, 1117, 975, 922, 748, 721, 694, 539 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.069476. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.52-8.50 (m, 1H), 8.38 (s, 0.5H) 8.13 (s, 0.5H), 7.86-7.78 (m, 1H), 7.58-7.55 (m, 1H), 7.41-7.31 (m, 2H), 3.51-3.47 (m, 2H), 3.35-3.30 (m, 2H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 170.79, 168.58, 159.02, 148.71, 147.93, 147.78, 142.91, 139.32, 138.22, 138.06, 131.79, 130.74, 124.67, 123.94, 123.86, 122.17, 122.12, 117.83, 36.58, 36.50, 32.17, 31.95.

    2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-109

    [0178] ##STR00051##

    [0179] To a solution of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-4-carbaldehyde oxime 11 (25 mg, 0.06 mmol) in CH.sub.2Cl.sub.2 (3 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 (2×3 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 NM-109 as a light brown solid (20 mg, 71%); IR (neat): v.sub.max 3055, 2922, 1617, 1435, 1189, 1117, 996, 752, 718, 692, 536 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.0696 found 234.0697; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.82-8.79 (m, 1H), 8.61-8.56 (m, 1H), 8.47 (s, 0.3H), 8.17 (s, 0.7H), 8.09 (dd, J=8.1, 4.9 Hz, 1H), 8.00 (d, J=6.4 Hz, 1H), 7.80 (s, 0.7H), 7.59 (s, 0.3H), 3.68 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 168.63, 156.79, 156.41, 148.23, 148.19, 145.46, 142.93, 142.49, 142.41, 139.86, 128.93, 126.90, 126.67, 126.60, 121.13, 33.41, 33.27, 31.72.

    (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-130

    [0180] ##STR00052##

    2-(pyridin-4-ylethynyl)thiazole-4-carbaldehyde oxime 13

    [0181] ##STR00053##

    [0182] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (132 mg, 0.637 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.087 mmol, 0.15 equiv) and CuI (33 mg, 0.173 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 4-ethynylpyridine 12 (60 mg, 0.582 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 50:50) to afford cis/trans isomer (6/4 ratio) of (E/Z)-2-(pyridin-4-ylethynyl)thiazole-4-carbaldehyde oxime 13 as off white solid (30 mg, 30%); R.sub.f (50% EtOAc/PE) 0.25; IR (neat): v.sub.max 3062, 2715, 2359, 1569, 1497, 1405, 1322, 1099, 994, 978, 925, 820, 701, 571, 542 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.8N.sub.3OS.sup.+ 230.038259 found 230.038473; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.27 (s, 0.6H), 11.56 (s, 0.4H), 8.73-8.71 (m, 2.6H), 8.24 (s, 0.4H), 8.14 (s, 0.4H), 7.75 (s, 0.6H), 7.69-7.62 (m, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 150.19, 146.61, 146.01, 145.21, 142.64, 139.00, 131.55, 131.45, 128.84, 128.73, 128.62, 128.19, 121.90, 90.67, 90.63, 85.50, 85.35.

    2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime 14

    [0183] ##STR00054##

    [0184] To a solution of (E/Z)-2-(pyridin-4-ylethynyl)thiazole-4-carbaldehyde oxime 13 (20 mg, 0.087 mmol) in 1:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (20 mg) at room temperature under Argon atmosphere and stirred the mixture for 1 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, 80:20) to afford cis/trans isomers (5.5/4.5 ratio) of (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime 14 as off white solid (15 mg, 74%); R.sub.f (100% EtOAc) 0.25; IR (neat) v.sub.max 2922, 2852, 2359, 1605, 1419, 1189, 1111, 969, 920, 853, 805, 751, 721, 540, 502 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.069628; .sup.1HNMR (400 MHz, CD.sub.3OD): δ ppm 8.31 (bs, 2H), 8.28 (s, 0.45H), 8.02 (s, 0.55H), 7.48 (s, 0.55H), 7.47 (s, 0.45H), 7.22 (m, 2H), 3.28 (td, J=7.6, 3.1 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 171.98, 169.73, 152.18, 150.19, 150.02, 150.02, 146.36, 144.27, 140.70, 126.09, 125.73, 119.32, 35.80, 35.76, 34.19, 33.93.

    2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-130

    [0185] ##STR00055##

    [0186] To a solution of (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime 14 (15 mg, 0.064 mmol) was added 2N HCl (2 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 (7/3 ratio) of (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-130 as a light brown solid (16.5 mg, 95%); IR (neat) v.sub.max 3298, 3107, 2989, 2599, 1635, 1304, 1436, 1011, 888, 849, 809, 785, 542 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.069336; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.82 (m, 2H), 8.56 (s, 0.3H), 8.21 (s, 0.7H), 8.11 (m, 2H), 7.97 (s, 0.7H), 7.65 (s, 0.3H), 3.82-3.63 (m, 2H), 3.57 (m, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 169.68, 162.07, 161.45, 141.16, 141.03, 139.55, 139.53, 136.84, 127.51, 125.85, 120.39, 120.32, 34.57, 34.52, 30.69, 30.35.

    2-(2-(pyridin-3-yl)ethyl)thiazole-5-carbaldehyde oxime hydrogen chloride NM-139

    [0187] ##STR00056##

    (E/Z)-2-bromothiazole-4-carbaldehyde oxime 16

    [0188] ##STR00057##

    [0189] A solution of commercially available 2-bromothiazole-5-carbaldehyde 15 (500 mg, 2.60 mmol, 1 equiv), hydroxylamine hydrochloride (361 mg, 5.19 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (640 mg, 7.80 mmol, 3 equiv) in EtOH (15 mL) was stirred at 80° C. for 12 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 cis/trans isomers (1/0.7 ratio) of (E/Z)-2-bromothiazole-5-carbaldehyde oxime 16 as off white solid (330 mg, 61.2%); R.sub.f (20% EtOAc/PE) 0.45; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.50 (s, 1H), 11.68 (s, 0.7H), 8.38 (s, 0.7H), 8.08 (s, 1H), 8.00 (s, 1H), 7.85 (s, 0.7H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 145.81, 143.85, 141.60, 141.28, 137.98, 136.72, 136.69, 129.34.

    2-(pyridin-3-ylethynyl)thiazole-5-carbaldehyde oxime 17

    [0190] ##STR00058##

    [0191] To a degassed solution of (E/Z)-2-bromothiazole-5-carbaldehyde oxime 16 (165.8 mg, 0.80 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (126.3 mg, 0.109 mmol, 0.15 equiv) and CuI (41.6 mg, 0.218 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine 3 (75 mg, 0.728 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at 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 50:50) to afford cis/trans isomers (9/1 ratio) of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-5-carbaldehyde oxime 17 as a pale yellow solid (55 mg, 33%); R.sub.f (50% EtOAc/PE) 0.25; IR (neat): v.sub.max 2665, 2358, 1482, 1410, 1266, 1212, 1110, 927, 889, 839, 805, 692, 625, 590 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.8N.sub.3OS.sup.+ 230.038259 found 230.037096; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.64 (s, 0.9H), 11.78 (s, 0.1H), 8.88 (s, 1H), 8.70 (s, 1H), 8.45 (s, 0.1H), 8.36 (s, 1H), 8.17-8.05 (m, 2H), 7.54 (dd, J=7.8, 4.7 Hz, 1H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 152.42, 150.69, 149.92, 147.63, 139.59, 138.00, 135.19, 127.30, 124.29, 92.69, 85.55.

    2-(2-(pyridin-3-yl)ethyl)thiazole-5-carbaldehyde oxime 18

    [0192] ##STR00059##

    [0193] To a solution of (E/Z)-2-(pyridin-3-ylethynyl)thiazole-5-carbaldehyde oxime 17 (25 mg, 0.109 mmol) in 1:1 ratio of MeOH/THF (5 mL) was added 10% Pd/C (20 mg) at room temperature under Argon atmosphere and stirred the mixture for 2 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad and concentrated under reduced pressure and the crude was purified by column chromatography (EtOAc/PE, 70:30) to afford cis/trans isomers (9/1 ratio) of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-5-carbaldehyde oxime 18 as white solid (23 mg, 90%); R.sub.f(100% EtOAc/PE) 0.25; IR (neat): v.sub.max 2996, 2348, 1578, 1480, 1416, 1187, 916, 884, 799, 704, 663, 609 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.070401; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.39 (bs, 2H), 8.23 (s, 0.1H), 8.00 (s, 0.9H), 7.75 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.36 (s, 1H), 3.37 (t, J=7.7 Hz, 2H), 3.17 (t, J=7.5 Hz, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 173.88, 148.78, 146.67, 144.99, 142.28, 140.93, 137.54, 137.03, 125.71, 33.29, 32.25.

    2-(2-(pyridin-3-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride NM-139

    [0194] ##STR00060##

    [0195] To a solution of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 18 (20 mg, 0.06 mmol) in 2N HCl (2 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 (2×4 mL). The solid was dried under vacuum to give cis/trans isomers (8/2 ratio) of (E/Z)-2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-139 as a light brown solid (22 mg, 95.2%); IR (neat): v.sub.max 3047, 1555, 1468, 1216, 994, 928, 799, 734, 679, 626 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.06959 found 234.069456; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.95 (bs, 1H), 8.82 (d, J=5.0 Hz, 1H), 8.69 (d, J=7.2 Hz, 1H), 8.47 (s, 0.8H), 8.32 (s, 0.2H), 8.17-8.05 (m, 1.2H), 7.98 (s, 0.8H), 3.81-3.63 (m, 2H), 3.56-3.41 (m, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 175.36, 148.62, 142.80, 141.65, 141.44, 141.29, 141.19, 141.01, 139.13, 138.08, 137.34, 128.71, 128.65, 128.52, 128.29, 33.15, 32.88, 32.67, 32.01.

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime hydrogen chloride NM-141

    2-(4-(pyridin-3-yl)butyl)thiazole-5-carbaldehyde oxime hydrogen chloride NM-143

    [0196] ##STR00061##

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime 19

    [0197] ##STR00062##

    [0198] To a degassed solution of (E/Z)-2-bromothiazole-5-carbaldehyde oxime 16 (173 mg, 0.835 mmol, 1.1 equiv) in THF/Et.sub.3N (9 mL/3 mL), Pd[PPh.sub.3].sub.4 (132 mg, 0.114 mmol, 0.15 equiv) and CuI (43.6 mg, 0.228 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-(but-3-yn-1-yl)pyridine 6 (100 mg, 0.763 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 100%) to afford cis/trans isomers (95/5 ratio) of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime 19 as an off white solid (90 mg, 46%); R.sub.f (100% EtOAc) 0.25; IR (neat): v.sub.max 3357, 3160, 2360, 2340, 2224, 1651, 1605, 1411, 1264, 1139, 791, 711, 624 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.12N.sub.3OS.sup.+ 258.069559 found 258.068945; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.45 (s, 0.95H), 11.64 (s, 0.5H), 8.77-8.28 (m, 2H), 8.20 (s, 1H), 8.01 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.44-7.32 (m, 1H), 2.91 (m, 4H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 151.17, 150.26, 148.25, 148.09, 148.09, 147.07, 138.00, 136.47, 126.15, 98.15, 75.42, 30.98, 21.02.

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime hydrochloride NM-141

    [0199] ##STR00063##

    [0200] To a solution of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime 19 (20 mg, 0.077 mmol) was added 2N HCl (2 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 (2×4 mL). The solid was dried under vacuum to give cis/trans mixture isomers (7.5/2.5 ratio) of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime hydrochloride NM-141 as a light brown solid (20.5 mg, 90%); IR (neat): v.sub.max 3004, 2555, 2360, 2341, 1633, 1558, 1263, 1156, 928, 802, 681 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.13ClN.sub.3OS.sup.+ 294.046237 found 294.046258; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.91 (bs, 1H), 8.78 (bs, 1H), 8.67 (d, J=7.3 Hz, 1H), 8.47 (s, 0.75H), 8.34 (s, 2.5H), 8.12 (bs, 1H), 7.28 (bs, 0.75H), 7.12 (bs, 0.25), 341-3.34 (m, 4H), 3.21 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 147.30, 147.24, 145.24, 141.26, 140.58, 139.99, 139.69, 138.01, 127.26, 118.15, 40.39, 40.35, 30.04.

    2-(4-(pyridin-3-yl)butyl)thiazole-5-carbaldehyde oxime 20

    [0201] ##STR00064##

    [0202] To a solution of (E/Z)-2-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-5-carbaldehyde oxime 19 (40 mg, 0.0155 mmol) in 4:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (40 mg) at room temperature under Argon atmosphere and stirred the mixture for 2 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad and concentrated under reduced pressure and the crude was purified by column chromatography (EtOAc, 100%) to afford cis/trans isomers (9.4/0.6 ratio) of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-5-carbaldehyde oxime 20 as white solid (35 mg, 86%); R.sub.f(100% EtOAc) 0.20; IR (neat): v.sub.max 2949, 1578, 1461, 1421, 1188, 1050, 1036, 924, 801, 708, 664, 643, 662 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 260.100860 found 262.101595; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.48-8.30 (m, 2H), 8.26 (s, 0.06H) 8.00 (s, 0.94H), 7.78 (s, 0.94H), 7.74 (s, 0.06H) 7.70 (d, J=7.9 Hz, 1H), 7.36 (dd, J=7.7, 4.9 Hz, 1H), 3.08 (t, J=7.4 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.89-1.82 (m, 2H), 1.78-1.70 (m, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 175.68, 148.63, 146.16, 144.88, 138.37, 137.61, 136.88, 125.52, 123.79, 31.91, 31.86, 30.09, 29.02.

    2-(4-(pyridin-3-yl)butyl)thiazole-4-carbaldehyde oxime hydrochloride NM-143

    [0203] ##STR00065##

    [0204] To a solution of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-5-carbaldehyde oxime 20 (30 mg, 0.06 mmol) was added 2N HCl (2.5 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 (2×5 mL). The solid was dried under vacuum to give cis/trans isomers (8/2 ratio) of (E/Z)-2-(4-(pyridin-3-yl)butyl)thiazole-5-carbaldehyde oxime hydrochloride NM-143 as a light brown solid (32 mg, 93.8%); IR (neat): v.sub.max 2934, 2360, 1555, 1468, 1219, 997, 930, 797, 734, 681 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 262.100860 found 262.101253; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.85 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 8.61 (d, J=7.7 Hz, 1H), 8.55 (s, 0.8H), 8.34 (s, 0.2H), 8.24 (s, 0.2H), 8.08-8.04 (m, 1H), 7.99 (s, 0.8H), 3.48-3.35 (m, 2H), 3.04-2.94 (m, 2H), 2.07-1.81 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 178.40, 178.08, 148.40, 144.05, 142.33, 140.48, 140.21, 136.80, 136.27, 136.23, 134.03, 128.50, 128.20, 32.82, 31.48, 30.80, 30.66, 30.62, 29.85, 29.79.

    5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime NM-152

    [0205] ##STR00066##

    2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime 22

    [0206] ##STR00067##

    [0207] To a degassed solution of (E/Z)-2-bromothiazole-5-carbaldehyde oxime 16 (69 mg, 0.333 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (53 mg, 0.045 mmol, 0.15 equiv) and CuI (17 mg, 0.0892 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 21 (60 mg, 0.305 mmol, 1.0 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/CH.sub.2Cl.sub.2, 10:90) to afford cis-trans isomers (94/6) of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime 22 as pale yellow solid (32 mg, 32.5%); R.sub.f (10% MeOH/CH.sub.2Cl.sub.2) 0.20; HRMS (ESI.sup.+): m/z calcd for C.sub.17H.sub.15N.sub.4OS.sup.+ 323.096109 found 323.095000; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.46 (s, 0.94H), 11.64 (s, 0.06H), 9.14 (s, 1H), 8.57 (d, J=6.8 Hz, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.38 (s, 0.06H), 8.20 (s, 0.94H), 8.01 (s, 0.94H), 7.98 (s, 0.06H), 7.96-7.86 (m, 2H), 7.71 (ddd, J=8.3, 5.6, 2.6 Hz, 1H), 7.02 (d, J=6.9 Hz, 0.94H), 6.79 (d, J=6.8 Hz, 0.06H), 3.92-3.80 (m, 2H), 3.03 (t, J=6.7 Hz, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 155.29, 150.95, 147.05, 144.08, 139.63, 137.94, 133.43, 126.86, 126.28, 123.25, 121.91, 117.37, 99.01, 96.24, 75.87, 41.47, 19.55.

    2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime hydrochloride NM-152

    [0208] ##STR00068##

    [0209] To a solution of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime 22 (20 mg, 0.062 mmol) was added 2N HCl (2 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 (2×4 mL). The solid was dried under vacuum to give cis-trans mixture of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime hydrochloride as a light brown solid NM-152 (20.5 mg, 92%); HRMS (ESI.sup.+): m/z calcd for C.sub.17H.sub.15N.sub.4OS.sup.+ 323.096109 found 323.0951581; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.59-8.31 (m, 2.5H), 8.26-8.05 (m, 0.5H), 8.03-7.81 (m, 2.5H), 7.80-7.59 (m, 1H), 7.44 (bs, 0.5H), 7.15-6.94 (m, 1H), 4.07 (s, 2H), 3.34 (d, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 156.39, 145.43, 144.72, 144.46, 142.32, 139.78, 137.88, 137.54, 136.18, 133.72, 133.58, 127.11, 126.85, 122.67, 122.33, 119.82, 119.68, 118.57, 117.07, 98.47, 98.43, 41.33, 41.29, 39.24, 39.19.

    2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-4-carbaldehyde hydrochloride NM-176

    [0210] ##STR00069##

    2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-4-carbaldehyde oxime 23

    [0211] ##STR00070##

    [0212] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (69 mg, 0.570 mmol, 1.1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (53 mg, 0.0778 mmol, 0.15 equiv) and CuI (17 mg, 0.155 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 15 (100 mg, 0.519 mmol, 1.0 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/CH.sub.2Cl.sub.2, 10:90) to afford cis-trans isomers (7.5/2.5) of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-5-carbaldehyde oxime 23 as a pale yellow solid (32 mg, 42%); R.sub.f (10% MeOH/CH.sub.2Cl.sub.2) 0.20; IR (neat): v.sub.max 3281, 3054, 2360, 2235, 1579, 974, 724 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.17H.sub.15N.sub.4OS.sup.+ 323.096109 found 323.0957321; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 12.17 (s, 0.75H), 11.45 (s, 0.25H), 8.52 (s, 0.75H), 8.44 (s, 0.75H), 8.22 (d, J=8.3 Hz, 1H), 8.15 (s, 0.25H), 7.92 (s, 0.25H), 7.81 (d, J=8.0 Hz, 1H), 7.69-7.58 (m, 2H), 7.53-7.39 (m, 2H), 6.62 (d, J=5.1 Hz, 1H), 3.63 (dd, J=12.7, 6.6 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ ppm 150.81, 150.15, 149.74, 148.60, 147.13, 145.68, 143.17, 139.55, 129.43, 129.23, 127.19, 124.55, 122.09, 120.39, 95.40, 75.19, 74.98, 41.15, 19.41, 19.37.

    2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-4-carbaldehyde oxime hydrochloride NM-176

    [0213] ##STR00071##

    [0214] To a solution of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-4-carbaldehyde oxime 23 (20 mg, 0.062 mmol) was added 2N HCl (2 mL) at room temperature and stirred for 20 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulted solid was washed with diethyl ether (2×4 mL). The solid was dried under vacuum to give cis-trans mixture of (E/Z)-2-(4-(quinolin-4-ylamino)but-1-ynyl)thiazole-4-carbaldehyde oxime hydrochloride NM-176 as a light brown solid (21 mg, 94%); IR (neat): v.sub.max 3186, 3098, 2828, 1608, 1592, 1564, 1447, 1350, 1219, 759 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.17H.sub.15N.sub.4OS.sup.+ 323.096109 found 323.0959331; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.53-8.37 (m, 2.25H), 8.18-7.80 (m, 2.75H), 7.73 (dd, J=17.0, 8.5 Hz, 1H), 7.64-7.49 (m, 0.5H), 7.45-7.22 (m, 0.5H), 7.12-6.95 (m, 1H), 4.09-3.90 (m, 2H), 3.23 (dt, J=16.4, 6.5 Hz, 1H), 3.13-3.00 (m, 1H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 156.59, 156.43, 142.15, 142.04, 141.98, 141.98, 141.94, 137.92, 137.88, 133.67, 133.67, 127.05, 127.01, 122.53, 122.46, 119.78, 117.07, 117.00, 98.33, 98.30, 41.28, 41.14, 19.12, 18.99.

    4-(2-(pyridin-3-yl)ethyl)thiazole-2-carbaldehyde oxime hydrochloride NM-171

    [0215] ##STR00072##

    4-bromothiazole-2-carbaldehyde oxime 25

    [0216] ##STR00073##

    [0217] A solution of commercially available 4-bromothiazole-2-carbaldehyde 24 (1 g, 5.20 mmol, 1 equiv), hydroxylamine hydrochloride (723 mg, 10.40 mmol, 2 equiv) and Na.sub.2CO.sub.3 (1.655 g, 15.61 mmol, 3 equiv) in 1:1 ratio of MeOH/H.sub.2O (20 mL) was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure and 30 mL of water was added. The mixture was extracted with EtOAc (2×30 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 2:8) to afford cis-trans isomers (1/0.66) of (E/Z)-4-bromothiazole-2-carbaldehyde oxime 25 as an off white solid (824 mg, 78%); R.sub.f (20% EtOAc/PE) 0.35; .sup.1H NMR (400 MHz, Acetone-d.sub.6): δ ppm 12.19 (s, 1H), 11.28 (s, 0.66H), 8.29 (d, J=0.8 Hz, 0.66H), 7.93 (d, J=0.8 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.65 (d, J=0.8 Hz, 0.66H); .sup.13C NMR (101 MHz, Acetone-d.sub.6): δ ppm 143.50, 139.97, 126.00, 125.10, 122.16, 118.46.

    4-(pyridin-3-ylethynyl)thiazole-2-carbaldehyde oxime 26

    [0218] ##STR00074##

    [0219] To a degassed solution of (E/Z)-4-bromothiazole-2-carbaldehyde oxime 25 (165.8 mg, 0.80 mmol, 1.1 equiv) in THF/Et.sub.3N (9 mL/3 mL), Pd[PPh.sub.3].sub.4 (126.3 mg, 0.109 mmol, 0.15 equiv) and CuI (41.6 mg, 0.109 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine 3 (75 mg, 0.728 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 50:50) to give cis-trans isomers (7/3, ratio) of (E/Z)-4-(pyridin-3-ylethynyl)thiazole-2-carbaldehyde oxime 26 as an off white solid (46 mg, 27.7%); R.sub.f (50% EtOAc/PE) 0.25; IR (neat): v.sub.max 3061, 2918, 1566, 1494, 1407, 1007, 799, 697, 639, 539 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.8N.sub.3OS.sup.+ 230.038259 found 230.039853; .sup.1H NMR (400 MHz, Acetone-d.sub.6): δ ppm 8.79 (s, 1H), 8.64 (dd, J=9.3, 8.0 Hz, 1H), 8.33 (d, J=0.8 Hz, 0.7H), 8.20 (d, J=0.9 Hz, 0.3H), 8.03-7.92 (m, 2H), 7.47 (dd, J=7.5, 5.2 Hz, 1H); .sup.13C NMR (101 MHz, Acetone-d.sub.6): δ ppm 162.24, 151.94, 149.33, 143.92, 143.83, 138.42, 137.26, 128.16, 124.98, 123.41, 119.30, 86.13, 85.35.

    2-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 27

    [0220] ##STR00075##

    [0221] To a solution of (E/Z)-4-(pyridin-3-ylethynyl)thiazole-2-carbaldehyde oxime 26 (20 mg, 0.087 mmol) in EtOAc (3 mL) was added 10% Pd/C (10 mg) at room temperature under Argon atmosphere and stirred the mixture for 1 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad, concentrated under reduced pressure followed by column chromatography (10% MeOH/CH.sub.2Cl.sub.2) to afford (E/Z)-4-(2-(pyridin-3-yl)ethyl)thiazole-4-carbaldehyde oxime 27 as an off white solid (17.3 mg, 85%). R.sub.f (100% EtOAc) 0.20. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.42-8.30 (m, 2H), 8.24 (d, J=1.0 Hz, 0.3H), 7.86 (d, J=1.0 Hz, 0.7H), 7.71-7.66 (m, 1H), 7.40-7.31 (m, 1.7H), 7.09-7.07 (m, 0.3H), 3.20-3.05 (m, 4H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 162.73, 155.94, 155.22, 154.62, 148.73, 148.61, 146.36, 146.13, 143.17, 139.68, 138.54, 137.47, 137.45, 136.99, 136.83, 123.73, 119.09, 115.04, 32.06, 32.02, 31.94, 31.90.

    4-(2-(pyridin-3-yl)ethyl)thiazole-2-carbaldehyde oxime hydrochloride NM-171

    [0222] ##STR00076##

    [0223] To a solution of (E/Z)-4-(2-(pyridin-3-yl)ethyl)thiazole-2-carbaldehyde oxime 27 (11 mg, 0.085 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 mixture of cis-trans isomers (1/1, ratio) of (E/Z)-4-(2-(pyridin-3-yl)ethyl)thiazole-2-carbaldehyde oxime hydrochloride NM-171 as a light brown solid (11.5 mg, 90.6%); HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.0696 found 234.0694; .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.93-8.69 (m, 2H), 8.61 (d, J=7.0 Hz, 1H), 8.14 (s, 0.5H), 8.08 (bs, 1H), 7.83 (s, 0.5H), 7.70-7.55 (m, 1H), 3.55-3.33 (m, 4H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 149.31, 147.19, 141.38, 141.27, 141.27, 141.14, 139.57, 138.88, 135.87, 132.44, 132.42, 131.73, 131.63, 128.67, 128.55, 127.21, 127.15, 121.58, 31.17, 31.14, 29.66, 29.08.

    2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime NM-168

    [0224] ##STR00077##

    Ethyl 2-(pyridin-3-ylethynyl)oxazole-4-carboxylate 29

    [0225] ##STR00078##

    [0226] To a degassed solution of ethyl 2-bromooxazole-4-carboxylate 28 (470 mg, 2.135 mmol, 1.1 equiv) in THF/Et.sub.3N (12 mL/4 mL), Pd[PPh.sub.3].sub.4 (336 mg, 0.290 mmol, 0.15 equiv) and CuI (110 mg, 0.577 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 3-ethynylpyridine 3 (200 mg, 1.941 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 ethyl 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carboxylate 29 as an off white solid (220 mg, 46.8%); R.sub.f(50% EtOAc/PE) 0.35; IR (neat): v.sub.max 3148, 2922, 2852, 2360, 2228, 1731, 1543, 1330, 1307, 1174, 1148, 1107, 812, 771, 702 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.10N.sub.2NaO.sub.3.sup.+ 265.058363 found 265.059171; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.85 (bs, 1H), 8.68 (bs, 1H), 8.28 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.37 (dd, J=7.5, 5.0 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 160.38, 152.74, 150.42, 146.63, 144.53, 139.17, 134.71, 89.04, 79.17, 77.34, 77.02, 76.71, 61.58, 14.26.

    Ethyl 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carboxylate 30

    [0227] ##STR00079##

    [0228] To a solution of ethyl 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carboxylate 29 (120 mg, 0.495 mmol) in MeOH (10 mL) was added 10% Pd/C (60 mg) at room temperature under Argon atmosphere and stirred the mixture for 12 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered through a small celite pad, concentrated under reduced pressure and purified by SiO.sub.2 column chromatography (EtOAc/PE, 70:30) ethyl 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carboxylate 30 as a light brown syrup (91 mg, 74.6%); R.sub.f(50% EtOAc+PE) 0.3; IR (neat): v.sub.max 3134, 3092, 2990, 1717, 1583, 1314, 1165, 1024, 780, 715 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.14N.sub.2NaO.sub.3.sup.+ 269.089663 found 269.089903; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.42 (bs, 2H), 8.12 (s, 1H), 7.50 (dd, J=6.2, 1.6 Hz, 1H), 7.21 (dd, J=7.7, 4.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.12 (bs, 4H), 1.36 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 164.16, 161.16, 149.72, 148.08, 143.73, 135.70, 135.12, 133.52, 123.49, 61.18, 30.09, 29.48, 14.28.

    2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime 32

    [0229] ##STR00080##

    [0230] To a solution of ethyl 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carboxylate 30 (80 mg, 0324 mmol, 1 equiv) in CH.sub.2Cl.sub.2 (4 mL) was added DIBAL-H (0.8 mL, 1M in THF, 0.809 mmol, 2.5 equiv) at −78° C. and stirred over 2 h at same temperature. The mixture was quenched with MeOH (2 mL) at −78° C. and concentrated under reduced pressure. The white aluminum salts were removed by filtered in CH.sub.2Cl.sub.2, concentrated under reduced pressure and purified by column chromatography to give 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde 31 as an off white solid (22 mg, 53.6% w.r.t SM, 30 mg SM recovered). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.92 (s, 1H), 8.50 (d, J=2.3 Hz, 2H), 8.19 (d, J=4.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.25 (dd, J=7.8, 4.2 Hz, 1H), 3.18 (s, 4H). To a solution of 2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde 31 (20 mg, 0.0989 mmol, 1 equiv) in EtOH (5 mL) was added hydroxylamine hydrochloride (13.7 mg, 0.1971 mmol, 2 equiv), NaOAc (24.34 mg, 2.429 mmol, 3 equiv) and refluxed for 16 h. After concentration under reduced pressure, the crude product was purified by SiO.sub.2 column chromatography (100% EtOAc) to afford cis-trans isomers of (8/2, ratio) of (E/Z)-2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime 32 as an off white solid (15.2 mg, 70.7%); R.sub.f (100% EtOAc) 0.35; HRMS (ESI.sup.+): m/z calcd for C.sub.11H.sub.12N.sub.3O.sub.2.sup.+ 218.092403 found 218.091853; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.51 (bs, 2H), 8.43 (s, 0.8H), 8.06 (s, 0.2H), 7.77 (s, 0.2H), 7.61-7.50 (m, 1.8H), 7.28-7.23 (m, 1H), 3.17 (bs, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 162.59, 149.53, 147.74, 143.02, 136.16, 135.52, 123.64, 30.07, 29.28.

    2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime hydrochloride NM-168

    [0231] ##STR00081##

    [0232] To a solution of ((E/Z)-2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime 32 (13.5 mg, 0.062 mmol) in CH.sub.2Cl.sub.2 (2 ml) was added 2N HCl (2 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 (E)-2-(2-(pyridin-3-yl)ethyl)oxazole-4-carbaldehyde oxime hydrochloride NM-168 as an off white solid (12.8 mg, 81.3%); .sup.1H NMR (400 MHz, CD.sub.3OD): δ ppm 8.88 (s, 1H), 8.77 (d, J=5.7 Hz, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.52 (s, 1H), 8.07 (dd, J=8.0, 5.8 Hz, 1H), 7.37 (s, 1H), 3.42 (t, J=7.0 Hz, 2H), 3.32-3.27 (m, 2H); .sup.13C NMR (101 MHz, CD.sub.3OD): δ ppm 162.42, 147.09, 143.08, 141.33, 141.23, 141.16, 139.44, 137.95, 127.03, 28.69, 27.33.

    (E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime hydrochloride-260

    [0233] ##STR00082##

    (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime

    [0234] ##STR00083##

    [0235] To a degassed solution of (E/Z)-4-bromothiazole-2-carbaldehyde oxime (150 mg, 0.724 mmol, 1 equiv) in DMF/Et.sub.3N (9 mL/3 mL), Pd[PPh.sub.3].sub.4 (167.6 mg, 0.144 mmol, 0.20 equiv) and CuI (55.18 mg, 0.289 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at r.t, 3-(but-3-yn-1-yl)pyridine 6 (113.9 mg, 0.869 mmol, 1 equiv) was added to the mixture and the reaction mixture was subjected to microwave irradiation at 100° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 70:30) to afford cis/trans isomers (5.5/4.5 ratio) of (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime as an off white solid (85 mg, 46%). R.sub.f (100% EtOAc) 0.30; IR (neat): v.sub.max 2831, 1684, 1481, 1436, 1181, 1118, 992, 719, 693, 536 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.12N.sub.3OS.sup.+ 258.069559 found 258.067707. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.87-8.43 (m, 2H), 8.31 (s, 0.55), 7.95 (s, 0.45H) 7.70-7.62 (m, 1H), 7.52 (s, 0.45H), 7.38-7.28 (m, 1H), 7.24 (s, 0.55), 3.02-2.89 (m, 2H), 2.81-2.68 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 161.87, 154.10, 149.47, 149.43, 147.00, 146.92, 144.38, 140.62, 137.86, 137.24, 137.18, 137.09, 136.66, 136.25, 132.11, 126.49, 125.88, 123.95, 122.59, 88.87, 88.75, 31.74, 29.70, 21.36, 21.30.

    (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime hydrochloride NM-259

    [0236] ##STR00084##

    [0237] To a solution of (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime (11 mg, 0.042 mmol) was added 2N aq.HCl (2 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 L). The solid was dried under vacuum to give cis/trans mixture (6/4 ratio) of (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime hydrochloride NM-259 as an off white solid (14 mg, 94%). IR (neat): v.sub.max 3071, 2985, 2360, 2340, 1156, 1395, 1043, 1002, 930, 908, 830, 727, 682, 514 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.12N.sub.3OS.sup.+ 258.069559 found 258.068295. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.98-8.91 (bs, 1H), 8.83-8.78 (m, 1H), 8.75-8.68 (m, 1H), 8.21 (s, 0.4H), 8.15-8.08 (m, 1H), 7.88 (s, 0.6H), 7.87 (s, 0.6H), 7.63 (s, 0.4H), 3.27-3.19 (m, 2H), 3.00-2.91 (m, 2H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 162.92, 154.27, 147.33, 142.37, 141.24, 141.20, 139.51, 138.51, 136.71, 127.05, 126.61, 123.26, 88.76, 88.16, 75.71, 75.47, 30.58, 19.46, 19.44.

    (E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime

    [0238] ##STR00085##

    [0239] To a solution of (E/Z)-4-(4-(pyridin-3-yl)but-1-yn-1-yl)thiazole-2-carbaldehyde oxime (20 mg, 0.116 mmol) in 3:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (20 mg) at r.t under Argon atmosphere and stirred the mixture for 2 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered using celite pad, concentrated under reduced pressure and purified by column chromatography to afford cis/trans isomers (1/1 ratio) of ((E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime as an off white solid (25 mg, 87%). R.sub.f(100% EtOAc) 0.3; IR (neat): v.sub.max 3012, 2929, 2853, 1577, 1505, 1459, 1419, 1225, 1188, 906, 758, 703, 642 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 262.100860 found 260.100262. 1H NMR (400 MHz, CDCl.sub.3): δ 8.46 (s, 2H), 8.38 (s, 0.05H), 8.02 (d, J=1.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.30-7.23 (m, 1H), 7.12 (d, J=0.9 Hz, 1H), 6.83 (d, J=0.9 Hz, 0.05H), 2.87 (t, J=7.4 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.85-1.60 (m, 4H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 162.17, 157.59, 156.77, 154.74, 148.94, 146.35, 144.63, 140.74, 138.22, 136.92, 123.76, 117.80, 113.98, 32.79, 31.01, 30.95, 30.54, 30.49, 29.70, 28.86, 28.66.

    (E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime hydrochloride NM-261

    [0240] ##STR00086##

    [0241] To a solution of (E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime (20 mg, 0.076 mmol) was added 2N HCl (2 mL) at r.t 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. The solid was dried under vacuum to give cis/trans mixture (8/2 ratio) of (E/Z)-4-(4-(pyridin-3-yl)butyl)thiazole-2-carbaldehyde oxime hydrochloride NM-261 as an off white solid (22 mg, 96%). IR (neat): v.sub.max 3381, 3114, 3045, 2937, 2360, 1620, 1466, 1114, 967, 942 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.13H.sub.16N.sub.3OS.sup.+ 262.100860 found 262.099918. 1H NMR (400 MHz, Methanol-d4): δ 8.86 (s, 1H), 8.76 (d, J=5.5 Hz, 1H), 8.62 (d, J=7.9 Hz, 1H), 8.48 (s, 0.2H), 8.29 (s, 0.8H), 8.09-8.06 (m, 1H), 8.00 (s, 0.8H), 7.75 (s, 0.2H), 3.08-2.99 (m, 4H), 2.01-1.72 (m, 4H). 13C NMR (101 MHz, MeOD) δ 153.76, 148.73, 146.99, 143.00, 142.96, 140.89, 139.02, 138.48, 133.72, 127.08, 121.60, 31.61, 31.59, 29.31, 27.62, 27.56, 27.18.

    (E/Z)-2-(2-(pyrimidin-2-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-250

    [0242] ##STR00087##

    (E/Z)-2-(pyrimidin-2-ylethynyl)thiazole-4-carbaldehyde oxime

    [0243] ##STR00088##

    [0244] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (100 mg, 0.483 mmol, 1.0 equiv) in DMF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.096 mmol, 0.2 equiv) and CuI (36.8 mg, 0.1931 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 2-ethynylpyrimidine (60.35 mg, 0.579 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation at 100° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 50:50) to afford cis/trans isomer (1:0.25 ratio) of (E/Z)-2-(pyrimidin-2-ylethynyl)thiazole-4-carbaldehyde oxime as off white solid (60 mg, 55%). IR (neat): v.sub.max 3174, 3042, 2918, 2850, 2359, 1546, 1406, 1282, 1182, 1118, 1082, 711, 691, 640, 539 cm.sup.−1; R.sub.f (50% EtOAc/PE) 0.25; HRMS (ESI.sup.+): m/z calcd for C.sub.10H.sub.7N.sub.4OS.sup.+ 231.033508 found 231.033347. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.27 (s, 1H), 11.15 (s, 0.25 H), 9.29 (s, 1.25H), 9.15 (s, 2.5H), 8.73 (s, 1H), 8.24 (s, 0.25), 8.12 (s, 0.25), 7.75 (s, 1H). .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ 160.61, 159.75, 159.73, 158.25, 150.64, 147.05, 146.43, 145.66, 143.10, 139.46, 128.98, 122.22, 117.70, 88.24, 88.08, 87.79.

    (E/Z)-2-(2-(pyrimidin-2-yl)ethyl)thiazole-4-carbaldehyde oxime

    [0245] ##STR00089##

    [0246] To a solution of (E/Z)-2-(pyrimidin-2-ylethynyl)thiazole-4-carbaldehyde oxime (20 mg, 0.086 mmol) in 3:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (20 mg) at r.t under Argon atmosphere and stirred the mixture for 1 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 preparative TLC to afford cis/trans isomers (1/1 ratio) of (E)-2-(2-(pyrimidin-2-yl)ethyl)thiazole-4-carbaldehyde oxime as an off white solid (15 mg, 75%). R.sub.f (100% EtOAc) 0.25; IR (neat): v.sub.max 3150, 2852, 2360, 1567, 1448, 1411, 1096, 959, 914, 741, 722, 643 cm.sup.−1; HRMS (ESI.sup.+) m/z calcd for C.sub.10H.sub.11N.sub.4OS.sup.+ 235.064808 found 235.065823. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.01 (d, J=2.3 Hz, 1H), 8.70 (s, 2H), 8.42 (s, 0.5H), 8.14 (s, 0.5H), 7.60 (d, J=11.3 Hz, 1H), 3.45-3.40 (m, 2H), 3.22 (t, J=7.5 Hz, 2H). .sup.13C NMR (101 MHz, MeOD): δ 170.13, 167.87, 156.96, 156.94, 155.98, 148.89, 142.86, 139.30, 134.39, 124.80, 118.11, 32.94, 32.67, 29.49, 29.47.

    (E/Z)-2-(2-(pyrimidin-2-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-250

    [0247] ##STR00090##

    [0248] To a solution of (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime 14 (15 mg, 0.064 mmol) was added 2N HCl/Ether (2 mL) at r.t 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 (7/3 ratio) of (E/Z)-2-(2-(pyridin-4-yl)ethyl)thiazole-4-carbaldehyde oxime hydrochloride NM-130 as a light brown solid (16 mg, 93%). IR (neat): v.sub.max 3415, 2924, 2360, 1569, 1435, 1411, 913, 788, 720, 644, 456 cm.sup.−1; HRMS (ESI.sup.+) m/z calcd for C.sub.10H.sub.11N.sub.4OS.sup.+ 235.064808 found 235.065442. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 9.19 (d, J=3.4 Hz, 1H), 8.95 (d, J=4.0 Hz, 2H), 8.35 (s, 0.35), 8.06 (bs, 0.65H), 7.65 (s, 0.65H), 7.48 (s, 0.35H), 3.45-3.39 (m, 2H), 3.33-3.22 (m, 2H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 171.40, 168.10, 157.21, 152.77, 152.51, 147.50, 147.00, 144.18, 141.62, 140.83, 138.61, 135.84, 135.50, 125.19, 118.52, 31.85, 31.82, 29.12, 29.08.

    (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime hydrochloride NM-247

    [0249] ##STR00091##

    (E/Z)-2-(4-phenylbut-1-yn-1-yl)thiazole-4-carbaldehyde oxime

    [0250] ##STR00092##

    [0251] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime 2 (150 mg, 0.724 mmol, 1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (167 mg, 0.144 mmol, 0.2 equiv) and CuI (55 mg, 0.288 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at r.t, but-3-yn-1-ylbenzene (113 mg, 0.867 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation at 100° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 30:70) to afford cis/trans isomers (1/1 ratio) of (E/Z)-2-(4-phenylbut-1-yn-1-yl)thiazole-4-carbaldehyde oxime as an off white solid (95 mg, 51%). IR (neat): v.sub.max 3158, 3057, 2938, 2855, 2360, 2340, 1488, 1457, 1257, 1132, 982, 888, 731, 700, 505 cm.sup.−1; R.sub.f(30% EtOAc/PE) 0.30; HRMS (ESI.sup.+) m/z calcd for C.sub.14H.sub.13N.sub.2OS.sup.+ 257.074310 found 257.071919. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.21 (bs, 1H), 7.72 (s, 0.5H), 7.44 (s, 0.5H), 7.44-7.19 (m, 2H), 7.20-7.11 (m, 3H), 2.91-2.86 (m, 2H), 2.71-2.66 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 149.84, 148.67, 148.18, 144.35, 140.42, 139.96, 139.91, 128.58, 128.56, 128.43, 126.62, 126.58, 126.25, 96.85, 96.64, 74.40, 74.10, 34.28, 21.77.

    (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime

    [0252] ##STR00093##

    [0253] To a solution of (E/Z)-2-(4-phenylbut-1-yn-1-yl)thiazole-4-carbaldehyde oxime (30 mg, 0.117 mmol) in 3:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (10 mg) at room temperature under Argon atmosphere and stirred the mixture for 2 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered using celite pad, concentrated under reduced pressure and purified by column chromatography (EtOAc/PE), 40:60 to afford cis/trans isomers (1/1 ratio) of (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime as an off white solid (25 mg, 82%). R.sub.f (30% EtOAc/PE) 0.20; IR (neat): v.sub.max 3158, 3023, 2919, 2853, 1488, 1458, 1257, 1179, 1131, 754, 699 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.14H.sub.17N.sub.2OS.sup.+ 261.105611 found 260. 261.103834. 1H NMR (400 MHz, CDCl.sub.3): δ 8.13 (s, 0.5 H), 7.95 (s, 0.5H), 7.64 (s, 0.5H), 7.29 (s, 0.5H), 7.24-7.14 (m, 2H), 7.14-7.00 (m, 3H), 3.00-2.96 (m, 2H), 2.61-2.56 (m, 2H), 1.83-1.60 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 172.53, 170.70, 148.14, 145.33, 144.31, 142.02, 141.92, 140.13, 128.40, 128.39, 128.35, 125.88, 125.83, 123.89, 118.27, 35.51, 33.32, 32.95, 30.78, 30.72, 29.71, 29.54, 29.39.

    (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime hydrochloride NM-247

    [0254] ##STR00094##

    [0255] To a solution of (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime (25 mg, 0.06 mmol) was added 2N HCl/Ether (2 mL) at r.t 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 mixture (7.3/2.7 ratio) of (E/Z)-2-(4-phenylbutyl)thiazole-4-carbaldehyde oxime hydrochloride as a light brown solid (28 mg, 98%). IR (neat): v.sub.max 3098, 3050, 2332, 1871, 1491, 1454, 1331, 1002, 935, 749, 701, 502 cm.sup.−1; HRMS (ESI.sup.+): m/z calcd for C.sub.14H.sub.17N.sub.2OS.sup.+ 261.105611 found 260. 261.105488. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.54 (s, 0.27 H), 8.19 (s, 0.73H), 7.94 (s, 0.73H), 7.61 (s, 0.27H), 7.34-7.11 (m, 5H), 3.28-3.18 (m, 2H), 2.72-3.68 (m, 2H), 1.94-1.69 (m, 4H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 173.66, 141.71, 141.59, 139.00, 136.14, 128.04, 128.01, 125.57, 125.52, 125.25, 34.87, 34.80, 31.02, 30.43, 30.39, 28.94.

    (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride NM-204

    [0256] ##STR00095##

    (E/Z)-2-(pyridin-2-ylethynyl)thiazole-5-carbaldehyde oxime

    [0257] ##STR00096##

    [0258] To a degassed solution of (E/Z)-2-bromothiazole-5-carbaldehyde oxime (132 mg, 0.637 mmol, 1 equiv) in THF/Et.sub.3N (6 mL/2 mL), Pd[PPh.sub.3].sub.4 (101 mg, 0.087 mmol, 0.15 equiv) and CuI (33 mg, 0.173 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, 2-ethynylpyridine (60 mg, 0.582 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at 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 50:50) to afford cis/trans isomer of (E/Z)-2-(pyridin-2-ylethynyl)thiazole-5-carbaldehyde oxime as a light yellow solid. ESI-MS: m/z 230.05.

    (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime

    [0259] ##STR00097##

    [0260] To a solution of (E/Z)-2-(pyridin-2-ylethynyl)thiazole-5-carbaldehyde oxime (25 mg, 0.109 mmol) in 4:1 ratio of EtOAc/MeOH (5 mL) was added 10% Pd/C (20 mg) at r.t under Argon atmosphere and stirred the mixture for 1 h under H.sub.2 atmosphere using balloon pressure. Upon completion, the mixture was filtered using small celite pad and concentrated under reduced pressure. The crude was purified by preparative TLC to afford cis/trans isomers (9.4/0.6 ratio) of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime as lite yellow solid (20 mg, 79%). R.sub.f (100% EtOAc) 0.25; HRMS (ESI.sup.+) m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.069337. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.50-8.47 (m, 1H), 8.00 (s, 1H), 7.79-7.71 (m, 2H), 7.34-7.24 (m, 2H), 3.47 (t, J=7.6 Hz, 2H), 3.30 (t, J=7.6 Hz, 2H). .sup.13C NMR (101 MHz, CD.sub.3OD): δ 174.25, 159.35, 148.49, 144.97, 142.23, 137.58, 137.38, 125.67, 123.53, 121.89, 36.93, 36.81, 32.46, 32.02.

    (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride NM-204

    [0261] ##STR00098##

    [0262] To a solution of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime (15 mg, 0.064 mmol) was added aq. 2N HCl (2 mL) at r.t 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 (8/2 ratio) of (E/Z)-2-(2-(pyridin-2-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride NM-204 as a light yellow solid (16 mg, 92%). HRMS (ESI.sup.+) m/z calcd for C.sub.11H.sub.12N.sub.3OS.sup.+ 234.069559 found 234.069252. .sup.1H NMR (400 MHz, Methanol-d4): δ 8.87-8.80 (m, 1H), 8.66-8.58 (m, 1H), 8.41 (s, 0.8H), 8.31 (s, 0.2H), 8.16-8.09 (m, 1H), 8.07-7.98 (m, 1.2H), 7.96 (s, 0.8H), 3.88-3.63 (m, 4H). .sup.13C NMR (101 MHz, MeOD) δ 172.72, 154.17, 147.09, 141.37, 139.11, 136.21, 127.50, 125.54, 31.93, 29.25.

    (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime hydrochloride FR-78

    [0263] ##STR00099##

    (E/Z)-2-(phenylethynyl)thiazole-4-carbaldehyde oxime FR-72

    [0264] ##STR00100##

    [0265] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (80 mg, 0.386 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (89.3 mg, 0.077 mmol, 0.2 equiv) and CuI (29.44 mg, 0.154 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the ethynylbenzene, (47.36 mg, 0.463 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/Pentane 1:5) to afford cis/trans isomers (0.56/0.44 ratio) of (E/Z)-2-(phenylethynyl)thiazole-4-carbaldehyde oxime as off white solid (57 mg, 65%). R.sub.f(20% EA/Pentane) 0.30; IR (neat): v.sub.max 3055, 2209, 1572, 1268, 1158, 920, 752, 537 cm.sup.−1. HRMS (ESI.sup.+): m/z calcd 251.025495 for C.sub.12H.sub.8N.sub.2NaOS.sup.+ found 251.024955. .sup.1H NMR (400 MHz, Chloroform-d): δ 8.36 (s, 0.56H), 8.29 (s, 0.44H), 7.84 (s, 0.56H), 7.60 (ddd, J=7.9, 4.7, 1.7 Hz, 2.44H), 7.43-7.34 (m, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): δ (ppm) 149.58, 147.98, 140.62, 132.22, 129.94, 126.98, 121.23, 95.02, 81.97.

    (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime FR-74

    [0266] ##STR00101##

    [0267] To a degassed solution of (E/Z)-2-(phenylethynyl)thiazole-4-carbaldehyde oxime (30 mg, 0.13 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (3.5 mg, 0.0177 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 10 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, 1/9) to afford cis/trans isomers (0.5/0.5 ratio) (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime of as off white solid (28 mg, 88%). R.sub.f (20% EA/PE) 0.25; IR (neat) v.sub.max:3055, 2851, 2209, 1572. 1158, 1117.44, 1093, 996, 720, 687 cm.sup.−1. HRMS (ESI.sup.+): m/z calcd 255.056799 for C.sub.12H.sub.12N.sub.2NaOS.sup.+ found 255.056255. .sup.1H NMR (400 MHz, Chloroform-d): δ 8.23 (s, 0.5H), 8.04 (dd, J=5.3, 2.8 Hz, 0.5H), 7.74 (s, 0.5H), 7.35 (s, 0.5H), 7.32-7.08 (m, 5H), 3.34 (t, J=7.9 Hz, 2H), 3.12 (t, J=7.9 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 171.49, 169.63, 148.26, 145.37, 144.41, 140.30, 140.18, 139.93, 128.73, 128.68, 128.58, 128.56, 126.65, 126.55, 124.34, 118.52, 35.95, 35.81, 35.23, 34.85.

    (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime hydrochloride FR-78

    [0268] ##STR00102##

    [0269] To a dry solid of (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime (10 mg), MeOH.Math.HCl (3 mL, 2N) was added. The reaction mixture was stirred at room temperature for 15 min. Upon completion (monitored by TLC), the solvent was evaporated and the dry mixture was washed with diethyl ether (2×3 mL). The solid was dried under vacuum to afford cis/trans isomers (0.5/0.5 ratio) (E/Z)-2-phenethylthiazole-4-carbaldehyde oxime hydrochloride as a white solide (11 mg, 91%). IR (neat) v.sub.max: 2921, 2851, 2359, 1732, 1330, 1111, 1030, 975, 945, 797, 739, 699, 472. HRMS (ESI.sup.+): m/z calcd 255.056799 for C.sub.12H.sub.12N.sub.2NaOS.sup.+ found 255.056255. .sup.1H NMR (400 MHz, Methanol-d.sub.4): δ 8.52 (s, 0.5H), 8.17 (s, 0.5H), 7.94 (s, 0.5H), 7.60 (s, 0.5H), 7.46-7.13 (m, 5H), 3.58 (ddt, J=20.2, 14.5, 9.7 Hz, 2H), 3.22-3.08 (m, 2H). .sup.13C NMR (101 MHz, Methanol-d.sub.4): δ 169.71, 144.50, 139.93, 139.82, 139.12, 128.18, 128.17, 128.14, 126.13, 126.08, 124.65, 35.46, 34.06.

    (Z/E)-2-(2-(pyridin-4-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride FR-80

    [0270] ##STR00103##

    (E/Z)-5-(pyridin-4-ylethynyl)thiazole-2-carbaldehyde oxime FR-73

    [0271] ##STR00104##

    [0272] To a degassed solution of (E/Z)-2-bromothiazole-5-carbaldehyde oxime (80 mg, 0.386 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (89.3 mg, 0.077 mmol, 0.2 equiv) and CuI (29.44 mg, 0.154 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, a degassed solution of 4-ethynylpyridine (47.82 mg, 0.463 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/PE 1:1) to afford cis/trans isomers (0.9/0.1 ratio) (E/Z)-5-(pyridin-4-ylethynyl)thiazole-2-carbaldehyde oxime as a brown solid (62 mg, 70%). R.sub.f (55% EA+PE): 0.30; IR (neat): v.sub.max: 3045, 2716, 2359, 2122, 1731, 1668, 1540, 1466, 1318, 1266, 941, 876, 752, 683. HRMS (ESI.sup.+): m/z calcd 230.038806 for C.sub.11H.sub.8N.sub.3OS.sup.+ found 230.038259. .sup.1H NMR (400 MHz, Acetic acid-d.sub.4): δ 8.94 (s, 2H), 8.51 (s, 1H), 8.20 (s, 1H), 7.94 (d, J=4.6 Hz, 2H). .sup.13C NMR (101 MHz, Acetic acid-d.sub.4): δ 151.89, 148.45, 148.09, 145.57, 142.35, 138.81, 133.61, 128.86, 128.04, 93.59, 87.84.

    (Z/E)-2-(2-(pyridin-4-yl)ethyl)thiazole-5-carbaldehyde oxime FR-77

    [0273] ##STR00105##

    [0274] To a degassed solution of ((Z/E)-2-(2-(pyridin-4-yl)ethynyl)thiazole-5-carbaldehyde oxime (18 mg, 0.078 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (7 mg, 0.0354 mmol, 0.45 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 10 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) to afford cis/trans isomers (0.8/0.2 ratio) (E/Z)-5-(pyridin-4-ylethynyl)thiazole-2-carbaldehyde oxime as a yellow solid (15 mg, 81%). R.sub.f(EA) 0.30. IR (neat): v.sub.max 3045, 2716, 1731, 1540, 1495, 1466, 1212, 1176, 1108, 1064, 941, 876, 683. HRMS (ESI.sup.+): m/z calcd 234.07008 for C.sub.11H.sub.12N.sub.3OS.sup.+ found 230.069559. .sup.1H NMR (400 MHz, Acetic Acid-d.sub.4): δ 8.90 (d, J=6.1 Hz, 2H), 8.41 (s, 0.21 H), 8.24 (s, 0.81 H), 7.99 (s, 1H), 7.92 (d, J=6.3 Hz, 2H), 3.73-3.57 (m, 2H), 3.52 (d, J=8.3 Hz, 2H). .sup.13C NMR (101 MHz, Acetic Acid-d.sub.4): δ 175.56, 160.63, 146.98, 143.94, 143.70, 142.69, 139.05, 127.67, 49.77, 36.13, 36.03, 33.10, 32.64, 20.59, 20.39, 20.20, 20.00, 19.80, 19.61, 19.41.

    (Z/E)-2-(2-(pyridin-4-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride FR-80

    [0275] ##STR00106##

    [0276] To a dry solid of (Z/E)-2-(2-(pyridin-4-yl)ethyl)thiazole-5-carbaldehyde oxime (10 mg), H.sub.2O.Math.HCl (2 mL, 2N). was added The reaction mixture was stirred at room temperature for 15 min. Upon completion (monitored by TLC), the solvent was evaporated and the dry mixture was washed with diethyl ether (2×3 mL). The solid was dried under vacuum to afford cis/trans isomers (0.9/0.1 ratio) (Z/E)-2-(2-(pyridin-4-yl)ethyl)thiazole-5-carbaldehyde oxime hydrochloride (9 mg, 77%). IR (neat): v.sub.max 3044, 3005, 2716, 2340, 1715, 1598, 1495, 1317, 1266, 1176, 813, 752, 625, 588. HRMS: (ESI.sup.+): m/z calcd 234.07008 for C.sub.11H.sub.12N.sub.3OS.sup.+ found 230.069559. .sup.1H NMR (400 MHz, Methanol-d.sub.4): δ 8.81-8.71 (m, 2H), 8.26 (d, J=6.8 Hz, 1H), 8.07-7.97 (m, 2H), 7.88 (d, J=12.1 Hz, 1H), 3.71-3.45 (m, 4H). .sup.13C NMR: (101 MHz, Methanol-d.sub.4): δ 161.85, 141.06, 140.49, 136.49, 127.40, 48.24, 48.03, 47.82, 47.60, 47.39, 47.18, 46.96, 34.49, 31.15, 30.27.

    (Z/E)-2-heptylthiazole-4-carbaldehyde oxime hydrochloride FR-79

    [0277] ##STR00107##

    (E/Z)-4-(hept-1-yn-1-yl)thiazole-2-carbaldehyde oxime FR-75

    [0278] ##STR00108##

    [0279] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (80 mg, 0.386 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (89.3 mg, 0.077 mmol, 0.2 equiv) and CuI (29.44 mg, 0.154 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the hept-1-yne (44.59 mg, 0.463 mmol, 1.2 equiv) was added dropwise and the reaction mixture was subjected to microwave irradiation for 1 hour at 90° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE, 1:5) to afford cis/trans isomers (1/1 ratio) (E/Z)-4-(hept-1-yn-1-yl)thiazole-2-carbaldehyde oxime as a white solid (66 mg, 76%). R.sub.f(20% EA/PE): 0.30; IR (neat): v.sub.max, 3151, 2927, 2857, 2230, 1667, 1588, 1508, 1458, 1436, 1375, 1322, 1290, 1250, 1203, 1119, 993, 916, 773, 721, 693. HRMS (ESI.sup.+): m/z calcd 245.073045 for C.sub.11H.sub.14N.sub.2NaOS.sup.+ found 245.071905. .sup.1H NMR (400 MHz, Chloroform-d): δ 8.24 (s, 1H), 7.76 (s, 0.5H), 7.61 (s, 0.5H) 2.52-2.41 (m, 2H), 1.70-1.57 (m, 2H), 1.47-1.31 (m, 4H), 0.91 (td, J=7.2, 2.9 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): δ (ppm) 150.11, 148.57, 144.45, 125.85, 98.00, 73.37, 31.09, 27.64, 22.16, 19.53, 13.91.

    (Z/E)-2-heptylthiazole-4-carbaldehyde oxime FR-76

    [0280] ##STR00109##

    [0281] To a degassed solution of (E/Z)-4-(hept-1-yn-1-yl)thiazole-2-carbaldehyde oxime (25 mg, 0.112 mmol, 1 equiv) in dry EtOAc (3 mL), 10% Pd/C (7 mg, 0.0354 mmol, 0.3 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 6 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated to afford cis/trans isomers (0.5/0.5 ratio) of (Z/E)-2-heptylthiazole-4-carbaldehyde oxime as a white solid (23 mg, 90%). R.sub.f(20% EA+PE): 0.30 IR (neat): v.sub.max 3151, 2927, 1667, 1588, 1508, 1458, 1436, 1290, 1119, 993, 916, 773, 721. HRMS (ESI.sup.+): m/z calcd 249.10388 for C.sub.11H.sub.14N.sub.2NaOS.sup.+ found 249.103205. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.20 (s, 0.45H), 7.97 (s, 0.55H), 7.71 (s, 0.55H), 7.37 (s, 0.45H), 3.02 (td, J=7.7, 1.6 Hz, 2H), 1.86-1.74 (m, 2H), 1.43-1.26 (m, 8H), 0.87 (dt, J=7.0, 3.4 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 172.95, 171.24, 148.02, 145.38, 144.46, 140.04, 123.58, 118.26, 77.35, 77.03, 76.71, 33.52, 33.14, 31.65, 30.02, 29.85, 29.06, 28.98, 28.93, 28.90, 22.60, 14.06.

    (Z/E)-2-heptylthiazole-4-carbaldehyde oxime hydrochloride FR-79

    [0282] ##STR00110##

    [0283] To a dry solid of (Z/E)-2-heptylthiazole-4-carbaldehyde oxime (10 mg), Dioxane.Math.HCl was added (1 mL, 4N). The reaction mixture was stirred at room temperature for 5 min. Upon completion (monitored by TLC), the solvent was evaporated and the dry mixture was washed with diethyl ether (2×3 mL). The solid was dried under vacuum to afford cis/trans isomers (0.5/0.5 ratio) of (Z/E)-2-heptylthiazole-4-carbaldehyde oxime hydrochloride (10.5 mg, 90%). IR (neat): v.sub.max 2923, 2853, 2359, 1455, 1132, 969, 922, 756, 723, 669, 541. HRMS (ESI.sup.+): m/z calcd 249.10388 for C.sub.11H.sub.14N.sub.2NaOS.sup.+ found 249.103205. .sup.1H NMR (400 MHz, Methanol-d.sub.4): δ 8.46 (s, 0.5H), 8.14 (s, 0.5H), 7.87 (s, 0.5H), 7.57 (s, 0.5H), 3.10 (dd, J=18.0, 10.5 Hz, 2H), 1.92-1.67 (m, 2H), 1.39-1.23 (m, 8H), 0.95-0.84 (m, 3H). .sup.13C NMR (101 MHz, Methanol-d.sub.4): δ 172.99, 172.95, 140.21, 137.24, 125.06, 125.02, 31.62, 31.41, 31.39, 29.61, 28.66, 28.62, 28.58, 28.55, 22.83, 22.25, 13.01.

    (Z/E)-2-(3-cyclohexylprop-1-yn-1-yl)thiazole-4-carbaldehyde oxime FR-84

    [0284] ##STR00111##

    [0285] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (50 mg, 0.241 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (55.81 mg, 0.048 mmol, 0.2 equiv) and CuI (18.4 mg, 0.096 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the prop-2-yn-1-ylcyclohexane (35.42 mg, 0.289 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/PE 1:5) to afford cis/trans isomers (0.5/0.5 ratio) of (Z/E)-2-(3-cyclohexylprop-1-yn-1-yl)thiazole-4-carbaldehyde oxime as a white solid (30 mg, 50%). R.sub.f (20% EA+PE) 0.30; IR (neat): v.sub.max 2846.76, 2228.43, 1446.96, 1321.44, 1277.02, 975.14, 676.93, 705.34. HRMS (ESI.sup.+): m/z calcd 249.10617 for C.sub.13H.sub.17N.sub.2OS.sup.+ found 249.106475. .sup.1H NMR (400 MHz, Chloroform-d): δ 8.22 (s, 1H), 7.80 (s, 0.5H), 7.51 (s, 0.5H), 2.36 (t, J=6.5 Hz, 2H), 1.86 (d, J=12.1 Hz, 2H), 1.67 (dddt, J=35.2, 14.7, 7.7, 3.5 Hz, 4H), 1.31-1.00 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ 148.61, 126.01, 97.23, 96.87, 74.24, 37.05, 32.85, 32.83, 27.36, 26.14, 26.09.

    Methyl 6-(4-((hydroxyimino)methyl)thiazol-2-yl)hex-5-ynoate FR-85

    [0286] ##STR00112##

    [0287] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (50 mg, 0.241 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (55.81 mg, 0.048 mmol, 0.2 equiv) and CuI (18.4 mg, 0.096 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the methyl hex-5-ynoate (37.69 mg, 0.289 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 1:4) to afford cis/trans isomers (0.5/0.5 ratio) of methyl 6-(4-((hydroxyimino)methyl)thiazol-2-yl)hex-5-ynoate as a white solid (40 mg, 65%). R.sub.f (30% EA+P) 0.30; IR (neat): v.sub.max 3179, 3099, 3003, 2925, 2360, 2234, 1726, 1632, 1508, 1436, 1375, 1319, 1248, 1197, 977, 766, 666, 421. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.77 (s, 0.5H), 7.53 (s, 0.5H), 3.68 (d, J=2.3 Hz, 3H), 2.55 (q, J=6.9 Hz, 2H), 2.50 (td, J=7.3, 3.0 Hz, 2H), 1.95 (h, J=7.1 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.46, 173.43, 149.71, 148.77, 148.01, 144.28, 126.33, 96.16, 96.00, 74.51, 74.19, 51.79, 51.78, 32.78, 32.76, 29.73, 23.15, 22.98, 19.00. HRMS (ESI.sup.+): m/z calcd 275.046629 for C.sub.11H.sub.12N.sub.2NaOS.sup.+ found 275.045988.

    (E/Z)-2-(pyren-2-ylethynyl)thiazole-4-carbaldehyde oxime FR-109

    [0288] ##STR00113##

    [0289] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (50 mg, 0.241 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (55.81 mg, 0.048 mmol, 0.2 equiv) and CuI (18.4 mg, 0.096 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 2 min at room temperature, the alkyne (2-ethynylpyrene, 65.57 mg, 0.289 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 preparative chromatography (EtOAc/Pentane, 1:4) to afford cis/trans isomers (0.6/0.4 ratio) of (E/Z)-2-(pyren-2-ylethynyl)thiazole-4-carbaldehyde oxime as a yellow solid (51 mg, 60%). R.sub.f (25% EA+Pentane) 0.30; IR (neat): v.sub.max 3734, 2921, 2360, 2340, 1507, 1456, 1188, 1050, 1033.06, 995, 923, 835, 819, 751, 710, 677, 668. HRMS (ESI.sup.+) m/z calcd 353.07483 for C.sub.22H.sub.13N.sub.2OS.sup.+ found 353.074310. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.24 (s, 0.4H), 11.52 (s, 0.6H), 8.70 (s, 0.4H), 8.51 (d, J=9.1 Hz, 1H), 8.44-8.36 (m, 3H), 8.34 (s, 2H), 8.30 (d, J=8.9 Hz, 1H), 8.27-8.20 (m, 1.6H), 8.14 (t, J=7.7 Hz, 1H), 8.10 (s, 1H), 7.77 (s, 0.4H). .sup.13C NMR (101 MHz, DMSO-d.sub.6): δ 150.54, 146.73, 146.40, 143.25, 139.62, 132.48, 132.08, 131.17, 130.84, 130.53, 130.09, 129.71, 128.32, 127.70, 127.49, 127.02, 126.97, 125.54, 124.72, 123.97, 123.68, 121.57, 114.69.

    2-(3-hydroxyprop-1-yn-1-yl)thiazole-4-carbaldehyde oxime FR-101

    [0290] ##STR00114##

    [0291] To a degassed solution of (E/Z)-2-bromothiazole-4-carbaldehyde oxime (80 mg, 0.386 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (89.3 mg, 0.077 mmol, 0.2 equiv) and CuI (29.44 mg, 0.154 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 2 min at room temperature, the alkyne (prop-2-yn-1-ol, 0.027 mL, 0.463 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/Pentane 1:5) to afford the desired coupled oxime as a white solid (24 mg, 34%). R.sub.f (25% EA+Pentane) 0.30. IR (neat): v.sub.max 3095, 2359, 1429, 1209, 1036, 984, 753. HRMS (ESI.sup.+) m/z calcd 183.0228 for C.sub.7H.sub.6N.sub.2O.sub.2S.sup.+ found 183.022275. .sup.1H NMR (400 MHz, Acetone-d.sub.6): δ 11.33 (s, 0.25H), 10.60 (s, 0.75H), 8.59 (s, 0.25H), 8.21 (s, 0.75H), 7.86 (s, 0.75H), 7.65 (s, 0.25H), 4.60 (s, 1H), 4.49 (d, J=5.1 Hz, 2H). .sup.13C NMR (101 MHz, Acetone-d.sub.6): δ 150.87, 148.75, 147.31, 146.81, 143.87, 140.30, 127.19, 119.39, 94.98, 94.92, 77.45, 77.27, 50.65, 50.54.

    2-((hydroxyimino)methyl)-4-phenethylthiazol-3-ium chloride CV-05

    [0292] ##STR00115##

    4-(phenylethynyl)thiazole-2-carbaldehyde oxime CV-01

    [0293] ##STR00116##

    [0294] To a degassed solution of oxime (100 mg, 0.483 mmol, 1 equiv) in DMF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (112 mg, 0.097 mmol, 0.2 equiv) and CuI (37 mg, 0.193 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne (phenylacetylene, 59.2 mg, 0.580 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 1:4) to afford the desired coupled oxime as an orange-yellow solid (80 mg, 73%). R.sub.f (20% EA+P) {0.36; 0.51}; IR (neat) v.sub.max 3103.55, 2920.87, 2849.95, 1499.95 cm.sup.−1. HRMS (ESI.sup.+) m/z calcd 229.04353 for C.sub.12H.sub.9N.sub.2OS.sup.+ found 229.043010. .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 12.24 (s, 0.5H), 11.37 (s, 0.5H), 8.33 (d, J=0.9 Hz, 0.5H), 8.09 (d, J=1.0 Hz, 0.5H), 7.97 (d, J=1.1 Hz, 0.5H), 7.84 (d, J=0.9 Hz, 0.5H), 7.58 (tdd, J=5.3, 3.0, 1.6 Hz, 2H), 7.43 (ddt, J=5.5, 4.0, 2.0 Hz, 3H). .sup.13C NMR (101 MHz, Acetone) δ 162.70, 154.68, 144.55, 140.97, 138.43, 137.85, 132.58, 132.48, 132.18, 132.16, 129.64, 129.29, 127.96, 124.69, 122.87, 122.83, 122.75, 89.43, 89.26, 83.98, 83.84.

    4-phenethylthiazole-2-carbaldehyde oxime CV-03

    [0295] ##STR00117##

    [0296] To a degassed solution of CV01 (30 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 for 5 min, the reaction mixture was stirred under H.sub.2 pressure for 1 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative chromatography (EtOAc/P 1:5; 3 times) to afford the desired hydrogenated compound as a white solid (15 mg, 50%). R.sub.f (20% EA+P) {0.62; 0.85}; IR (neat) v.sub.max 2920.68, 2851.88, 2360.37, 1452.98 cm.sup.−1. HRMS (ESI.sup.+) m/z calcd 232,06703 for C.sub.12H.sub.13N.sub.2OS.sup.+ found 233.074310 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.35 (s, OH), 7.99 (s, OH), 7.24-7.15 (m, 2H), 7.12 (td, J=7.0, 1.8 Hz, 3H), 6.73 (s, OH), 3.13-2.91 (m, 4H).sup.13C NMR (101 MHz, CDCl.sub.3) δ 161.86, 157.73, 156.99, 145.68, 141.54, 141.48, 128.90, 128.87, 128.85, 126.56, 126.53, 119.13, 115.31, 46.56, 35.97, 35.87, 33.60, 33.45.

    2-((hydroxyimino)methyl)-4-phenethylthiazol-3-ium chloride CV-05

    [0297] ##STR00118##

    [0298] To a solution of CV03 (14 mg, 0.060 mmol, 1 equiv) in minimal volume of dichloromethane dry HCl/ether (2 mL) was added dropwise. The mixture was stirred at room temperature. After completion (monitored by TLC), the formed salt (12 mg, 75%) was concentrated under reduced pressure and washed with pentane IR (neat) v.sub.max 2918.47, 2752.43, 2360.18, 2340.23, 1513.34, 1452.39 cm.sup.−1. HRMS (ESI.sup.+) m/z calcd 232,06703 for C.sub.12H.sub.13N.sub.2OS.sup.+ found 233.074310 .sup.1H NMR (400 MHz, MeOD) δ 8.36 (s, OH), 8.15-8.07 (m, 1H), 7.73 (d, J=3.4 Hz, 1H), 7.50 (s, OH), 7.21-7.14 (m, 3H), 7.14-7.05 (m, 4H), 3.12 (dt, J=25.4, 7.7 Hz, 4H). .sup.13C NMR (101 MHz, MeOD) δ 150.37, 134.67, 129.43, 129.39, 129.19, 127.40, 127.34, 123.01, 49.21, 49.00, 48.79, 48.57, 35.21, 30.54.

    ##STR00119##

    Bromooxazole-4-carbaldehyde oxime CV-19

    [0299] ##STR00120##

    [0300] To a degassed solution of aldehyde (100 mg, 0.568 mmol, 1 equiv) in EtOH (8 mL), NaOAc (140 mg, 1.70 mmol, 3 equiv) and hydroxylamine hydrochloride (60 mg, 0.852 mmol, 1.5 equiv) were added. The mixture was stirred at rt for 16 h. After completion monitored by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (EtOAc/PE 3:7) to obtain the cis/trans isomer (15/85, ratio) (97 mg, 89%). R.sub.f (30% EtOAc/PE) 0.37; 0.46. IR (neat) v.sub.max 3171.99, 3133.58, 3092.36, 2922.25, 2848.70, 1672.12, 1519.88 cm.sup.−1 1H NMR (400 MHz, Acetone) δ 8.69 (s, 1H), 8.29 (s, 0.15H), 7.99 (s, 0.15H), 7.41 (s, 1H). .sup.13C NMR (101 MHz, Acetone) δ 206.35, 147.50, 138.62, 134.49, 134.46.

    2-(4-(pyridin-3-yl)but-1-yn-1-yl)oxazole-4-carbaldehyde oxime CV-22

    [0301] ##STR00121##

    [0302] To a degassed solution of oxime (43 mg, 0.225 mmol, 1 equiv) in THF/Et.sub.3N (8 mL/2 mL), Pd[PPh.sub.3].sub.4 (52 mg, 0.045 mmol, 0.2 equiv) and CuI (17 mg, 0.090 mmol, 0.4 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne (3-(but-3-yn-1-yl)pyridine, 35 mg, 0.270 mmol, 1.2 equiv) was added dropwise and the reaction mixture was stirred at the room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography column (EtOAc/PE 7:3) followed by preparative TLC (MeOH/DCM 1:9) to afford the desired coupled oxime as a white solid (51 mg, 59%). R.sub.f(100% EtOAc) 0.52; IR (neat) v.sub.max 3141.78, 3008.49, 2921.77, 2852.27, 2244.65, 1743.79, 1543.98 cm.sup.−1 1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.46-8.41 (m, 1H), 7.87-7.82 (m, 1H), 7.42 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.36 (s, 1H), 3.02 (t, J=7.0 Hz, 2H), 2.88 (td, J=7.0, 0.9 Hz, 2H). .sup.13C NMR (101 MHz, MeOD) δ 150.28, 148.30, 147.12, 144.78, 138.85, 138.53, 132.75, 125.23, 94.53, 70.22, 31.82, 21.40.

    4-(pyridin-3-yl)butyl)oxazole-4-carbaldehyde oxime CV-23

    [0303] ##STR00122##

    [0304] To a solution of 2-(4-(pyridin-3-yl)but-1-yn-1-yl)oxazole-4-carbaldehyde oxime (25 mg, 0.104 mmol in EtOAc (3 mL) was added 10% Pd/C (10 mg) After degassing for 5 min, the reaction mixture was stirred under H.sub.2 pressure for 1 h. Upon completion, the mixture was filtered through a small celite pad, concentrated under reduced pressure followed by column chromatography (EtOAc/PE, 8:2) to afford 4-(pyridin-3-yl)butyl)oxazole-4-carbaldehyde oxime as a white solid (18 mg, 72%). R.sub.f (100% EtOAc) 0.49. IR (neat) v.sub.max 3099.54, 3023.32, 2922.20, 2851.19, 2698.84, 2359.07, 1577.19 cm.sup.−1 1H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 8.38 (s, 2H), 7.99 (s, OH), 7.71 (dt, J=8.0, 1.8 Hz, 1H), 7.36 (s, 2H), 2.86 (t, J=7.3 Hz, 2H), 2.72 (dd, J=9.0, 6.0 Hz, 2H), 1.89-1.78 (m, 2H), 1.78-1.67 (m, 2H). .sup.13C NMR (101 MHz, MeOD) δ 165.86, 150.03, 147.58, 144.09, 139.45, 138.25, 131.90, 33.25, 31.47, 28.21, 27.27. HRMS (ESI.sup.+) m/z calcd 246.12370 for C.sub.13H.sub.16N.sub.3O.sub.2.sup.+ found 246.124385.

    3-(4-(4-((hydroxyimino)methyl)oxazol-2-yl)butyl)pyridin-1-ium chloride CV-24

    [0305] ##STR00123##

    [0306] To a solution of 4-(pyridin-3-yl)butyl)oxazole-4-carbaldehyde oxime (17.8 mg, 0.073 mmol) was added methanolic HCl (3N, 3 mL) at room temperature and stirred for 20 min at same temperature. Upon completion, solvent was distilled off under reduced pressure and the resulted solid was washed with diethyl ether (2×4 mL). The solid was dried under vacuum to give the desired compound as a yellow solid (20.2 mg, 98%) IR (neat) v.sub.max 2921.57, 2852.21, 2364.21, 1745.30, 1639.93, 463.23 cm.sup.−1 1H NMR (400 MHz, MeOD) δ 8.82 (d, J=2.0 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.59 (d, J=12.7 Hz, 2H), 8.33 (s, 0.2H), 8.06 (dd, J=8.1, 5.8 Hz, 1H), 7.42 (s, 0.6H), 2.97 (q, J=7.0 Hz, 4H), 1.98-1.78 (m, 4H). .sup.13C NMR (101 MHz, MeOD) δ 166.46, 148.33, 148.29, 144.59, 144.32, 144.20, 142.16, 140.40, 137.84, 130.32, 128.43, 32.89, 30.65, 27.95, 26.75. HRMS (ESI.sup.+) m/z calcd 246.12370 for C.sub.13H.sub.16N.sub.3O.sub.2.sup.+ found 246.124385.

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

    [0307] Compounds NM-55, NM-109, NM-130, NM-131, NM-132, NM-139, NM-141, NM-143, NM-152, NM-168, NM-171 and NM-176 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 HI6 (asoxime chloride or [1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl-oxoazanium dichloride) were used as comparative compounds.

    [0308] 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).

    [0309] 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×IC50/(IC50+[Ox]).

    [0310] 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 10M, 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 μL. 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.

    [0311] 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):

    ##STR00124##

    [00001] k obs = k r [ O ⁢ X ] K D + [ OX ] Eq ⁢ ( 1 )

    [0312] When [OX]«K.sub.D, Eq (1) simplifies to Eq (2):

    [00002] k o ⁢ b ⁢ s = ( k r K D ) [ OX ] Eq ⁢ ( 2 )

    [0313] The second order reactivation rate constant k.sub.r2, describing the specific reactivity can be derived from Eq (2).

    [00003] k r ⁢ 2 = k r K D Eq ⁢ ( 3 )

    [0314] 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] v t = v 0 ( 1 - e - k obs ⁢ t ) Eq ⁢ ( 4 ) - d [ S ] = ∫ 0 t vdt = v 0 ⁢ t + v 0 k obs ⁢ ( e - k obs ⁢ t - 1 ) Eq ⁢ ( 5 )

    [0315] The results are as follows:

    TABLE-US-00001 TABLE 1 Reactivation of OP-inhibited human hAChE by oximes 2-PAM, HI-6 and NMs OP Oximes k.sub.r (min.sup.−1) K.sub.D (μM) k.sub.r2 (mM.sup.−1 .Math. min.sup.−1) VX 2-PAM 0.2 ± 0.01 26 ± 7  7 HI-6 0.4 ± 0.02 19 ± 4  20 NM-55 0.06 ± 0.002 6 ± 1 10 NM-109 0 0 0 NM-130 0 0 0 NM-131  0.1 ± 0.004 7 ± 1 14 NM-132 0.07 ± 0.002   2 ± 0.3 35 CV05 0.61 ± 0.01  2.3 ± 0.3 260 NM-250 0.38 ± 0.03  48 ± 14 8 NM-261 0.54 ± 0.01  12.8 ± 2.5  42 Sarin 2-PAM 0.3 ± 0.02 25 ± 7  11 HI-6 0.8 ± 0.06 57 ± 11 13 NM-55 0.08 ± 0.003 3 ± 1 27 NM-109 0 0 0 NM-130 0 0 0 NM-131 0.08 ± 0.003 5 ± 1 16 NM-132  0.3 ± 0.002 3 ± 1 88 Tabun 2-PAM 0.5 ± 0.2  211 ± 113 2 HI-6 0 0 0 NM-55 0 0 0 NM-109 0 0 0 NM-130 0 0 0 NM-131 0 0 0 NM-132 0 0 0 Paraoxon 2-PAM 0.07 ± 0.02  68 ± 16 1 HI-6 0.8 ± 0.06 290 ± 70  0.4 NM-55 0.11 ± 0.004 0.12 ± 0.03 917 NM-109 0 0 0 NM-130 0 0 0 NM-131  0.2 ± 0.006 12 ± 2  17 NM-132 0.3 ± 0.02 56 ± 11 5

    TABLE-US-00002 TABLE 2 Reactivation of OP-inhibited human hAChE by oximes 2-PAM, HI-6 and NMs OP Oximes k.sub.r (min.sup.−1) K.sub.D (μM) k.sub.r2 (mM.sup.−1 .Math. min.sup.−1) VX 2-PAM 0.2 ± 0.01 26 ± 7 7 HI-6 0.4 ± 0.02 19 ± 4 20 NM-139  0.2 ± 0.008 19 ± 4 8 NM-141 0.09 ± 0.004   1 ± 0.2 90 NM-143  0.07 ± 0.0007  0.1 ± 0.02 700 NM-152 0 0 0 Sarin 2-PAM 0.3 ± 0.02 25 ± 7 11 HI-6 0.8 ± 0.06  57 ± 11 13 NM-139 0.18 ± 0.02  111 ± 22 1.6 NM-141 0.11 ± 0.002 45 ± 3 2.5 NM-143  0.1 ± 0.002 10 ± 1 10 NM-152 0 0 0 Tabun 2-PAM 0.5 ± 0.2   211 ± 113 2 HI-6 0 0 0 NM-139 0 0 0 NM-141 0 0 0 NM-143 0 0 0 NM-152 0 0 0 Paraoxon 2-PAM 0.07 ± 0.02   68 ± 16 1 HI-6 0.8 ± 0.06 290 ± 70 0.4 NM-139  0.6 ± 0.005 257 ± 45 2 NM-141 0.14 ± 0.005  6 ± 1 24 NM-143  0.3 ± 0.008 11 ± 2 27 NM-152 0 0 0

    TABLE-US-00003 TABLE 3 IC50 for AChE of oximes: 2-PAM, HI6 and NMs Oxime IC50 (μM) 2-PAM 580 ± 28 HI-6 82 ± 6 NM-55  57 ± 12 NM-109 246 ± 28 NM-130 590 ± 47 NM-131  99 ± 12 NM-132 133 ± 12 NM-139 328 ± 30 NM-141 114 ± 6  NM-143 436 ± 22 NM-152    1 ± 0.06 NM-168 394 ± 33 NM-171 398 ± 17 NM-176    2 ± 0.01 CV-05 437 ± 49 NM-250 526 ± 25 NM-261 375 ± 28

    [0316] These results show 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. In addition, we found that CV-05, NM-250 and NM-261 exhibited highly selective efficacy in reactivation VX-hAChE.