3,6-DISUBSTITUTED-2-PYRIDINALDOXIME SCAFFOLDS

Abstract

The present invention relates to a compound of formula (I), or one of its pharmaceutically acceptable salts: (I) wherein R1, R2 and —X—Y— have specific definitions. It also relates to the use of such a compound in therapy; and to a process for preparing it.

##STR00001##

Claims

1. Compound of formula (I), or one of its pharmaceutically acceptable salts: ##STR00102## wherein: R1 is H, or a linear or cyclic C1-C7 alkoxy radical; —X—Y— is —CH2-(CH2)n-, —C≡C—, ##STR00103## or —X—Y— is Br and R2 does not exist; n is an integer between 0 and 5; R2 is a group chosen from alkyl, aryl, aralkyl, heteroaryl, —R3-N(R4)(R5), radical A, radical B, radical C and radical D, wherein radical A or radical B or radical C or radical D is optionally linked to —Y—X— by an alkyl group, ##STR00104## R3 is a C1-C4 alkyl group, and R4 and R5 are identical or different and each independently represent H, a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or a 8-methoxyquinolin-4-yl radical or R4 and R5 form together with the nitrogen atom a 4-benzyl-piperazin-1-yl radical or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl radical.

2. Compound according to claim 1, wherein t the compound has scaffold 1 below: ##STR00105## Scaffold 1 wherein R1 is as defined in claim 1.

3. Compound according to claim 1, wherein the compound has scaffold 2 below: ##STR00106## Scaffold 2 wherein R1 and R2 are as defined in claim 1.

4. Compound according to claim 3, wherein R2 is chosen from radical A, radical B, radical C and radical D: ##STR00107##

5. Compound according to claim 3, wherein R2 is alkyl, heteroaryl, aralkyl or —R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, R4 is H, and R5 is chosen from a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or a 8-methoxyquinolin-4-yl radical.

6. Compound according to claim 3, wherein R2 is —R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, and R4 and R5 form together with the nitrogen atom a 4-benzyl-piperazin-1-yl radical or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl radical.

7. Compound according to claim 1, wherein the compound has scaffold 3 below: ##STR00108## Scaffold 3 wherein R1 and R2 are as defined in claim 1 and n is an integer between 0 and 5.

8. Compound according to claim 7, wherein R2 is alkyl, aryl, aralkyl or —R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, R4 is H, and R5 is chosen from a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or a 8-methoxyquinolin-4-yl radical.

9. Compound according to claim 7, wherein R2 is —R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, and R4 and R5 form together with the nitrogen atom a 4-benzyl-piperazin-1-yl radical.

10. Compound according to claim 1, wherein the compound has scaffold 4 below: ##STR00109## Scaffold 4 wherein R1 and R2 are as defined in claim 1.

11. Compound according to claim 10, wherein R2 is chosen from radical A, radical C and radical D: ##STR00110##

12. Compound according to claim 1, wherein the compound is chosen from: ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##

13. Process for preparing a compound of formula (I) according claim 1, wherein —X—Y— is —CH2-CH2- or —C≡C—, comprising performing a Sonogashira coupling reaction between a 6-bromopyridinaldoxime and a compound comprising a terminal alkyne, optionally followed by a reduction step by reaction with hydrogen.

14. A method for treating a disease or condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound according to claim 1, wherein the disease or condition is: a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent; a neurological disease; inflammation; cancer; diabetes; and/or pain.

15. (canceled)

16. The method of claim 14, wherein the neurological disease is Alzheimer's or Parkinson's disease.

Description

EXAMPLES

Example 1: Synthesis of Compounds of the Invention

μI—Synthesis of Bifunctional Pyridinaldoxime Analogs

Synthesis of 6-(5-phenylpentyl)picolinaldehyde oxime

[0118] ##STR00024##

##STR00025##

##STR00026##

##STR00027##

6-Bromopicolinaldehyde oxime 2

[0119] ##STR00028##

[0120] This compound was synthesized by following the work published by L. Zhang et al..sup.1; To a solution of 6-bromopicolinaldehyde 1 (3.00 g, 16.1 mmol) in anhydrous EtOH (50 mL) at room temperature (rt) was added hydroxylamine hydrochloride (2.24 g, 32.3 mmol) and sodium acetate (2.65 g, 32.3 mmol). Upon addition, the colourless solution with a white suspension was stirred at 90° C. for 3 h. The solution was cooled to rt and concentrated in vacuo. The resulting white solid was dissolved in EtOAc (50 mL). The organic layer was washed with H.sub.2O (5×20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound 2 (3.21 g, 16.0 mmol, 99%) as a white solid. Physical and spectroscopic data are consistent with reported values..sup.1 mp=168-170° C. (lit..sup.2 164-166° C.); IR (neat) v.sub.max 3203, 3084, 2912, 1546, 1158, 1119, 704 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ 11.90 (s, 1H, CHNOH), 8.04 (s, 1H, CHNOH), 7.82-7.74 (m, 2H, NCCHCHCH, NCCHCHCH), 7.63 (dd, J=6.8, 1.7 Hz, 1H, NCCHCHCH); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 153.3, 147.5, 141.0, 140.1, 128.1, 119.3; HRMS (ESI).sup.+m/z calcd for C.sub.6H.sub.5BrN.sub.2O.sup.+200.9658, found 200.9657.

REFERENCE

[0121] 1. Bioorg. Med. Chem. Lett. 2016, 26, 778-781.

6-(5-phenylpent-1-yn-1-yl)picolinaldehyde 4

[0122] ##STR00029##

[0123] To a degassed solution of bromopiconaldehyde 1 (568 mg, 3.056 mmol, 1.1 equiv) in THF/Et.sub.3N (10 mL/30 mL), Pd[PPh.sub.3].sub.4 (482 mg, 0.0.417 mmol, 0.15 equiv) and CuI (159 mg, 0.834 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 3 (400 mg, 2.78 mmol, 1 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 column chromatography (EtOAc/PE 6:94 to EtOAc/PE 1:9) to afford the desired coupled piconaldehyde 4 as a colourless oil (500 mg, 72%). R.sub.f (20% EtOAc+PE) 0.65; IR (neat) v.sub.max 3026, 2928, 2856, 2229, 1710, 1580, 1451, 1211, 987, 805, 698, 647, 542 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.99 (s, 1H, H.sub.18), 7.82-7.71 (m, 2H, H.sub.3, H.sub.4), 7.53 (dd, J=7.5 Hz, 1H, H.sub.5), 7.26-7.10 (m, 5H, H.sub.13-H.sub.17), 2.74 (t, J=7.5 Hz, 2H, H.sub.11), 2.43 (t, J=7.1 Hz, 2H, H.sub.9), 1.92 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 193.09 (C18), 152.76 (C2), 144.43 (C6), 141.21 (C12), 137.21 (C4), 130.92 (C5), 128.47 (C14, C16), 128.41 (C13, C17), 126.02 (C15), 119.94 (C3), 92.32 (C7), 79.93 (C8), 34.90 (C11), 29.74 (C10), 18.81 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.16NO.sup.+250.1226 found 250.1239.

6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 5

[0124] ##STR00030##

Method 1:

[0125] A solution of aldehyde 4 (100 mg, 0.402 mmol, 1 equiv), hydroxylamine hydrochloride (56 mg, 0.803 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (100 mg, 1.206 mmol, 3 equiv) in dry ethanol (6 mL) was stirred at reflux during 16 h. Upon completion (monitored by TLC), the solids were removed by filtration through a short celite pad, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the oxime 5 as a white solid (100 mg, 94%). R.sub.f (20% EtOAc+PE) 0.35; IR (neat) v.sub.max 3177, 3005, 2933, 2876, 2226, 1568, 1495, 1445, 1257, 1159, 985, 807, 734, 703, 657, 576, 490 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.85 (s, 1H, OH), 8.24 (s, 1H, H.sub.18), 7.68 (dd, J=0.7, 7.8 Hz, 1H, H.sub.3), 7.56 (t, J=7.8 Hz, 1H, H.sub.4), 7.29 (dd, J=0.7, 7.7 Hz, 1H, H.sub.5), 7.29-7.08 (m, 5H, H.sub.13-H.sub.17), 2.71 (t, J=7.5 Hz, 2H, H.sub.11), 2.39 (t, J=7.1 Hz, 2H, H.sub.9), 1.89 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 151.95 (C2), 150.51 (C18), 144.46 (C6), 141.33 (C12), 136.73 (C4), 128.50 (C14, C16), 128.35 (C13, C17), 127.13 (C5), 125.92 (C15), 119.23 (C3), 91.47 (C7), 80.19 (C8), 34.84 (C11), 29.78 (C10), 18.77 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.17N.sub.2O.sub.1.sup.+265.1335 found 265.1360.

Method 2:

[0126] To a degassed solution of oxime 2 (77 mg, 0.381 mmol, 1.1 equiv) in THF/Et.sub.3N (5 mL/2 mL), Pd[PPh.sub.3].sub.4 (60 mg, 0.052 mmol, 0.15 equiv) and CuI (20 mg, 0.104 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 3 (50 mg, 0.347 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired coupled oxime 5 as a white solid (68 mg, 74%).

6-(5-phenylpentyl)picolinaldehyde 6

[0127] ##STR00031##

[0128] To a degassed solution of 6-substituted piconaldehyde 4 (200 mg, 0.802 mmol, 1 equiv) in dry EtOAc (4 mL), 10% Pd/C (21 mg, 0.201 mmol, 0.25 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 90 min. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford oxime 6 as a colourless liquid (185 mg, 91%); R.sub.f (20% EtOAc+PE) 0.70; IR (neat) v.sub.max 3026, 2929, 2856, 1709, 1591, 1455, 1213, 1089, 745, 689, 646, 570, 496 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.97 (s, 1H, H.sub.18), 7.73-7.63 (m, 2H, H.sub.3, H.sub.4), 7.26 (dd, J=1.5, 7.7 Hz, 1H, H.sub.5), 7.24-7.05 (m, 5H, H.sub.13-H.sub.17), 2.80 (t, J=7.7 Hz, 2H, H.sub.7), 2.54 (t, J=7.7 Hz, 2H, H.sub.11), 1.73 (quintet, J=7.7 Hz, 2H, H.sub.8), 1.60 (quintet, J=7.7 Hz, 2H, H.sub.10), 1.35 (quintet, J=7.3, 7.8 Hz, 2H, H.sub.9); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 193.87 (C18), 163.12 (C6), 152.35 (C2), 142.50 (C12), 137.08 (C4), 128.33 (C14, C16), 128.20 (C13, C17), 127.04 (C5), 125.60 (C15), 119.08 (C3), 37.99 (C7), 35.74 (C11), 31.20 (C10), 29.59 (C8), 28.84 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.20NO.sup.+254.1537 found 254.1539.

6-(5-phenylpentyl)picolinaldehyde oxime 7

[0129] ##STR00032##

[0130] A solution of aldehyde 6 (150 mg, 0.592 mmol, 1 equiv), hydroxylamine hydrochloride (82 mg, 1.184 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (146 mg, 1.776 mmol, 3 equiv) in dry ethanol (12 mL) was stirred at reflux during 16 h. Upon completion (monitored by TLC), the solids were removed by filtration through a short celite pad, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford the desired oxime 7 as a white solid (135 mg, 85%). R.sub.f (20% EtOAc+PE) 0.40; IR (neat) v.sub.max 3080, 2926, 2856, 1720, 1575, 1452, 1269, 986, 780, 699, 658, 569, 458 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.20 (br s, 1H, —OH), 8.30 (s, 1H, H.sub.18), 7.59 (br d, J=8.0 Hz, 1H, H.sub.3), 7.50 (t, J=7.8 Hz, 1H, H.sub.4), 7.27-6.93 (m, 6H, H.sub.5, H.sub.13-H.sub.17), 2.74 (t, J=7.8 Hz, 2H, H.sub.7), 2.50 (t, J=7.5 Hz, 2H, H.sub.11), 1.68 (quintet, J=7.5, 7.8 Hz, 2H, H.sub.8), 1.57 (quintet, J=7.5 Hz, 2H, H.sub.10), 1.32 (quintet, J=7.1, 7.8 Hz, 2H, H.sub.9); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 162.23, *160.10 (C6), 151.36, *150.73 (C2), 150.40 (C18), 142.61, *142.23 (C12), *138.33, 136.97 (C4), *129.46, 128.33 (C14, C16), 128.16 (C13, C17), 125.61, *125.53 (C5), *124.23, 123.01 (C15), *120.84, 118.112 (C3), 37.86, *37.29 (C7), 35.75 (C11), 31.22, *31.10 (C10), 29.82 (C8), 28.91, *28.69 (C9) (*cis and trans mixture); HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.21N.sub.2O.sup.+269.1648 found 269.1670.

Synthesis of 6-pentadecylpicolinaldehyde oxime 10

[0131] ##STR00033##

6-(pentadec-1-yn-1-yl)picolinaldehyde oxime 9

[0132] ##STR00034##

[0133] To a degassed solution of oxime 2 (51 mg, 0.252 mmol, 1.05 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (42 mg, 0.036 mmol, 0.15 equiv) and CuI (14 mg, 0.072 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the alkyne 8 (50 mg, 0.240 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 6:94) to afford the desired coupled oxime 9 as a white solid (65 mg, 83%). R.sub.f (20% EtOAc+PE) 0.55; IR (neat) v.sub.max 3179, 3092, 2914, 2850, 2226, 1722, 1567, 1450, 1268, 1160, 992, 809, 733, 709, 657, 640, 549, 496 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.50 (s, 1H, OH), 8.26 (s, 1H, H.sub.22), 7.72 (br d, J=7.8 Hz, 1H, H.sub.3), 7.61 (t, J=7.8 Hz, 1H, H.sub.4), 7.23 (br d, J=7.7 Hz, 1H, H.sub.5), 2.41 (t, J=7.2 Hz, 2H, H.sub.9), 1.61 (quintet, J=7.2 Hz, 2H, H.sub.10), 1.41 (m, 2H, H.sub.11), 1.24 (s, 18H, H.sub.12-H.sub.20), 0.85 (t, J=6.5 Hz, 3H, H.sub.21); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 151.89 (C2), 150.73 (C22), 143.69 (C6), 136.64 (C4), 127.13 (C5), 125.92 (C15), 119.12 (C3), 92.10 (C7), 79.76 (C8), 31.91, 29.64, 29.49, 29.35, 29.13, 29.00, 28.31, 22.68, 19.40, 14.11 (C9-C21); HRMS (ESI.sup.+) m/z calcd for C.sub.21H.sub.33N.sub.2O.sub.1.sup.+329.2587 found 329.2549.

6-pentadecylpicolinaldehyde oxime 10

[0134] ##STR00035##

[0135] To a degassed solution of oxime 9 (35 mg, 0.107 mmol, 1 equiv) in dry EtOAc (2 mL), 10% Pd/C (3 mg, 0.027 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 2 h. Upon completion, 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 6:94) to afford oxime 3 as a white solid (30 mg, 85%); R.sub.f (20% EtOAc+PE) 0.65; IR (neat) v.sub.max 3187, 3083, 2914, 2849, 1575, 1457, 1160, 985, 777, 718, 656, 517, 479 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.36 (br s, 1H, OH), 8.25 (s, 1H, H.sub.22), 7.61-6.54 (m, 2H, H.sub.3, H.sub.4), 7.11 (dd, J=2.5, 6.1 Hz, 1H, H.sub.5), 2.78 (t, J=7.2 Hz, 2H, H.sub.7), 1.70 (m, 2H, H.sub.8), 1.24 (s, 24H, H.sub.12-H.sub.20), 0.86 (t, J=6.6 Hz, 1H, H.sub.21); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 162.71 (C6), 151.12 (C2), 151.02 (C23), 136.73 (C4), 123.09 (C5), 118.21 (C3), 38.28, 31.92, 29.99, 29.69, 29.56, 29.49, 29.41, 29.36, 22.69, 14.12 (C7-C22). HRMS (ESI.sup.+) m/z calcd for C.sub.21H.sub.37N.sub.2O.sup.+333.2900 found 333.2918.

Synthesis of 2-((hydroxyimino)methyl)-6-(Pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13

[0136] ##STR00036##

3-fluoro-6-(pyridin-3-ylethynyl)picolinaldehyde oxime 12

[0137] ##STR00037##

[0138] To a degassed solution of oxime 2 (211 mg, 1.05 mmol, 1.05 equiv) in THF/Et.sub.3N (3 mL/3 mL), Pd[PPh.sub.3].sub.4 (173 mg, 0.15 mmol, 0.15 equiv) and CuI (57 mg, 0.30 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, the degassed alkyne 11 (103 mg, 1 mmol, 1 equiv) in dry THF (3 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 45:55) to afford the desired coupled oxime 12 as a white solid (200 mg, 90%). R.sub.f (60% EtOAc+PE) 0.35; IR (neat) v.sub.max 3065, 2764, 1578, 1561, 1443, 1288, 1143, 1042, 990, 981, 798, 697, 637, 563, 499 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.84 (s, 1H, OH), 8.83 (br s, 1H, H.sub.14), 8.65 (br s, 1H, H.sub.12), 8.11-8.04 (m, 2H, H.sub.10, H.sub.15), 7.91 (br t, J=7.8 Hz, 1H, H.sub.4), 7.83 (br d, J=7.8 Hz, 1H, H.sub.3), 7.68 (br d, J=7.8 Hz, 1H, H.sub.5), 7.50 (dd, J=4.8, 7.8 Hz, 1H, H.sub.11); .sup.13C NMR (100 MHz, DMSO-d6) δ (ppm) 152.855 (C2), 151.93 (C14), 149.70 (C12), 148.34 (C15), 141.51 (C6), 139.03 (C10), 137.65 (C4), 127.50 (C5), 123.78 (C11), 119.84 (C3), 118.48 (C9), 91.27 (C7), 85.48 (C8); HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.10N.sub.3O.sup.+224.0818 found 224.0840.

2-((hydroxyimino)methyl)-6-(pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13

[0139] ##STR00038##

[0140] To a compound 12 (40 mg) in water (1 mL), was added 1.2 N HCl (1 mL) and agitated for 2 min and stirred it for 3 h at rt. The reaction mixture was concentrated under reduced pressure to afford HCl salt 13 as a white solid in quantitative yield. IR (neat) v.sub.max 3018, 2970, 2502, 2080, 1561, 1465, 1290, 1005, 813, 726, 674, 548, 499 cm.sup.−1; .sup.1H NMR (400 MHz, D.sub.2O) δ (ppm) 9.05 (br s, 1H), 8.83 (br d, J=5.8 Hz, 1H), 8.75 (dt d, J=1.6, 8.3 Hz, 1H), 8.19 (s, 1H), 8.15-8.04 (m, 2H), 7.87 (dd, J=0.6, 8.0 Hz, 1H), 7.81 (br d, J=0.6, 7.8 Hz, 1H); .sup.13C NMR (100 MHz, D.sub.2O) δ (ppm) 150.85, 149.74, 148.30, 144.75, 142.04, 141.28, 139.9, 130.03, 128.12, 123.99, 122.81, 92.14, 85.20; HRMS (ESI.sup.+) m/z calcd for C.sub.13H.sub.10N.sub.3O.sup.+224.0818 found 224.0826.

Synthesis of 6-(4-(naphthalen-1-ylamino)butyl)picolinaldehyde oxime 20

[0141] ##STR00039## ##STR00040##

2-(Naphthylamino)-ethanol 15

[0142] ##STR00041##

[0143] Following the procedure from Couty et al..sup.1 for the synthesis of substituted aromatic amines; To a solution of 1-iodonaphthalene 14 (2.50 g, 9.8 mmol), 2-aminoethanol (1.78 mL, 29.5 mmol), copper chloride (132 mg, 1.0 mmol) and freshly crushed KOH (1.10 g, 19.7 mmol) in DMSO (2 mL) was stirred at rt for 18 h. To the maroon solution was added a saturated aqueous solution of NH.sub.4Cl (5 mL) and the solution was extracted (EtOAc, 3×20 mL). The combined extracts were washed (brine, 20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (30% EtOAc in light petroleum ether) afforded the title compound 15 (1.68 g, 9.0 mmol) as a beige oil. IR (neat) v.sub.max 3404, 3051, 2973, 2869, 1581, 785 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.93-7.76 (m, 2H, ArH), 7.52-7.29 (m, 4H, ArH), 6.67 (d, J=7.3 Hz, 1H, CHCNH), 4.01 (t, J=5.1 Hz, 2H, NHCH.sub.2CH.sub.2OH), 3.49 (t, J=5.1 Hz, 2H, NHCH.sub.2CH.sub.2OH); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 142.8, 134.6, 128.7, 126.4, 125.9, 125.0, 123.9, 120.0, 118.5, 105.5, 61.0, 46.6.

2-[(2-Hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16

[0144] ##STR00042##

[0145] Following a procedure from Couty et al..sup.1 for the N-cyanomethylation of aromatic aminoethanols; To a solution of 2-(naphthylamino)-ethanol 15 (745 mg, 4.0 mmol) and paraformaldehyde (717 mg, 8.0 mmol) in MeCN (20 mL) heated to 90° C. for 18 h. The white suspension was cooled to rt and to the reaction was added TMSCN (1.06 mL, 8.0 mmol) and AcOH (0.46 mL, 8.0 mmol) and the pale yellow reaction solution was stirred for 18 h at 90° C. The reaction was cooled to rt, H.sub.2O (40 mL) was added and the aqueous mixture was extracted (CH.sub.2Cl.sub.2, 10 mL). The organic extract was washed with aq. NaOH (1 M, 20 mL), brine (10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (30% EtOAc in light petroleum ether) afforded the title compound 16 (850 mg, 3.8 mmol, 94% over two steps) as a colourless solid. mp=70-71° C. (lit.sup.1=71-73° C.); IR (neat) v.sub.max 3422, 3050, 2956, 2236, 1705, 1418, 802 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.17 (d, J=8.3 Hz, 1H, 8-CH), 7.91 (d, J=7.6 Hz, 1H, 2-CH), 7.75 (d, J=7.6 Hz, 1H, 4-CH), 7.61-7.42 (m, 4H, ArH), 4.17 (s, 2H, CH.sub.2CN), 3.78 (br t, J=5.0, 2H, NCH.sub.2CH.sub.2OH), 3.54 (t, J=5.0 Hz, 2H, NCH.sub.2CH.sub.2OH); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 145.8, 134.8, 129.7, 128.5, 126.2, 126.1, 125.8, 125.7, 122.9, 119.1, 116.0, 61.1, 55.1, 44.7.

1-(Naphthalen-1-yl)azetidine-2-carbonitrile 17

[0146] ##STR00043##

[0147] Following a procedure from Couty et al..sup.1 for formation of aromatic azetidines; To a solution of 2-[(2-hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16 (500 mg, 2.2 mmol) and Et.sub.3N (0.77 mL, 5.5 mmol) in CH.sub.2Cl.sub.2 (10 mL) at 0° C. was added dropwise MsCl (0.21 mL, 2.6 mmol). The colourless reaction solution was stirred at 0° C. for 30 min and slowly warmed to rt. The reaction was stirred for an additional 30 min at rt. H.sub.2O (20 mL) was added, the organic layer was separated and the aqueous layer was extracted (CH.sub.2Cl.sub.2, 20 mL). The combined extracts were washed with aq. HCl (2 M, 10 mL) and brine (10 mL) before being dried (MgSO.sub.4), filtered and concentrated in vacuo. The pale yellow residue was directly subjected to the next step and was taken up in anhydrous THF (15 mL). To the solution, at 0° C., was added .sup.tBuOK (297 mg, 2.6 mol). The reaction was allowed to slowly warm to rt and H.sub.2O (20 mL) was added. The solution was extracted (EtOAc, 3×20 mL) and the combined organics were washed with brine (20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (10% EtOAc in light petroleum ether) afforded the title compound 17 (850 mg, 3.8 mmol, 94% over two steps) as a colourless solid. mp=129-131° C. (lit.sup.1=130-131° C.); IR (neat) v.sub.max 3433, 3045, 2958, 2248, 1577, 788 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.96-7.82 (m, 2H, ArH), 7.56-7.38 (m, 4H, ArH), 6.75 (d, J=7.3 Hz, 1H, 2-CH), 4.93 (dd, J=8.3, 6.6 Hz, 1H, NCH.sub.2CH.sub.2CHCN), 4.51 (ddd, J=8.3, 6.6, 4.9 Hz, 1H, NCHHCH.sub.2CHCN), 3.88 (dt, J=8.3, 6.8 Hz, 1H, NCHHCH.sub.2CHCN), 2.91-2.80 (m, 1H, 2H, NCH.sub.2CHHCHCN), 2.78-2.66 (m, 1H, NCH.sub.2CHHCHCN); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 145.0, 134.7, 128.6, 126.1, 125.6, 125.2, 125.1, 122.9, 122.5, 118.4, 109.5, 54.3, 51.0, 22.7.

N-(3-Butyn-1-yl)naphthylamine 18

[0148] ##STR00044##

[0149] Following a procedure from Couty et al..sup.2 for formation of aromatic homopropargyl amines from aromatic azetidines; To a solution of 1-(naphthalene-1-yl)azetidine-2-carbonitrile 17 (1.00 g, 4.8 mmol) in toluene (15 mL) was added dibutyltin oxide (298 mg, 1.2 mmol) and TMSN.sub.3 (0.95 mL, 7.2 mmol) and the reaction was stirred at 60° C. for 96 h. The brown reaction solution was cooled to rt and concentrated in vacuo. Chromatography on silica gel (2% EtOAc in hexanes) afforded the title compound 18 (454 mg, 2.3 mmol, 48%) as a colourless oil. IR (neat) v.sub.max 3293, 3050, 2975, 2117, 1690, 767 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.90-7.79 (m, 2H, 5-CH, 8-CH), 7.57-7.29 (m, 4H, 3-CH, 4-CH, 6-CH, 7-CH), 6.66 (d, J=7.3 Hz, 1H, 2-CH), 3.50 (t, J=6.5 Hz, 2H, NHCH.sub.2CH.sub.2CCH), 2.69 (td, J=6.5, 2.7 Hz, 2H, NHCH.sub.2CH.sub.2CCH), 2.11 (t, J=2.7, 1H, NHCH.sub.2CH.sub.2CCH); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 146.7, 134.4, 128.7, 126.4, 125.9, 125.0, 123.8, 121.0, 119.9, 118.3, 85.2, 70.4, 27.4, 18.9.

N-(4-{6-[(hydroxyimino)methyl]pyridine-2-yl}but-3-yn-1-yl)naphthalene-1-amine 19

[0150] ##STR00045##

[0151] To a degassed solution of N-(3-Butyn-1-yl)naphthylamine 18 (400 mg, 2.0 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (238 mg, 0.2 mmol) and CuI (78 mg, 0.4 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (453 mg, 2.2 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 16 h at rt. The reaction was concentrated in vacuo. Chromatography on silica gel (hexanes to 10% EtOAc in hexanes) afforded the title compound 19 (350 mg, 54%) as an orange solid: mp=143-144° C.; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.28 (s, 1H, NOH), 7.95-7.73 (m, 4H, ArH), 7.67 (t, J=7.8 Hz, 1H, 3-CH), 7.53-7.33 (m, 4H, ArH), 6.70 (d, J=7.8 Hz, 1H, 2-CH), 3.66 (t, J=6.7 Hz, 2H, NHCH.sub.2CH.sub.2), 2.96 (t, J=6.7 Hz, 2H, NHCH.sub.2CH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 152.0, 150.5, 143.1, 142.1, 136.8, 134.4, 128.7, 127.8, 127.3, 126.4, 125.9, 125.0, 123.8, 120.0, 119.8, 105.2, 88.6, 81.4, 42.6, 19.8; IR (neat) ν 3350, 3152, 3047, 2864, 2645, 2200 cm.sup.−1, HRMS (ESI).sup.+ m/z for C.sub.20H.sub.18N.sub.3O.sup.+ calculated 316.1444, found 316.1445.

N-(4-{6-[(hydroxyimino)methyl]pyridine-2-yl}but-3-yn-1-yl)naphthalene-1-amine 20

[0152] ##STR00046##

[0153] To a degassed suspension of N-(4-{6-[(1 E)-(hydroxyimino)methyl]pyridine-2-yl}but-3-yn-1-yl)naphthalene-1-amine 19 (173 mg, 0.5 mmol) in anhydrous methanol (10 mL), was added Pearlman's catalyst (77 mg, 0.5 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 18 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo. Chromatography on silica gel (50% EtOAc in hexanes) to afford the title compound 20 (60 mg, 34%) as a colourless solid: mp=151-152° C.; IR (neat) v.sub.max 3351, 3047, 2867, 2642, I cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.21 (s, 1H, NOH), 7.77-7.67 (m, 2H, ArH), 7.60-7.49 (m, 2H, ArH), 7.41-7.30 (m, 2H, ArH), 7.26 (t, J=8.2 Hz, 1H, NCCHCHCH), 7.15 (d, J=8.2 Hz, 1H, NCCHCHCH), 7.09 (dd, J=7.1, 1.7 Hz, 1H, 7-CH), 6.53 (d, J=7.5 Hz, 1H, 2-CH), 3.26 (t, J=6.9 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.85 (t, J=6.7 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.00-1.65 (m, 4H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 162.0, 151.1, 151.0, 143.4, 137.1, 134.3, 128.6, 126.6, 125.7, 124.7, 123.4, 123.3, 119.9, 118.6, 117.3, 104.4, 44.1, 37.7, 28.8, 27.6; HRMS (ESI).sup.+ m/z for C.sub.20H.sub.22N.sub.3O.sup.+ calculated 320.1757, found 320.1759.

REFERENCES

[0154] 1. Couty et al. J. Org. Chem. 2016, 81, 2899-2910 [0155] 2. Couty et al. Chem. Comms. 2016, 52, 10072-10075

Synthesis of methyl 3-hydroxy-6-(4-(quinoline-4-ylamino)butyl)picolinate 26

[0156] ##STR00047##

4-Bromoquinoline 22

[0157] ##STR00048##

[0158] Following the procedure from Margolis et al..sup.1 for the synthesis of bromoquinolines; To a solution of 4-quinolinol 21 (5.00 g, 34.4 mmol) in DMF (50 mL) at 60° C. was added dropwise PBr.sub.3 (3.34 mL, 35.5 mmol). Upon addition, a colour change was observed from yellow to vivid orange, with effervescence. The orange reaction mixture was stirred at 45° C. for 45 min. The solution was cooled to rt and diluted with H.sub.2O (20 mL) and a saturated solution of aqueous NaHCO.sub.3 was slowly added to basify the reaction mixture to pH 10. The solution was extracted with CH.sub.2Cl.sub.2 (5×20 mL), then the organic solutions were combined and washed with H.sub.2O (20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (EtOAc) afforded the title compound 22 (5.56 g, 26.7 mmol, 78%) as a cream solid. Physical and spectroscopic data are consistent with reported values..sup.2 mp=28-29° C. (lit..sup.2 29.5-30.5° C.); IR (neat) ν 3062, 1615, 1058 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.68 (d, J=4.6 Hz, 1H, NCH), 8.20 (dd, J=8.4, 0.9 Hz, 1H, NCCHCHCHCH), 8.11 (d, J=8.4 Hz, 1H, NCCHCHCHCH), 7.78 (ddd, J=8.4, 7.0, 1.4 Hz, 1H, NCCHCH), 7.71 (d, J=4.6 Hz, 1H, NCHCH), 7.66 (ddd, J=8.4, 7.0, 1.4 Hz, 1H, NCCHCHCHCH); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 149.9, 149.0, 134.2, 130.4, 129.9, 127.9, 127.9, 126.8, 125.1.

N-(But-3-yn-1-yl)quinolin-4-amine 24

[0159] ##STR00049##

[0160] Following a procedure adapted from Musonda et al..sup.3 for the synthesis of alkylated quinolines; Commercially available 3-butyn-1-amine 23 (4.72 mL, 57.7 mmol) was added to 4-bromoquinoline 22 (3.00 g, 14.4 mmol) to form a thin cream-coloured paste. The paste was heated to 80° C. for 1 h without stirring. The temperature was increased to 140° C. and the paste was heated for 18 h with stirring. The viscous, brown reaction mixture was cooled to rt and purified by chromatography on silica gel (20% MeOH in EtOAc) to afford the title compound 24 (2.82 g, 14.4 mmol, 100%) as a cream solid: mp=165-166° C.; IR (neat) v.sub.max 3281, 3169, 3067, 1573, 1151 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.45 (d, J=5.9 Hz, 1H, NCH), 8.30 (dd, J=8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.93 (br. s, 1H, NH), 7.82 (dd, J=8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.71 (ddd, J=8.3, 7.0, 1.2 Hz, 1H, NCCHCHCHCH), 7.51 (ddd, J=8.3, 7.0, 1.2 Hz, 1H, NCCHCHCHCH), 6.63 (d, J=5.9 Hz, 1H, NCHCH), 3.54 (q, J=7.0 Hz, 2H, NHCH.sub.2CH.sub.2CCH), 2.91 (t, J=2.7 Hz, 1H, NHCH.sub.2CH.sub.2CCH), 2.58 (td, J=6.8, 2.7 Hz, 2H, NHCH.sub.2CH.sub.2CCH); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 151.3, 148.2, 145.1, 130.2, 126.4, 124.7, 122.1, 118.1, 98.3, 82.1, 72.6, 41.4, 17.8; HRMS (ESI).sup.+ m/z calcd for C.sub.13H.sub.13N.sub.2.sup.+197.1073, found 197.1072.

6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25

[0161] ##STR00050##

[0162] To a degassed solution of N-(but-3-yn-1-yl)quinoline-4-amine 24 (1.00 g, 5.1 mmol) in anhydrous THF/Et.sub.3N (50 mL/15 mL) was added Pd(PPh.sub.3).sub.4 (588 mg, 0.5 mmol) and CuI (194 mg, 1.0 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (1.13 g, 5.6 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 18 h at rt. The reaction was concentrated in vacuo. Chromatography on silica gel (20% MeOH in EtOAc) afforded the title compound 25 (1.55 g, 4.9 mmol, 96%) as an orange solid: mp=202-203° C. (decomposed); IR (neat) v.sub.max 3291, 3068, 2947, 2241, 1617, 1222, 1051 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.90-11.69 (m, 1H, CHNOH), 8.43 (br d, J=5.4 Hz, 1H, NCH), 8.23 (d, J=8.3 Hz, 1H, NCCH), 8.03 (s, 1H, CHNOH), 7.85-7.65 (m, 4H, ArH), 7.52-7.38 (m, 3H, ArH), 6.60 (d, J=5.4 Hz, 1H, NCHCH), 3.61 (q, J=6.7 Hz, 2H, NHCH.sub.2CH.sub.2), 2.88 (t, J=6.7 Hz, 2H, NHCH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 152.5, 150.3, 149.8, 148.4, 147.8, 142.4, 137.8, 129.0, 128.6, 126.8, 124.1, 121.7, 118.9, 118.7, 98.5, 88.7, 81.1, 48.6, 18.6; HRMS (ESI).sup.+ m/z calcd for C.sub.19H.sub.17N.sub.4O.sup.+317.1397, found 317.1396.

Methyl 3-hydroxy-6-(4-(quinoline-4-ylamino)butyl)picolinate 26

[0163] ##STR00051##

[0164] To a degassed suspension of (E)-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25 (575 mg, 1.8 mmol) in anhydrous methanol (20 mL), was added Pearlman's catalyst (255 mg, 1.8 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 18 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to afford the title compound 26 (550 mg, 1.7 mmol, 94%) as a cream solid: mp=218-219° C.; IR (neat) v.sub.max 3145, 3026, 2985, 1593, 1224, 1026, 658 cm.sup.−1; .sup.1H NMR (400 MHz, D.sub.2O) δ 8.15 (s, 1H, CHNOH), 8.01 (d, J=7.1 Hz, 1H, NCH), 7.89-7.49 (m, 7H, ArH), 6.62 (d, J=7.1 Hz, 1H, NCHCH), 3.54 (t, J=6.6 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 3.09 (t, J=7.2 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.99-1.76 (m, 4H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, D.sub.2O) δ 156.1, 146.7, 145.0, 142.7, 141.7, 137.6, 134.1, 127.5, 127.4, 123.2, 122.3, 122.1, 120.2, 116.8, 98.2, 42.9, 33.1, 26.1, 17.2; HRMS (ESI).sup.+ m/z calcd for C.sub.19H.sub.21N.sub.4O.sup.+321.1710, found 3321.1713.

REFERENCES

[0165] 1. Margolis, B. J. et al. J. Org. Chem. 2007, 72, 2232-2235. [0166] 2. Charette, A. B., et al. J. Org. Chem. 2017, 82, 5046-5067 [0167] 3. Musonda, C. C et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736.

Synthesis of 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31

[0168] ##STR00052##

4-Bromo-5-fluoroquinoline 28

[0169] ##STR00053##

[0170] Following an adapted procedure from Kilpin Guy et al..sup.1 for the synthesis of substituted quinolines from anilines and Pulley et al..sup.2 for the synthesis of bromo-quinolines from quinolinols; to a solution of m-fluoroaniline 27 (6.00 g, 54.0 mmol) in EtOH (100 mL) at rt was added Meldrum's acid (9.49 g, 65.9 mmol) and triethyl orthoformate (21.3 mL, 128.0 mmol). The yellow solution was stirred at 90° C. for 2.5 h. The solution was cooled to 0° C. and the resulting yellow solid was filtered and washed with cold EtOH (20 mL). The resulting pale yellow solid was dried and added slowly over 5 min into refluxing diphenyl ether (50 mL) at 280° C. Upon addition, large quantities of white gas were observed and the colourless solution turned orange/brown. Reflux was maintained for 5 min and the reaction mixture was cooled to rt. The solution developed a much darker brown colour during this time. Petroleum ether (50 mL) was added to the solution and the resulting brown crystals that were evolved, were separated by filtration. Chromatography on silica gel (10% MeOH in EtOAc) afforded an inseparable mixture of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol (approximately 9:1 by .sup.19FNMR, 7.76 g, 47.5 mmol). This mixture was directly subjected to the next step.

[0171] To a solution of the inseparable mixture of regioisomers of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol (4.00 g, 24.5 mmol) in DMF (30 mL) was added phosphorus tribromide (1.86 mL, 19.7 mmol) at 60° C. and the mixture was stirred at 45° C. for 45 min. After cooling to rt, H.sub.2O (25 mL) was added and a saturated solution of aqueous Na.sub.2CO.sub.3 was added to adjust the pH of the solution to 10. The resulting crystals were washed with H.sub.2O (10 mL). Chromatography on silica gel (25% EtOAc in hexanes) gave only 4-bromo-5-fluoroquinoline 28 (2.50 g, 11.1 mmol, 61% over three steps) as an orange solid. mp=89-90° C.; IR (neat) ν 3091, 3041, 1621 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.67 (d, J=4.6 Hz, 1H, NCH), 8.22 (dd, J=9.2, 5.9 Hz, 1H, NCCH), 7.75 (dd, J=9.2, 2.7 Hz, 1H, NCCHCHCH), 7.68 (d, J=4.6 Hz, 1H, NCHCH), 7.44 (ddd, J=9.2, 5.9, 2.7 Hz, 1H, NCCHCH); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 161.9, 150.6, 149.6, 133.7, 128.9, 124.7, 124.1, 118.0, 113.1; .sup.19FNMR (376 MHz, CDCl.sub.3) δ 108.7; HRMS (ESI).sup.+ m/z for C.sub.9H.sub.6BrFN.sup.+ calculated 225.9662, found 225.9658.

N-(but-3-yn-1-yl)-5-fluoroquinolin-4-amine 29

[0172] ##STR00054##

[0173] Following a procedure adapted from Musonda et al. for the synthesis of alkylated quinolines;.sup.3 3-butyn-1-amine 23 (0.55 mL, 6.6 mmol) was added to 4-bromo-5-fluoroquinoline 28 (1.50 g, 6.6 mmol) to form a thin orange-coloured paste. The paste was heated to 100° C. for 18 h with stirring. The reaction was heated to 120° C. for a further 2 h. The viscous, brown reaction mixture was cooled to rt and purified by chromatography on silica gel (100% EtOAc to 20% MeOH in EtOAc) to afford the title compound 29 (1.06 g, 4.9 mmol, 75%) as a cream solid. mp=225-226° C.; IR (neat) v.sub.max 3079, 2911, 2240, 1966 cm.sup.−1; .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 8.39 (d, J=5.4 Hz, 1H, NCH), 8.27 (dd, J=10.8, 8.3 Hz, 1H, NCCH), 7.47 (dd, J=10.8, 2.5 Hz, 1H, NCCHCHCH), 7.44-7.39 (m, 1H, NHCH.sub.2CH.sub.2CCH), 7.35 (ddd, J=10.8, 8.3, 2.5 Hz, 1H, NCCHCHCH), 6.49 (d, J=5.4 Hz, 1H, NCHCH), 3.45 (q, J=7.1 Hz, 2H, NHCH.sub.2CH.sub.2CCH), 2.88 (t, J=2.7 Hz, 1H, NHCH.sub.2CH.sub.2CCH), 2.55 (td, J=7.1, 2.7 Hz, 2H, NHCH.sub.2CH.sub.2CCH); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 163.4, 160.9, 151.9, 149.7, 124.5, 115.8, 113.5, 112.2, 98.2, 82.2, 72.4, 41.2, 17.7; .sup.19FNMR (376 MHz, DMSO-d.sub.6) δ 112.1; HRMS (ESI).sup.+ m/z calcd for C.sub.13H.sub.12FN.sub.2.sup.+215.0979, found 215.0983 Da.

6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30

[0174] ##STR00055##

[0175] To a degassed solution of N-(but-3-yn-1-yl)-5-fluoroquinolin-4-amine 29 (0.50 g, 2.3 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (270 mg, 0.2 mmol) and CuI (89 mg, 0.4 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (516 mg, 2.6 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 16 h at rt. The reaction was concentrated in vacuo. Chromatography on silica gel (EtOAc) afforded the title compound 30 (140 mg, 0.4 mmol, 18%) as pale cream solid: mp=168-169° C.; IR (neat) v.sub.max 3500, 3435, 3034, 2960, 2239, 1966, 1599, 991 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (s, 1H, CHNOH), 8.42 (d, J=5.4 Hz, 1H, NCHCH), 8.30 (dd, J=9.2, 7.1 Hz, 1H, NCCHCHCHCF), 8.02 (s, 1H, CHNOH), 7.83-7.69 (m, 2H, ArH), 7.53 (t, J=5.6 Hz, 1H, NHCH.sub.2CH.sub.2), 7.48 (dd, J=10.8, 2.7 Hz, 1H, NCCHCHCH), 7.41 (d, J=7.1 Hz, 1H, NCCHCHCHCF), 7.35 (td, J=8.7, 2.7 Hz, 1H, NCCHCHCH), 6.58 (d, J=5.4 Hz, 1H, NCHCH), 3.66-3.51 (m, 2H, NHCH.sub.2CH.sub.2), 2.86 (t, J=7.0 Hz, 2H, NHCH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 163.4, 160.9, 152.4, 151.9, 149.8, 148.4, 142.4, 137.3, 126.9, 124.5, 119.0, 115.9, 113.5, 112.2, 98.4, 88.7, 81.1, 41.0, 18.6; .sup.19FNMR (376 MHz, DMSO-d.sub.6) δ 111.9; HRMS (ESI).sup.+ m/z calcd for C.sub.19H.sub.16FN.sub.4O.sup.+335.1303, found 335.1298.

6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31

[0176] ##STR00056##

[0177] To a degassed suspension of 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30 (50 mg, 0.1 mmol) in anhydrous methanol (5 mL), was added Pearlman's catalyst (21 mg, 0.1 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 18 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to afford the title compound 31 (50 mg, 0.1 mmol, 99%) as a cream solid: mp=206-207° C.; IR (neat) v.sub.max 3247, 2935, 2859, 1978, 1584, 806 cm.sup.−1; .sup.1H NMR (400 MHz, D.sub.2O) δ 8.44 (t, J=8.1 Hz, 1H, NCCHCHCH), 8.19 (d, J=7.3 Hz, 1H, NCHCH), 8.16-8.13 (m, 2H, CHNOH, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 7.91-7.81 (m, 2H, NCCHCHCHCF, NCCHCHCHCF), 7.70 (d, J=8.1 Hz, 1H, NCCHCHCH), 7.42-7.32 (m, 2H, NCCHCHCH), 6.70 (d, J=7.3 Hz, NCHCH), 3.58 (t, J=6.8 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 3.12 (t, J=7.7 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.01-1.76 (m, 4H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, D.sub.2O) δ 166.0, 136.5, 161.5, 159.1, 155.8, 146.5, 141.9, 139.0, 127.0, 125.6, 124.0, 116.2, 113.5, 105.1, 98.0, 42.8, 39.9, 26.9, 25.9; .sup.19FNMR (376 MHz, D.sub.2O) δ 103.1; HRMS (ESI).sup.+ m/z calcd for C.sub.19H.sub.22FN.sub.4O.sup.+339.1980, found 339.1980.

REFERENCES

[0178] 1. Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015-1018 [0179] 2. Pulley et al. J. Org. Chem. 2007, 72, 2232-2235 [0180] 3. Musonda, C. C. et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

Synthesis of 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37

[0181] ##STR00057##

8-Methoxyquinolin-4-ol 33

[0182] ##STR00058##

[0183] Following an adapted procedure from Kilpin Guy et al..sup.1 for the synthesis of substituted quinolines from anilines; to a solution of o-anisidine 32 (2.50 g, 20.3 mmol) in EtOH (20 mL) at rt was added Meldrum's acid (3.57 g, 24.8 mmol) and triethyl orthoformate (8.00 mL, 48.0 mmol). The yellow solution was stirred at 90° C. for 2.5 h. The solution was cooled to 0° C. and the resulting yellow solid was filtered and washed with cold EtOH (20 mL). The resulting pale yellow solid was dried and added slowly over 5 min into refluxing diphenyl ether (50 mL) at 280° C. Upon addition, large quantities of white gas were observed and the colourless solution turned orange/brown. Reflux was maintained for 5 min and the reaction mixture was cooled to rt. The solution developed a much darker brown colour during this time. Petroleum ether (50 mL) was added to the solution and the resulting yellow crystals that were evolved, were separated by filtration. Chromatography on silica gel (5% MeOH in EtOAc) afforded 8-methoxyquinolin-4-ol 33 (7.76 g, 47.5 mmol) as a pale orange solid: mp=168° C. (lit.sup.2: 168-169° C.); IR (neat) ν 2921, 2851, 1272, 1041 cm.sup.−1; .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ (ppm) 11.35 (s, 1H, OH), 7.58-7.70 (m, 1H, NCH), 7.38-7.43 (m, 1H, ArH), 7.23-7.27 (m, 2H, OHCCCH, OMeCCH), 6.95-7.08 (m, 1H, OHCCH), 3.99 (s, 3H, OMe); .sup.13C NMR (101 MHz, DMSO-d.sub.6) δ (ppm) 177.1, 149.0, 139.3, 130.5, 123.2, 119.1, 116.7, 111.4, 109.6, 56.6; HRMS (ESI).sup.+ m/z for C.sub.10H.sub.10NO.sub.2.sup.+ calculated 176.0706, found 176.0707.

4-Bromo-8-methoxyquinoline 34

[0184] ##STR00059##

[0185] Following an adapted procedure from Pulley et al..sup.3 for the synthesis of bromo-quinolines from quinolinols; to a solution of 8-methoxyquinolin-4-ol 33 (2.50 g, 14.3 mmol) in DMF (20 mL) was added phosphorus tribromide (1.54 mL, 16.4 mmol) at 60° C. and the mixture was stirred at 45° C. for 45 min. After cooling to rt, H.sub.2O (25 mL) was added and a saturated solution of aqueous Na.sub.2CO.sub.3 was added to adjust the pH of the solution to 10. The resulting cream-coloured crystals were filtered and washed with H.sub.2O (10 mL) giving 4-bromo-5-fluoroquinoline 34 (2.58 g, 10.8 mmol, 76%) as cream solid. mp=99-101° C.; IR (neat) v.sub.max 1252, 1085 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.69 (d, J=4.6 Hz, 1H, NCH), 7.78 (d, J=8.1 Hz, 1H, BrCCCH), 7.75 (d, J=4.8 Hz, 1H, BrCCH), 7.58 (t, J=8.2 Hz, 1H, ArH), 7.14 (d, J=8.0 Hz, 1H, ArH), 4.12 (s, 3H, OMe); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 155.5, 148.5, 134.1, 129.0, 128.0, 125.8, 118.5, 108.5, 56.3; HRMS (ESI).sup.+ m/z for C.sub.10H.sub.9BrNO.sup.+ calculated 237.9862, found 237.9865.

N-(but-3-yn-1-yl)-8-methoxyquinolin-4-amine 35

[0186] ##STR00060##

[0187] Following a procedure adapted from Musonda et al. for the synthesis of alkylated quinolines;.sup.4 3-butyn-1-amine 23 (1.20 mL, 14.7 mmol) was added to 4-bromo-8-methoxyquinoline 34 (0.70 g, 2.9 mmol) to form a orange/yellow-coloured paste. The paste was heated to 80° C. for 1 h without stirring. The temperature was increased to 100° C. for 18 h with stirring. The viscous, brown reaction mixture was cooled to rt and purified by chromatography on alumina (basic) gel (10% MeOH in EtOAc) to afford the title compound 35 (0.80 g, 2.9 mmol, 99%) as a pale orange solid. mp=154-155° C.; IR (neat) v.sub.max 3279, 2938, 2240, 753 cm.sup.−1; .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ (ppm) 8.36 (d, J=5.4 Hz, 1H, NCH), 7.73 (d, J=7.8 Hz, 1H, MeOCCHCHCH), 7.35 (t, J=8.1 Hz, 1H, MeOCCHCH), 7.10 (d, J=7.3 Hz, 1H, OMeCCH), 6.55 (d, J=5.4 Hz, 1H, NCHCH), 3.91 (s, 3H, OMe), 3.39-3.53 (m, 2H, CH.sub.2CH.sub.2CCH), 2.89 (t, J=2.6 Hz, 1H, CH.sub.2CH.sub.2CCH), 2.56 (td, J=7.1, 2.7 Hz, 2H, CH.sub.2CH.sub.2CCH); .sup.13C NMR (101 MHz, DMSO-d.sub.6) δ (ppm) 155.2, 149.9, 148.8, 139.6, 124.3, 119.6, 113.3, 108.5, 99.1, 82.5, 72.6, 55.8, 41.5, 18.0; HRMS (ESI).sup.+ m/z calcd for C.sub.14H.sub.15N.sub.2O.sup.+227.1179, found 227.1183.

6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 36

[0188] ##STR00061##

[0189] To a degassed solution of N-(but-3-yn-1-yl)-8-methoxyquinolin-4-amine 35 (1.00 g, 4.4 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (511 mg, 0.4 mmol) and CuI (168 mg, 0.9 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (977 mg, 4.8 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 16 h at rt. The reaction was concentrated in vacuo. Chromatography on alumina (basic) gel (10% MeOH in EtOAc) afforded the title compound 36 (400 mg, 1.1 mmol, 26%) as yellow solid: mp=171-172° C.; IR (neat) v.sub.max 3084, 2900, 2236, 1617, 1277, 745 cm.sup.−1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (s, 1H, CHNOH), 8.35 (d, J=6.1 Hz, 1H, NCHCH), 7.98 (m, 2H, NCC(OMe)CHCHCH, CHNOH), 7.78 (t, J=7.8 Hz, 1H, NCCHCHCH), 7.72 (d, J=7.8 Hz, 1H, NCCHCHCH), 7.49 (d, J=8.2 Hz, 1H, NCC(OMe)CHCHCH), 7.39 (d, J=7.8 Hz, 1H, NCCHCHCH), 7.29 (d, J=8.2 Hz, 1H, NCC(OMe)CHCHCH), 6.84 (d, J=6.1 Hz, 1H, NCHCH), 3.99 (s, 3H, OMe), 3.71 (br t, J=7.0, 2H, NHCH.sub.2CH.sub.2), 2.90 (t, J=7.0 Hz, 2H, NHCH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 152.6, 152.5, 152.1, 148.3, 145.1, 142.3, 137.3, 134.2, 126.8, 125.4, 119.0, 118.5, 113.7, 110.3, 99.0, 88.3, 81.3, 56.1, 48.5, 18.7; HRMS (ESI).sup.+ m/z calcd for C.sub.20H.sub.19N.sub.4O.sub.2.sup.+347.1503, found 347.1506.

6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37

[0190] ##STR00062##

[0191] To a degassed suspension of 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 36 (110 mg, 0.3 mmol) in anhydrous methanol (10 mL), was added Pearlman's catalyst (9 mg, 0.1 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 18 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to afford the title compound 37 (40 mg, 0.1 mmol, 36%) as a cream solid: mp=107-108° C.; IR (neat) v.sub.max 2927, 1617, 1581, 980 cm.sup.−1; .sup.1H NMR (400 MHz, MeOD-d.sub.6) δ 8.29 (d, J=5.6 Hz, 1H, NCHCH), 8.08 (s, 1H, CHNOH), 7.71-7.57 (m, 3H, ArH), 7.34 (t, J=8.2 Hz, 1H, NCC(OMe)CHCHCH), 7.24-7.19 (m, 1H, NCC(OMe)CHCHCH), 7.08 (d, J=7.8 Hz, 1H, NCCHCHCH), 6.48 (d, J=5.6 Hz, NCHCH), 3.98 (s, 3H, OMe), 3.36 (t, J=7.1 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.83 (t, J=7.1 Hz, 2H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.94-1.66 (m, 4H, NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, MeOD-d.sub.6) δ 163.2, 156.2, 153.3, 152.7, 150.0, 149.6, 140.4, 138.8, 125.8, 124.5, 121.1, 119.3, 113.8, 109.3, 99.9, 56.4, 43.8, 38.4, 28.9, 28.7; HRMS (ESI).sup.+ m/z calcd for C.sub.20H.sub.23N.sub.4O.sub.2.sup.+351.1816, found 351.1817.

REFERENCES

[0192] 2. Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015-1018. [0193] 3. Lauer et al. J. Am. Chem. Soc., 1946, 68, 1268. [0194] 4. Pulley et al. J. Org. Chem. 2007, 72, 2232-2235. [0195] 5. Musonda, C. C.; Little, S.; Yardley, V.; Chibale, K. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43

[0196] ##STR00063##

N-Benzylpiperazine 39

[0197] ##STR00064##

[0198] Following the procedure from Bozell and Biannic..sup.1 for the synthesis of benzylpiperazine; To a solution of piperazine 38 (12.9 g, 149.0 mmol) in anhydrous CH.sub.2Cl.sub.2 (100 mL) was added dropwise at 0° C., benzyl bromide (3.56 mL, 29.8 mmol). The reaction was stirred for 1 h at 0° C. The pale yellow solution was washed with a saturated aqueous solution of NaHCO.sub.3 (2×50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Absolute EtOH was added and a white precipitate was filtered from the solution. The solution was concentrated in vacuo to afford the title compound 39 (24.8 g, 141.0 mmol, 94%) as a viscous yellow oil. IR (neat) v.sub.max 3289, 2990, 2960, 2120, 1120 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.36-7.28 (m, 5H, ArH), 3.50 (s, 2H, CH.sub.2Ph), 2.90 (t, J=4.9 Hz, 4H, CH.sub.2N(Bn)CH.sub.2), 2.55-2.30 (m, 5H, CH.sub.2NHCH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 138.1, 129.2, 128.2, 127.0, 63.7, 54.5, 46.1.

1-Benzyl-4-propargyl piperazine 41

[0199] ##STR00065##

[0200] Following a procedure from Corey, M..sup.2 for the propargyl substitution of piperazines; To a solution of N-benzylpiperazine 39 (1.75 g, 9.93 mmol), propargyl bromide 40 (80% in toluene) (1.28 mL, 14.9 mmol) and DIPEA (3.28 mL, 19.9 mmol) in CH.sub.2Cl.sub.2 (50 mL) was stirred for 18 h at rt. H.sub.2O (30 mL) was added and the aqueous phase was separated and extracted (3×20 mL). The combined organic layers were washed (brine, 30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (50% EtOAc in hexanes) gave the title compound 41 (2.04 g, 9.5 mmol, 96%) as an orange oil. IR (neat) v.sub.max 3290, 3026, 2933, 2807, 2117, 697 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.37-7.28 (m, 5H, ArH), 3.56 (s, 2H, PhCH.sub.2), 3.30 (d, J=2.5 Hz, 2H, NCH.sub.2CCH), 2.73-2.44 (m, 8H, PizCH.sub.2), 2.25 (t, J=2.5 Hz, 1H, NCH.sub.2CCH); .sup.13CNMR (101 MHz, CDCl.sub.3) δ (ppm) 129.5, 129.3, 128.3, 127.2, 78.9, 73.20, 62.8, 52.8, 51.7, 46.8; HRMS (ESI).sup.+ m/z for C.sub.xH.sub.xN.sub.x.sup.+ calculated 215.1543, found 215.1542.

6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42

[0201] ##STR00066##

[0202] To a degassed solution of 1-benzyl-4-propargyl piperazine 41 (1.30 g, 6.1 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (0.70 g, 0.6 mmol) and CuI (0.23 g, 1.2 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (1.34 g, 6.7 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 18 h at rt. The reaction was concentrated in vacuo. Chromatography on silica gel (EtOAc) afforded the title compound 42 (750 mg, 2.2 mmol, 37%) as a cream solid: mp=143-145° C.; IR (neat) v.sub.max 3150, 3048, 2944, 2808, 2364, 734 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 12.17 (s, 1H, NOH), 7.99 (s, 1H, CHNOH), 7.71 (dd, J=8.0, 1.0 Hz, 1H, NCCHCHCH), 7.53 (t, J=8.0 Hz, 1H, NCCHCHCH), 7.43-7.20 (m, 6H, ArH), 3.70 (s, 2H, NCH.sub.2CC), 3.63 (s, 2H, PhCH.sub.2), 3.08-2.36 (m, 8H, PizCH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 152.7, 149.0, 142.2, 136.4, 136.3, 129.9, 128.4, 127.6, 127.1, 119.1, 85.3, 84.3, 63.2, 52.9, 50.5, 47.2; HRMS (ESI)+m/z for C.sub.20H.sub.23N.sub.4O.sup.+ calculated 335.1866, found 335.1863.

6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43

[0203] ##STR00067##

[0204] To a degassed suspension of 6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42 (200 mg, 0.6 mmol) in anhydrous methanol (10 mL), was added Pearlman's catalyst (44 mg, 0.3 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 2 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo. Chromatography on silica gel (CH.sub.2Cl.sub.2 to 10% MeOH in CH.sub.2Cl.sub.2) afforded the title compound 43 as a pale yellow oil (53%). IR (neat) v.sub.max 3162, 3057, 2939, 2816, 808 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.19 (s, 1H, CHNOH), 7.58-7.51 (m, 2H, ArH), 7.36-7.27 (m, 5H, ArH), 7.10 (dd, J=6.5, 2.2 Hz, 1H, NCCHCHCH), 3.55 (s, 2H, PhCH.sub.2), 2.82 (t, J=7.8 Hz, 1H, NCH.sub.2CH.sub.2CH.sub.2), 2.72-2.35 (m, 10H, PizCH.sub.2, NCH.sub.2CH.sub.2CH.sub.2), 2.02 (quin, J=7.8 Hz, NCH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 161.3, 151.8, 150.3, 137.6, 136.6, 129.4, 128.3, 127.2, 122.8, 118.0, 62.9, 57.7, 25.8, 25.5, 35.8, 26.3; HRMS (ESI).sup.+ m/z for C.sub.20H.sub.27N.sub.4O.sup.+ calculated 339.2179, found 339.2176.

REFERENCES

[0205] 1. Bozell. J. J. et al. Org. Lett. 2013, 15, 2730-2733. [0206] 2. Corey, M., et al. WO2017/184996 A1 (2017).

Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 48

[0207] ##STR00068##

3-Butynyl p-toluenesulfonate 45

[0208] ##STR00069##

[0209] Following a procedure from Winssinger et al..sup.1 for the formation of p-tolunesulfonyl protected alcohols; To a solution of 3-butyn-1-ol 44 (3.00 g, 42.8 mmol), DMAP (522 mg, 4.3 mmol) and Et.sub.3N (55.6 mL, 7.70 mL mmol) in CH.sub.2Cl.sub.2 (15 mL) at 0° C. was added dropwise a solution of TsCl (8.98 g, 47.1 mmol). The yellow reaction solution was allowed to warm to rt and stirred for 2 h. H.sub.2O (30 mL) was added and the reaction was stirred for 20 min at rt. The organic layer was separated and the aqueous layer was extracted (CH.sub.2Cl.sub.2, 5×40 mL). The combined extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. This afforded the title compound 45 (9.60 g, 42.8 mmol, 100%) as a red/brown oil. IR (neat) v.sub.max 3433, 3045, 2958, 2248, 1577, 788 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.81 (d, J=8.3 Hz, 2H, ArH), 7.36 (d, J=8.3 Hz, 2H, ArH), 4.11 (t, J=7.1 Hz, 2H, TsOCH.sub.2CH.sub.2CCH), 2.56 (td, J=7.1, 2.7 Hz, 2H, TsOCH.sub.2 TsOCH.sub.2CH.sub.2CCH), 2.46 (s, 3H, PhCH.sub.3), 1.98 (t, J=2.7 Hz, 1H, TsOCH.sub.2CH.sub.2CCH); .sup.13CNMR (101 MHz, CDCl.sub.3) δ (ppm) 145.0, 132.8, 129.9, 128.0, 78.3, 70.7, 67.4, 21.6, 19.4.

1-Benzyl-4-(buty-3-yn-1-yl)piperazine 46

[0210] ##STR00070##

[0211] Following a procedure from Guarna et al..sup.2 for the formation of alkylated piperazines; To a solution of 3-butynyl p-tolunesulfonate 45 (2.30 mL, 10.3 mmol) in DMF (60 mL) was added Na.sub.2CO.sub.3 (1.20 g, 11.3 mmol) and N-benzylpiperazine 39 (2.00 g, 11.3 mmol). The orange solution was stirred overnight at 80° C. The reaction mixture was quenched with H.sub.2O (10 mL) and ether (10 mL) was added. The organic layer was separated and washed with H.sub.2O (5×10 mL), brine (10 mL) and dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Chromatography on silica gel (100% CH.sub.2Cl.sub.2 to 10% MeOH in CH.sub.2Cl.sub.2) afforded the title compound 46 (1.70 g, 7.4 mmol, 72%) as an orange oil. IR (neat) v.sub.max 3291, 3026, 2939, 2807, 2119, 1676, 697 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 7.35-7.28 (m, 5H, ArH), 3.52 (s, 2H, PhCH.sub.2), 2.61 (t, J=7.6 Hz, 2H, NCH.sub.2CH.sub.2CCH), 2.58-2.42 (m, 8H, PizCH.sub.2), 2.41-2.34 (m, 2H, NCH.sub.2CH.sub.2CCH), 1.97 (t, J=2.7 Hz, 1H, NCH.sub.2CH.sub.2CCH); .sup.13CNMR (101 MHz, CDCl.sub.3) δ (ppm) 138.1, 129.2, 128.2, 127.0, 82.8, 69.0, 63.0, 57.0, 52.9, 52.8, 16.8; HRMS (ESI).sup.+ m/z for C.sub.xH.sub.xN.sub.x.sup.+ calculated 229.1699, found 229.1695.

6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47

[0212] ##STR00071##

[0213] To a degassed solution of 1-benzyl-4-(buty-3-yn-1-yl)piperazine 46 (1.55 g, 6.8 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (1.16 g, 0.7 mmol) and CuI (0.19 g, 1.4 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (1.50 g, 7.47 mmol) in anhydrous THF (20 mL). The brown solution was stirred for 18 h at rt. The reaction was concentrated in vacuo. Chromatography on silica gel (50% EtOAc in hexanes to EtOAc) afforded the title compound 47 (150 mg, 0.4 mmol, 6%) as a cream solid. mp=134-136° C.; IR (neat) v.sub.max 3161, 3060, 2954, 2808, 2231, 740 cm.sup.−1; .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 11.48 (s, 1H, NOH), 8.20 (s, 1H, CHNOH), 7.76 (dd, J=8.0, 1.0 Hz, 1H, NCCHCHCH), 7.59 (t, J=8.0 Hz, 1H, NCCHCHCH), 7.35-7.27 (m, 6H, ArH), 3.56 (s, 2H, PhCH.sub.2), 2.82-2.41 (m, 12H, PizCH.sub.2, NCH.sub.2CH.sub.2CC); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 152.9, 149.7, 143.1, 137.4, 136.5, 129.5, 128.3, 127.3, 126.7, 119.1, 89.1, 80.8, 63.0, 56.6, 52.6, 52.5, 17.4; HRMS (ESI).sup.+ m/z for C.sub.21H.sub.25N.sub.4O.sup.+ calculated 349.2023, found 349.2018.

REFERENCES

[0214] 1. Winssinger et al. Chem. Comms. 2010, 46, 5476-5478. [0215] 2. Guarna et al. J. Med. Chem. 2010, 53, 7119-7128.

6-(4-(4-benzylpiperazin-1-yl)butyl)picolinaldehyde oxime 48

[0216] ##STR00072##

[0217] To a degassed suspension of 6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47 (60 mg, 0.2 mmol) in anhydrous methanol (5 mL), was added palladium (10% on carbon, 4 mg, 0.04 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred for 1.5 h at rt. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo, to afford the title compound 48 (53 mg, 0.2 mmol, 87%) as a yellow oil. IR (neat) v.sub.max 3181, 3060, 2938, 2818, 791 cm.sup.−1, .sup.1HNMR (400 MHz, CDCl.sub.3) δ (ppm) 8.18 (s, 1H, CHNOH), 7.62-7.50 (m, 2H, ArH), 7.34-7.29 (m, 5H, ArH), 7.11 (dd, J=7.3, 1.4 Hz, 1H, NCCHCHCH), 5.31 (s, 2H, PhCH.sub.2), 2.82 (t, J=7.3 Hz, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.59-2.31 (m, 10H, PizCH.sub.2, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.76 (quin, J=7.3 Hz, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.58 (br s, 2H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2); .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm) 161.9, 151.5, 150.6, 136.7, 136.6, 129.3, 128.2, 127.1, 122.9, 118.1, 63.0, 58.4, 53.0, 52.7, 37.9, 27.6, 26.1; HRMS (ESI).sup.+ m/z for C.sub.20H.sub.27N.sub.4O.sup.+ calculated 353.2336, found 353.2332.

Synthesis of 6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-Purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51

[0218] ##STR00073##

1-(But-3-yn-1-yl)-3,7-dimethyl-dihydro-1H-purine-2,6-dione 50

[0219] ##STR00074##

[0220] Following an adapted procedure from Itô et al..sup.1 for the synthesis of substituted amines by Mitsunobu reaction; To a solution of 3-butyn-1-ol 44 (0.10 mL, 1.4 mmol), theobromine 49 (500 mg, 2.8 mmol) and triphenyl phosphine (728 mg, 2.8 mmol) in THF (15 mL) at rt was added ADDP (700 mg, 2.8 mmol). The yellow reaction was heated to 60° C. for 24 h. The cream-coloured reaction solution was diluted (H.sub.2O, 50 mL), and the aqueous solution was extracted (EtOAc, 3×20 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo. The white residue was purified by chromatography on silica gel (EtOAc) to afford 1-(but-3-yn-1-yl)-3,7-dimethyl-dihydro-1H-purine-2,6-dione 50 (120 mg, 0.5 mmol, 37%) as a white solid: mp=192-193° C.; IR (neat) v.sub.max 3228, 3107, 2951, 1697, 1651 cm.sup.−1; .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ (ppm) 8.00 (s, 1H, NCHN), 3.99 (t, J=7.6 Hz, 2H, NCH.sub.2CH.sub.2CCH), 3.87 (s, 3H, NCHN(CH.sub.3)), 3.40 (s, 3H, NCON(CH.sub.3)), 2.84 (t, J=2.7 Hz, 1H, NCH.sub.2CH.sub.2CCH), 2.45 (td, J=7.6, 2.7 Hz, 1H, NCH.sub.2CH.sub.2CCH); .sup.13C NMR (101 MHz, DMSO-d.sub.6) δ (ppm) 154.6, 151.1, 148.7, 143.5, 107.0, 81.5, 73.0, 40.6, 33.6, 29.8, 17.3; HRMS (ESI).sup.+ m/z for C.sub.11H.sub.13N.sub.4O.sub.2.sup.+ calculated 233.1033, found 233.1035 and m/z for C.sub.11H.sub.12N.sub.4NaO.sub.2.sup.+ calculated 255.0852, found 255.0857.

6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51

[0221] ##STR00075##

[0222] To a degassed solution of 1-(but-3-yn-1-yl) 3,7-dimethyl-dihydro-1H-purine-2,6-dione 50 (200 mg, 0.9 mmol) in anhydrous THF/Et.sub.3N (7 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (99 mg, 0.1 mmol) and CuI (33 mg, 0.2 mmol). To the resulting orange reaction mixture was added dropwise a degassed solution of 6-bromopicolinaldehyde oxime 2 (190 mg, 1.0 mmol) in anhydrous THF (10 mL). The brown solution was stirred for 16 h at rt. The reaction was concentrated in vacuo giving an orange solid as the crude product. Chromatography on silica gel (EtOAc to 10% MeOH in EtOAc) afforded the title compound 51 (111 mg, 0.3 mmol, 36%) as a colourless: mp=210-211° C.; IR (neat) v.sub.max 3178, 3087, 2872, 2230, 1700, 1647, 759 cm.sup.−1, .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (s, 1H, CHNOH), 8.03 (s, 1H, CHNOH), 8.00 (s, 1H, NCHN), 7.79 (t, J=8.1 Hz, 1H, NCCHCHCH), 7.73 (dd, J=8.1, 1.0 Hz, 1H, NCCHCHCH), 7.39 (dd, J=8.1, 1.0 Hz, 1H, NCCHCHCH), 4.12 (t, J=7.5 Hz, 2H, NHCH.sub.2CH.sub.2), 3.88 (s, 3H, NCHN(CH.sub.3), 3.42 (s, 3H, NCON(CH3), 2.75 (t, J=7.5 Hz, 2H, NHCH.sub.2CH.sub.2); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 154.2, 152.4, 150.7, 148.4, 148.3, 143.1, 142.3, 137.3, 126.8, 119.0, 118.9, 106.5, 87.4, 81.3, 33.2, 29.4, 17.7; HRMS (ESI).sup.+ m/z for C.sub.17H.sub.17N.sub.6O.sub.3.sup.+ calculated 353.1357, found 353.1358.

REFERENCES

[0223] 1. Itô, S. et al. Tet. Letts., 1993, 34, 1639-1642.

μII—Synthesis of Bifunctional Neca Analogs

[0224] ##STR00076##

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 54

[0225] ##STR00077##

[0226] The synthesis of (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid 53 was achieved by using an adapted procedure from Debnath, J. et al..sup.1.

[0227] To a stirred solution of acid 53 (500 mg, 1.56 mmol, 1 equiv) in dry pyridine (15 mL), 1-amino-3-butyne 22 (140 μL, 1.71 mmol, 1.1 equiv), and EDCI (598 mg, 3.12 mmol, 2 equiv) were successively added and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for overnight. After completion, the reaction mixture was directly concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc to EtOAc/MeOH 95:5) to afford the desired amide 54 as light yellow solid (500 mg, 80%). R.sub.f (pure EtOAc) 0.18; IR (neat) v.sub.max 3289, 3142, 1672, 1601, 1526, 1206, 1090, 1058, 868, 789, 645, 514 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.32 (s, 1H), 7.89 (s, 1H), 7.28 (m, 1H), 6.33 (s, 2H), 6.13 (d, J=2.5 Hz, 1H), 5.47 (dd, J=2.1, 6.2 Hz, 1H), 5.39 (dd, J=2.5, 6.2 Hz, 1H), 4.74 (d, J=2.1 Hz, 1H), 3.21 (m, 2H), 2.21 (m, 1H), 2.10 (m, 1H), 1.82 (t, J=2.6 Hz, 1H), 1.63 (s, 3H), 1.40 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 168.98, 155.86, 153.11, 148.99, 139.82, 120.21, 114.37, 91.70, 86.33, 83.59, 82.88, 80.81, 69.83, 37.49, 26.95, 25.07, 18.85; HRMS (ESI.sup.+) m/z calcd for C.sub.17H.sub.21N.sub.6O.sub.4.sup.+373.1575 found 373.1619.

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-formylpyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 55

[0228] ##STR00078##

[0229] To a degassed solution of methyl 6-bromopicolinaldehyde 1 (275 mg, 1.478 mmol, 1.1 equiv) in THF/Et.sub.3N (10 mL/8 mL), Pd[PPh.sub.3].sub.4 (233 mg, 0.202 mmol, 0.15 equiv) and CuI (77 mg, 0.403 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, a degassed solution of alkyne 54 (500 mg, 1.344 mmol, 1 equiv) in THF (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc to EtOAc/MeOH 9:1) to afford the desired coupled picolinaldehyde 55 as thick syrup (510 mg, 80%). IR (neat) v.sub.max 3318, 1638, 1582, 1452, 1209, 1078, 868, 797, 646, 509 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.90 (s, 1H), 8.24 (s, 1H), 7.85-7.65 (m, 3H), 7.38 (m, 1H), 6.40 (s, 1H), 6.02 (s, 1H), 5.33 (s, 2H), 4.70 (s, 1H), 3.35 (m, 2H), 2.60-2.32 (m, 2H), 1.57 (s, 3H), 1.31 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 192.88, 169.13, 155.67, 153.12, 152.63, 148.97, 143.63, 139.87, 137.20, 130.85, 120.19, 114.62, 91.94, 88.87, 85.74, 83.55, 82.54, 80.66, 37.41, 27.09, 25.11, 20.08; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.24N.sub.7O.sub.5.sup.+ 478.1806 found 478.1833.

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 56

[0230] ##STR00079##

[0231] A solution of picolinaldehyde 55 (80 mg, 0.168 mmol, 1 equiv), hydroxylamine hydrochloride (23 mg, 0.336 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (41 mg, 0.503 mmol, 3 equiv) in dry ethanol (5 mL) was stirred at reflux during 16 h. After concentration under reduced pressure, the crude product was washed with CH.sub.2Cl.sub.2 (5*10 mL) to remove all the impurities. The existing compound in the round bottom flask was picolinaldehyde oxime 56, which was dried in high vacuo (82 mg, quant. yield) and confirmed by .sup.1H NMR. R.sub.f (EtOAc); IR (neat) v.sub.max 3186, 2925, 1643, 1579, 1207, 1089, 980, 867, 797, 726, 649, 509 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.20 (s, 1H), 8.11 (s, 1H), 7.92 (m, 2H), 7.46 (m, 2H), 7.02 (m, 3H), 6.05 (d, J=2.7 Hz, 1H), 5.35 (dd, J=2.0, 6.2 Hz, 1H), 5.29 (dd, J=2.7, 6.2 Hz, 1H), 4.74 (d, J=2.0 Hz, 1H), 3.41 (m, 2H), 2.57-2.33 (m, 2H), 1.59 (s, 3H), 1.433 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 169.14, 155.54, 152.89, 152.05, 149.16, 148.60, 142.61, 139.82, 136.66, 126.72, 119.58, 119.47, 114.74, 91.86, 88.15, 85.78, 83.45, 82.68, 81.13, 37.45, 27.11, 25.14, 20.21; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.25N.sub.8O.sub.5.sup.+ 493.1901 found 493.1942. (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(4-(6-(hydroxyimino) methyl)pyridin-2-yl)but-3-yn-1-yl)tetrahydrofuran-2-carboxamide 57:

##STR00080##

[0232] To a stirred solution of oxime 56 (30 mg, 0.061 mmol, 1 equiv) in dry MeOH (5 mL), 1.2 N HCl (185 μL, 0.610 mmol, 10 equiv) was added and the reaction mixture was stirred at 55° C. for 5 h. After completion, the reaction mixture was directly concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (MeOH/H.sub.2O 1:4) to afford the salt 57 as a white solid in quantitative yield. IR (neat) v.sub.max 3192, 2927, 1644, 1580, 1448, 1305, 1254, 1045, 989, 808, 726, 642, 533 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.26 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.68 (br d, J=7.8 Hz, 1H), 7.0 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.30 (d, J=7.9 Hz, 1H), 4.85 (s, 1H), 4.54 (s, 1H), 4.39 (br d, J=4.3 Hz, 1H), 3.63 (m, 2H), 2.74 (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 172.76, 157.47, 154.03, 153.96, 150.15, 149.49, 143.97, 142.67, 138.49, 128.24, 121.22, 120.73, 90.84, 89.91, 86.78, 82.11, 75.30, 73.56, 38.93, 21.02; HRMS (ESI.sup.+) m/z calcd for C.sub.23H.sub.25N.sub.8O.sub.5.sup.+ 493.1901 found 493.1942.

REFERENCES

[0233] 1. Debnath, J. et al. Bioorg. Med. Chem. 2010, 18, 8257-8263.

III—Synthesis of Bifunctional Pseudo Neca Analog

[0234] ##STR00081##

N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-formylpyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 59

[0235] ##STR00082##

[0236] The synthesis of N-(9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((prop-2-yn-1-yloxy)methyl)-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 58 was achieved by using a known procedure from Silvia, F. et al..sup.1.

[0237] To a degassed solution of 6-bromopicolinaldehyde 1 (91 mg, 0.490 mmol, 1.1 equiv) in THF/Et.sub.3N (3 mL/2 mL), Pd[PPh.sub.3].sub.4 (77 mg, 0.067 mmol, 0.15 equiv) and CuI (25 mg, 0.134 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, a degassed solution of alkyne 58 (200 mg, 0.445 mmol, 1 equiv) in THF (3 mL) 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 (EtOAc/petroleum ether 4:1) to afford the desired coupled picolinaldehyde 59 as a thick syrup (200 mg, 81%). IR (neat) v.sub.max 2935, 1704, 1609, 1580, 1452, 1248, 1210, 1074, 864, 709, 645, 541 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.97 (s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.85-7.77 (m, 2H), 7.63-7.51 (m, 2H), 7.45 (t, J=7.6 Hz, 2H), 6.25 (d, J=2.1 Hz, 2H), 5.32 (dd, J=2.1, 6.2 Hz, 1H), 5.03 (dd, J=2.1, 6.2 Hz, 1H), 4.56 (q, J=2.9 Hz, 1H), 4.37 (s, 2H), 3.89-3.77 (m, 2H), 1.61 (s, 3H), 1.37 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 192.58, 164.85, 152.75, 152.59, 151.49, 149.28, 142.85, 141.91, 137.53, 13335, 132.81, 131.23, 128.78, 127.81, 123.24, 120.91, 114.32, 91.61, 85.94, 85.47, 85.20, 84.55, 70.32, 59.09, 27.12, 25.28; HRMS (ESI.sup.+) m/z calcd for C.sub.29H.sub.27N.sub.6O.sub.6.sup.+ 555.2005 found 555.1987.

N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-(hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 60

and 6-(3-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)prop-1-yn-1-yl)picolinaldehyde oxime 61

[0238] ##STR00083##

[0239] A solution of picolinaldehyde 59 (200 mg, 0.361 mmol, 1 equiv), hydroxylamine hydrochloride (50 mg, 0.722 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (89 mg, 1.083 mmol, 3 equiv) in dry ethanol (10 mL) was stirred at reflux during 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography and elution first with DCM to MeOH/DCM (2:98) gave the 60 as a white solid (80 mg, 39%). IR (neat) v.sub.max 3196, 2924, 1698, 1610, 1581, 1453, 1246, 1210, 1075, 907, 727, 644, 551 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.83 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.99-7.89 (m, 2H), 7.54-7.27 (m, 6H), 6.27 (d, J=2.3 Hz, 2H), 5.31 (dd, J=2.3, 6.0 Hz, 1H), 5.03 (dd, J=2.3, 6.1 Hz, 1H), 4.48 (br q, J=3.4 Hz, 1H), 4.37, 4.30 (2d, J=16.1 Hz, 2H), 3.88 (dd, J=3.4, 10.3 Hz, 1H), 3.76 (dd, J=4.0, 10.3 Hz, 1H), 1.62 (s, 3H), 1.38 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 165.11, 152.73, 152.22, 151.35, 149.67, 149.37, 141.87, 136.74, 133.45, 132.69, 128.63, 127.92, 127.22, 122.87, 120.30, 114.28, 91.87, 86.05, 85.03, 84.34, 81.89, 70.23, 59.17, 27.11, 25.26; HRMS (ESI.sup.+) m/z calcd for C.sub.29H.sub.28N.sub.7O.sub.6.sup.+ 570.2075 found 570.2096.

[0240] Further elution (MeOH/DCM 5:95) afforded 61 as a white solid (75 mg, 45%). IR (neat) v.sub.max 3176, 2925, 1639, 1450, 1374, 1207, 1077, 978, 865, 796, 717, 648, 510 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.30 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.64-7.52 (m, 2H), 7.26 (s, 1H), 7.01-6.87 (m, 2H), 6.20 (d, J=1.8 Hz, 2H), 5.35 (m, 1H), 5.03 (m, 1H), 4.57 (m, 1H), 4.35 (m, 2H), 3.88-3.76 (m, 2H), 1.61 (s, 3H), 1.38 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 155.35, 152.55, 152.47, 149.34, 149.08, 141.96, 139.32, 136.75, 132.82, 127.10, 119.93, 114.13, 91.70, 86.10, 85.72, 84.86, 84.38, 81.88, 70.21, 59.11, 27.07, 25.27; HRMS (ESI.sup.+) m/z calcd for C.sub.22H.sub.24N.sub.7O.sub.5.sup.+ 466.1812 found 466.1833.

REFERENCES

[0241] 1. Silvia, F. et al. J. Med. Chem. 2015, 58, 8269-8284

IV—Synthesis of Bifunctional 3-Methoxy Pyridinaldoxime Analogs

Synthesis of 3-methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65

[0242] ##STR00084##

3-methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde 63

[0243] ##STR00085##

[0244] To a degassed solution of commercial 6-bromo-3-methoxypicolinaldehyde 62 (75 mg, 0.347 mmol, 1.0 equiv) in THF/Et.sub.3N (4 mL/2 mL), Pd[PPh.sub.3].sub.4 (60 mg, 0.052 mmol, 0.15 equiv) and CuI (20 mg, 0.104 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, alkyne 3 (50 mg, 0.347 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/PE 1:4) to afford the desired coupled methoxy piconaldehyde 63 as a colourless liquid (80 mg, 83%). R.sub.f (30% EtOAc+PE) 0.25; IR (neat) v.sub.max 2941, 2230, 1709, 1552, 1466, 1267, 1007, 747, 699, 542 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.21 (s, 1H, H.sub.18), 7.52 (d, J=8.8 Hz, 1H, H.sub.4), 7.33 (d, J=8.8 Hz, 1H, H.sub.5), 7.28-7.13 (m, 5H, H.sub.13-H.sub.17), 3.93 (s, 3H, −OMe), 2.74 (t, J=7.5 Hz, 2H, H.sub.11), 2.39 (t, J=7.1 Hz, 2H, H.sub.9), 1.91 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 195.52 (C18), 156.25, 141.28, 140.73, 136.02, 132.0, 128.44, 128.32, 125.91, 120.41 (Ar), 90.27 (C7), 79.44 (C8), 56.03 (−OMe), 34.86 (C11), 29.76 (C10), 18.72 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.18H.sub.18N.sub.1O.sub.2.sup.+280.1332 found 280.1348.

3-methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 64

[0245] ##STR00086##

[0246] A solution of aldehyde 63 (45 mg, 0.161 mmol, 1 equiv), hydroxylamine hydrochloride (22 mg, 0.322 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (40 mg, 0.483 mmol, 3 equiv) in dry ethanol (3 mL) was stirred at reflux for 16 h. Upon completion (monitored by TLC), the solids were removed by filtration through a short celite pad, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (EtOAc/PE 3:7) to afford oxime 64 as a white solid (45 mg, 95%). R.sub.f (50% EtOAc+PE) 0.35; IR (neat) v.sub.max 3247, 2938, 2234, 1564, 1463, 1263, 975, 828, 745, 698, 649, 487 cm.sup.−1; .sup.*1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.42 (br s, 1H, OH), 8.42, 8.10 (2s, 1.2H, H.sub.18, H.sub.18′), 7.46-7.19 (m, 7.6H, Ar), 3.94, 3.91 (2s, 3.6H, −OMe), 2.81, 2.80 (2t, J=7.5 Hz, 2.4H, H.sub.11, H.sub.11′), 2.47, 2.44 (2t, J=7.1 Hz, 2.4H, H.sub.9, H.sub.9′), 2.02-1.92 (m, 2.4H, H.sub.10, H.sub.10); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 153.54, 151.66, 147.87, 141.41, 141.17, 140.65, 140.23, 136.37, 135.53, 131.86, 129.18, 128.47, 128.34, 128.29, 127.83, 125.93, 125.84, 119.29, 118.69 (Ar), 90.98, 89.24 (C7), 79.93, 78.76 (C8), 55.93, 55.70 (−OMe), 34.85, 34.76 (C11), 29.86, 29.73 (C10), 18.74, 18.57 (C9) (*1:5 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.18H.sub.18N.sub.2NaO.sub.2.sup.+317.1260 found 317.1256.

3-methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65

[0247] ##STR00087##

[0248] To a degassed solution of methoxy pyridinaldoxime 64 (25 mg, 0.085 mmol, 1 equiv) in dry EtOAc (2 mL), 10% Pd/C (4.5 mg, 0.042 mmol, 0.5 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm.) for 3 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 oxime 65 as a colourless liquid (24 mg, 95%); R.sub.f (50% EtOAc+PE) 0.40; IR (neat) v.sub.max 3253, 2927, 2855, 1570, 1464, 1269, 1127, 975, 746, 698 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.40, 8.02 (2s, 1.2H, H.sub.18, H.sub.18), 7.24-6.96 (m, 9.4H, Ar), 3.79, 3.78 (2s, 3.6H, −OMe), 2.70-2.62 (m, 2.5H, H.sub.11, H.sub.11′), 2.55-2.49 (m, 2.5H, H.sub.7, H.sub.7′), 1.68-1.52 (m, 5H, H.sub.8, H.sub.8′, H.sub.10, H.sub.10′), 1.35-1.28 (m, 2.5H, H.sub.9, H.sub.9′); *13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 154.25, 152.57, 150.87, 150.67, 146.82, 142.71, 142.47, 140.12, 139.24, 137.09, 128.35, 128.21, 128.16, 125.59, 125.51, 125.06, 123.58, 119.91, 119.18 (Ar), 55.82, 55.63 (−OMe), 37.23, 36.25 (C11), 35.78, 35.73 (C7), 31.25, 31.12 (C10), 29.85, 29.67 (C9), 28.90, 28.65 (C8) (*1:4 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.18H.sub.23N.sub.2O.sub.2.sup.+299.1754 found 299.1740.

V—Synthesis of Quinoline Derived Methoxy Pyridinaldoxime Analogs

[0249] ##STR00088##

3-methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde 6

[0250] ##STR00089##

[0251] To a degassed solution of commercially available 6-bromo-3-methoxypicolinaldehyde 62 (97 mg, 0.448 mmol, 1.1 equiv) in THF/Et.sub.3N (3 mL/3 mL), Pd[PPh.sub.3].sub.4 (71 mg, 0.061 mmol, 0.15 equiv) and CuI (23 mg, 0.122 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, alkyne 24 (80 mg, 0.408 mmol, 1 equiv) in THF (3 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc 1:9) to afford the desired coupled methoxy piconaldehyde 66 as a light yellow solid (126 mg, 93%). R.sub.f (30% MeOH+EtOAc) 0.25; IR (neat) v.sub.max 3281, 2926, 2233, 1704, 1582, 1434, 1267, 1126, 1009, 763, 694, 521, 494 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.21 (s, 1H, H.sub.18), 7.52 (d, J=8.8 Hz, 1H, H.sub.4), 7.33 (d, J=8.8 Hz, 1H, H.sub.5), 7.28-7.13 (m, 5H, H.sub.13-H.sub.17), 3.93 (s, 3H, −OMe), 2.74 (t, J=7.5 Hz, 2H, H.sub.11), 2.39 (t, J=7.1 Hz, 2H, H.sub.9), 1.91 (quintet, J=7.1, 7.5 Hz, 2H, H.sub.10); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 195.52 (C18), 156.25, 141.28, 140.73, 136.02, 132.0, 128.44, 128.32, 125.91, 120.41 (Ar), 90.27 (C7), 79.44 (C8), 56.03 (−OMe), 34.86 (C11), 29.76 (C10), 18.72 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.18H.sub.18N.sub.1O.sub.2.sup.+280.1332 found 280.1348.

3-methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 67

[0252] ##STR00090##

[0253] A solution of aldehyde 66 (100 mg, 0.362 mmol, 1 equiv), hydroxylamine hydrochloride (50 mg, 0.724 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (89 mg, 1.086 mmol, 3 equiv) in dry ethanol (5 mL) was stirred at reflux for 16 h. Upon completion (monitored by TLC), the solids were removed by filtration through a short celite pad, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (MeOH/EtOAc 1:9) to afford the oxime 67 as a white solid (65 mg, 62%). R.sub.f (30% MeOH+EtOAc) 0.2; IR (neat) v.sub.max 3319, 2924, 1897, 1586, 1460, 1242, 1115, 982, 829, 760, 649, 524 cm.sup.−1; .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm) 11.63 (br s, 1H, OH), 8.41 (d, J=5.2 Hz, 1H, Ar), 8.22 (s, 1H, —C—NOH), 8.21 (d, J=8.5 Hz, 1H, Ar), 7.79 (d, J=8.5 Hz, 1H, Ar), 7.61 (t, J=7.6 Hz, 1H, Ar), 7.50-7.36 (m, 4H, Ar), 6.58 (d, J=5.4 Hz, 1H, Ar), 3.85 (s, 3H, −OMe), 3.58 (q, J=5.9, 7.1 Hz, 2H, H.sub.10), 2.83 (t, J=7.1 Hz, 2H, H.sub.9); .sup.13C NMR (125 MHz, DMSO-d6) δ (ppm) 153.77, 151.22, 149.97, 148.83, 145.06, 140.87, 134.59, 129.57, 129.24, 128.54, 124.42, 122.07, 120.24, 119.30, 98.94, (Ar), 87.06 (C8), 81.50 (C7), 56.46 (−OMe), 41.75 (C10), 19.08 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.20H.sub.19N.sub.4O.sub.2.sup.+ 347.1503 found 347.1491.

4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinolin-1-ium chloride 68

[0254] ##STR00091##

[0255] To compound 67 (9.5 mg) in MeOH/H.sub.2O (0.5 mL/0.5 mL), 1.2 N HCl (0.1 mL) was added and agitated for 2 min and left for 10 min at rt. The reaction mixture was concentrated under reduced pressure to afford HCl salt 68 as a white solid in quantitative yield. IR (neat) v.sub.max 3186, 3099, 2838, 2237, 1615, 1593, 1449, 1277, 1007, 760, 649, 530, 491 cm.sup.−1; .sup.1H NMR (500 MHz, D.sub.2O) δ (ppm)*8.18-8.08 (m, 3H, Ar), *7.96-7.91 (m, 1.5H, Ar), *7.74-7.70 (m, 1.5H, Ar), *7.62-7.54 (m, 3H, Ar), *7.51-7.40 (m, 4.5H, Ar), *6.73-6.70 (m, 1.5H, Ar), *3.92 (s, 1.5H, −OMe), *3.84 (t, J=6.6 Hz, 1H, H.sub.10′), 3.80 (s, 3H, −OMe), 3.75 (t, J=6.6 Hz, 2H, H.sub.10), *2.98 (t, J=6.6 Hz, 1H, H.sub.9′), 2.89 (t, J=6.6 Hz, 2H, H.sub.9); *.sup.13C NMR (125 MHz, D.sub.2O) δ (ppm) 156.49, 154.95, 142.15, 142.03, 141.86, 141.45, 140.04, 139.68, 138.68, 137.60, 137.00, 134.19, 131.06, 130.37, 128.51, 128.26, 17.55, 127.52, 125.38, 122.39, 120.29, 120.22, 119.12, 116.93, 116.81, 98.55, 98.47 (Ar), 94.74 (C8), 76.76 (C7), 57.71, 57.22 (−OMe), 41.65, 41.10 (C10), 19.5 (C9) (*1:2 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.20H.sub.20ClN.sub.4O.sub.2.sup.+ 347.1503 found 347.1461.

3-methoxy-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime 69

[0256] ##STR00092##

[0257] To a degassed solution of methoxy pyridinaldoxime 67 (25 mg, 0.085 mmol, 1 equiv) in dry EtOAc (2 mL), 10% Pd/C (4.5 mg, 0.042 mmol, 0.5 equiv) was added. After flushing with H.sub.2 three times, the reaction mixture was stirred at room temperature under H.sub.2 (1 atm) for 3 h. Upon completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (EtOAc/PE 1:9) to afford oxime 69 as a colourless liquid (24 mg, 95%); R.sub.f (50% EtOAc+PE) 0.40; IR (neat) v.sub.max 3327, 2923, 2853, 1582, 1457, 1272, 1126, 968, 763, 694, 540, 473 cm.sup.−1; .sup.*1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 8.42 (2s, 1H, H.sub.18, H.sub.18), 8.32 (d, J=5.7 Hz, 1H, Ar), 8.10 (dd, J=1.2, 8.6 Hz, 1H, Ar), 7.79 (d, J=1.2, 8.6 Hz, 1H, Ar), 7.64 (m, 1H, Ar), 7.44 (m, 1H, Ar), 7.39 (d, J=8.7 Hz, 1H, Ar), 7.26 (d, J=8.7 Hz, 1H, Ar), 6.50 (d, J=5.8 Hz, 1H, Ar), 3.87 (s, 3H, −OMe), 3.42 (t, J=6.9 Hz, 1H, H.sub.10), 3.42 (t, J=6.9 Hz, 1H, H.sub.10), 2.83 (t, J=7.5 Hz, 1H, H.sub.7), 1.87-1.77 (m, 4H, H.sub.8, H.sub.9); *.sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 155.21, 154.35, 153.13, 150.73, 148.33, 145.93, 140.73, 138.63, 130.85, 128.33, 125.82, 122.51, 121.43, 120.31, 99.30 (Ar), 56.53 (−OMe), 43.86 (C10), 37.37 (C7), 28.95 (C9), 28.82 (C8) (*1:4 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.20H.sub.23N.sub.4O.sub.2.sup.+ 351.1816 found 351.1827.

4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)butyl)amino)quinolin-1-ium 70

[0258] ##STR00093##

[0259] To a compound 69 (8 mg) in MeOH/H.sub.2O (0.5 mL/0.5 mL), 1.2 N HCl (0.1 mL) and agitated for 2 min and left for 10 min at rt. The reaction mixture was concentrated under reduced pressure to obtain HCl salt 70 as a white solid in quantitative yield. IR (neat) v.sub.max 3237, 3111, 2926, 1617, 1594, 1452, 1291, 1011, 764, 663, 592 cm.sup.−1; .sup.1H NMR (500 MHz, D.sub.2O) δ (ppm) 8.20 (s, 1H, H.sub.18), 8.19 (d, J=8.6 Hz, 1H, Ar), 8.04 (d, J=8.6 Hz, 1H, Ar), 7.94-7.87 (m, 2H, Ar), 7.75 (dd, J=8.6, 18.8 Hz, 1H, Ar), 7.64 (t, J=8.8 Hz, 1H, Ar), 6.64 (d, J=7.2 Hz, 1H, Ar), 3.93 (s, 3H, −OMe), 3.55 (t, J=6.5 Hz, 1H, H.sub.10), 3.01 (t, J=6.8 Hz, 1H, H.sub.7), 1.95-1.80 (m, 4H, H.sub.8, H.sub.9); *.sup.13C NMR (125 MHz, D.sub.2O) δ (ppm) 156.07, 154.21, 150.14, 141.63, 139.57, 137.60, 134.14, 133.86, 129.10, 128.69, 127.47, 122.29, 120.27, 116.86, 98.31 (Ar), 57.45 (−OMe), 42.83 (C10), 32.20 (C7), 26.12 (C9), 25.81 (C8) (*1:2 ratio of cis-trans isomers); HRMS (ESI.sup.+) m/z calcd for C.sub.20H.sub.23N.sub.4O.sub.2.sup.+351.1816 found 351.1782.

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-(-(hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 72

[0260] ##STR00094##

[0261] To a degassed solution of commercially available 6-bromo-3-methoxypicolinaldehyde 62 (192 mg, 0.887 mmol, 1.1 equiv) in THF/Et.sub.3N (5 mL/5 mL), Pd[PPh.sub.3].sub.4 (140 mg, 0.121 mmol, 0.15 equiv) and CuI (46 mg, 0.242 mmol, 0.3 equiv) were added. After degassing the reaction mixture for 5 min at room temperature, alkyne 54 (300 mg, 0.806 mmol, 1 equiv) in THF (5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was passed through a small filter column (MeOH/EtOAc 5:95) to afford the desired coupled methoxy piconaldehyde 71 (360 mg, 88%) as a light yellow solid. This crude aldehyde was directly used for the next step without purification.

[0262] A solution of aldehyde 71 (220 mg, 0.433 mmol, 1 equiv), hydroxylamine hydrochloride (60 mg, 0.867 mmol, 2 equiv), and CH.sub.3CO.sub.2Na (107 mg, 1.299 mmol, 3 equiv) in dry ethanol (7 mL) was stirred at reflux during 16 h. Upon completion (monitored by TLC), the solids were removed by filtration through a short celite pad, the solvent was evaporated, and the residue was purified by column chromatography (MeOH/EtOAc 1:9) to afford oxime 72 as a white solid (180 mg, 78%). R.sub.f (30% MeOH+EtOAc) 0.2; IR (neat) v.sub.max 3185, 2926, 1640, 1464, 1264, 1209, 1090, 971, 868, 797, 647, 510 cm.sup.1; .sup.1H NMR (400 MHz, MeOD) δ (ppm) 8.39-8.11 (3s, 3H, Ar, —C═NOH), 7.37 (d, J=8.6, 1 H, H.sub.4), 7.26 (d, J=8.6 Hz, 1H, H.sub.5), 6.34 (br s, H, —CH), 5.57 (dd, J=1.8, 6.0 Hz, 1H, —CH), 5.41 (br d, J=6.0 Hz, 1H, —CH), 4.68 (d, J=1.8 Hz, 1H, —CH), 3.89 (s, 3H, —OCH.sub.3), 3.21 (m, 1H, —CH.sub.2), 3.09 (m, 1H, —CH.sub.2), 2.27 (m, 1H, —CH.sub.2), 2.10 (m, 1H, —CH.sub.2), 1.57 (s, 3H, —CH.sub.3), 1.37 (s, 3H, —CH3); .sup.13C NMR (100 MHz, MeOD) δ (ppm) 172.07, 157.33, 155.15, 153.99, 150.30, 145.21, 142.55, 141.69, 135.92, 129.89, 120.84, 120.49, 115. 17 (Ar), 92.41 (C16), 88.65 (C15), 87.34 (C8), 85.36 (C14), 85.26 (C13), 81.58 (C7), 56.74 (C30), 38.79 (C10), 27.29 (C28), 25.54 (C29), 20.47 (C9); HRMS (ESI.sup.+) m/z calcd for C.sub.24H.sub.27N.sub.8O.sub.6.sup.+523.2048 found 523.2038.

VI—Synthesis of Tri Functional Neca Compounds

[0263] ##STR00095##

6-(azidomethyl)picolinaldehyde 75

[0264] ##STR00096##

[0265] The synthesis of methyl 6-(azidomethyl)picolinate 74 was achieved by using a well-established procedure from Harekrushna, B. et al..sup.1.

[0266] To the solution of azido ester 74 (100 mg 0.521 mmol, 1 equiv) in dry CH.sub.2Cl.sub.2 (5 mL) at −78° C., DIBAL-H (1 M solution in CH.sub.2Cl.sub.2, 1.563 mL, 1.563 mmol, 3 equiv) was added dropwise and the reaction mixture was stirred at −78° C. for 5 h. After completion of the reaction, the reaction mixture was quenched with MeOH (3 mL), and the cooling bath was removed. When the mixture was warmed to room temperature, the reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The combined organic layers are dried over MgSO.sub.4. The solids were filtered off and the solvent is evaporated to get aldehyde 75. This crude aldehyde 75 was directly subjected for the next step without purification. IR (neat) v.sub.max 2836, 2098, 1709, 1591, 1457, 1255, 990, 777, 641 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.04 (s, 1H), 7.94-7.86 (m, 2H), 7.56 (m, 2H), 4.57 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ (ppm) 193.07, 156.73, 152.59, 138.11, 126.05, 102.78, 55.15; HRMS (ESI.sup.+) m/z calcd for C.sub.7H.sub.7N.sub.4O.sub.1.sup.+ 163.0604 found 163.0614.

6-(azidomethyl)picolinaldehyde oxime 76

[0267] ##STR00097##

[0268] A solution of crude picolinaldehyde 75 (0.521 mmol, 1 equiv), hydroxylamine hydrochloride (73 mg, 1.042, 2 equiv), and CH.sub.3CO.sub.2Na (128 mg, 1.563 mmol, 3 equiv) in dry ethanol (5 mL) was stirred at 80° C. during 16 h. Upon completion, the solids were removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc/P.E: 1:9) to afford the oxime 76 (70 mg, 76%) as thick syrup. IR (neat) v.sub.max 3182, 30102889, 2084, 1572, 1590, 1459, 12666, 1233, 1158, 994, 966, 782, 741, 651, 619, 501 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.10 (s, 1H), 7.86-7.76 (m, 2H), 7.40 (dd, J=1.8, 6.8 Hz, 2H), 4.48 (s, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 157.29, 153.94, 149.93, 139.26, 1323.66, 120.86, 56.16; HRMS (ESI.sup.+) m/z calcd for C.sub.7H.sub.8N.sub.5O.sub.1.sup.+ 178.0721 found 178.0723508.1867.

(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(2-(1-((6-(-(hydroxyimino)meth-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 77

[0269] ##STR00098##

[0270] To a stirred solution of oxime 76 (52 mg, 0.295 mmol, 1.1 equiv) in t-BuOH/H.sub.2O (2 mL/1.5 mL), CuSO.sub.4 (17 mg, 0.107 mmol, 0.4 equiv), sodium ascarbate (21 mg, 0.107 mmol, 0.4 equiv) and alkyne 54 (100 mg, 0.268 mmol, 1 equiv) were added. The reaction mixture was allowed to stir for 6 h at 80° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH/EtOAc: 5:95) to afford the desired triazole compound 77 as a white solid (85 mg, 58%). IR (neat) v.sub.max 3192, 2924, 1644, 1598, 1458, 1376, 1209, 1155, 1057, 992, 868, 797, 648, 511 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 8.20 (s, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.75-7.70 (m, 2H), 7.12 (m, 1H), 6.30 (d, J=1.7 Hz, 1H), 5.62 (s, 2H), 5.50 (dd, J=1.9, 6.1 Hz, 1H), 4.62 (d, J=1.9 Hz, 1H), 3.24-3.01 (m, 2H), 2.61-2.41 (m, 2H), 1.57 (s, 3H), 1.38 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 171.91, 157.38, 156.08, 153.97, 150.27, 150.06, 146.45, 142.54, 139.28, 124.46, 123.53, 121.07, 120.55, 115.24, 92.65, 88.38, 85.28, 85.06, 56.09, 39.64, 27.31, 25.91, 25.55; HRMS (ESI.sup.+) m/z calcd for C.sub.24H.sub.28N.sub.11O.sub.5.sup.+ 550.2237 found 550.2269.

(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(2-(1-((6-(-(hydroxyimino)-methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)tetrahydrofuran-2-carboxamide. hydrochloride 78

[0271] ##STR00099##

[0272] To a stirred solution of triazole 77 (23 mg, 0.042 mmol, 1 equiv) in dry MeOH (2 mL), 1.2 N HCl (127 μL, 0.42 mmol, 10 equiv) was added and the reaction mixture was stirred at 55° C. for 4 h. After completion, the reaction mixture was directly concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (MeOH/H.sub.2O 3:7) to afford HClsalt 78 (15 mg, 72%) as a white solid. IR (neat) v.sub.max 3196, 1640, 1588, 1458, 1427, 1306, 1254, 1113, 1054, 997, 796, 647 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 7.99 (s, 1H), 8.89 (s, 1H), 7.83 (s, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.29 (t, J=9.3 Hz, 1H), 7.20 (s, 1H), 7.13 (t, J=7.8 Hz, 1H), 5.77 (d, J=8.3 Hz, 1H), 5.44-5.38 (2d, J=14.8 Hz, 2H), 4.43 (s, 1H), 4.32 (br d, J=5.0 Hz, 1H), 4.08 (dd, J=4.8, 8.3 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 3.08-299 (m, 1H), 3.96-288 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 172.32, 155.44, 153.78, 151.99, 150.84, 147.61, 142.13, 138.97, 124.62, 124.41, 121.56, 119.75, 89.21, 85.20, 73.72, 72.06, 55.28, 49.50 (MeOH), 39.92, 24.77; HRMS (ESI.sup.+) m/z calcd for C.sub.21H.sub.334N.sub.11O.sub.5.sup.+ 510.1957 found 510.1956.

REFERENCES

[0273] 1. Harekrushna, B. et al. Chem. Eur. J. 2015, 21, 10179-10184.

VII—Synthesis of Tri Functional Pseudo Neca Compound

[0274] ##STR00100##

N-(9-((3aR,4R,6R,6aR)-6-(((1-((6-(-(hydroxyimino)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 79

[0275] ##STR00101##

[0276] To a stirred solution of oxime 76 (44 mg, 0.245 mmol, 1.1 equiv) in t-BuOH/H.sub.2O (2 mL/1.5 mL), CuSO.sub.4 (17 mg, 0.045 mmol, 0.2 equiv), sodium ascarbate (18 mg, 0.045 mmol, 0.2 equiv) and alkyne 58 (100 mg, 0.223 mmol, 1 equiv) were added. The reaction mixture was allowed to stir for 6 h at 80° C. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc-MeOH/EtOAc: 5:95) to afford the desired triazole compound 79 as a white solid (100 mg, 72%). IR (neat) v.sub.max 2924, 1698, 1610, 1581, 1455, 1248, 1211, 1070, 994, 796, 709, 645, 563 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm) 10.88 (br s, 1H), 9.31 (br s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.95-7.80 (m, 3H), 7.51-7.28 (m, 5H), 6.99 (d, J=7.5 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.63 (s, 2H), 5.21 (dd, J=2.2, 5.9 Hz, 1H), 4.98 (dd, J=1.6, 5.9 Hz, 1H), 4.65-4.50 (m, 3H), 3.82 (dd, J=2.2, 10.6 Hz, 1H), 3.70 (dd, J=3.0, 10.6 Hz, 1H), 1.61 (s, 3H), 1.37 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ (ppm) 165.35, 154.38, 152.69, 151.64, 151.44, 150.02, 149.19, 143.91, 141.90, 137.62, 133.31, 128.56, 127.93, 124.13, 122.78, 122.07, 120.42, 114.09, 92.26, 86.27, 85.28, 81.85, 70.67, 64.47, 55.03, 27.11, 25.24; HRMS (ESI.sup.+) m/z calcd for C.sub.30H.sub.31N.sub.10O.sub.6.sup.+ 627.2414 found 627.2423.

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

[0277] Compounds 57, 78, 25 and 26 of example 1 were tested for their activation 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.

[0278] The protocol was as follows:

[0279] Materials and methods are already described in WO2017021319, in European Journal of Medicinal Chemistry 2014, 78, 455-467, and in J. Med. Chem. 2018, 61, 7630-7639.

[0280] IC.sub.50 measurements. Recombinant hAChE was produced and purified as previously described (Carletti et al 2008 J Am Chem Soc 130(47): 1601 1-20). Compounds were dissolved in MeOH to make a 5 mM or a 10 mM stock solution and further diluted in phosphate buffer (sodium phosphate 0.1 M, pH 7.4). Recombinant hAChE activity was measured spectrophotometrically (absorbance at 412 nm) in the presence of various concentrations of oximes in 1 mL Ellman's buffer (sodium phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25° C.). Measurements were performed at least in duplicate for each concentration tested. The concentration of compound producing 50% of enzyme inhibition was determined by non-linear fitting using ProFit (Quantumsoft) using the standard IC.sub.50 equation: % Activity=100*IC.sub.50/(IC.sub.50+[Ox]).

[0281] Inhibition of hAChE by OPNAs. Recombinant hAChE was produced and purified as previously described (see reference: http://www.ncbi.nlm.nih.gov/pubmed/18975951). VX and Tabun were from DGA maitrise NRBC (Vert le Petit, France). Stock solution of VX, Sarin, Tabun and Paraoxon were 5 mM in isopropanol. The inhibition of 120 μM hAChE was carried out with a 5-fold excess of OPNAs and was performed in tris buffer (20 mM, pH 7.4, 0.1% BSA) at 25° C. After incubation for 20 minutes, inhibited hAChE was desalted on PD-10 column (GE Healthcare).

[0282] Reactivation of hAChE inhibited by OPNAs. OPNA-inhibited hAChE was incubated at 37° C. with at least 4 or 5 concentrations of oxime in phosphate buffer (0.1 M, pH 7.4, 0.1% BSA). The final concentration of MeOH in the incubation mix was below 2% and had no influence on the enzyme stability. At time intervals ranging from 1 to 10 minutes depending on the reactivation rate, 10 aliquots of each solution containing the different concentrations of oxime were transferred to cuvettes containing 1 mM acetylthiocholine in 1 mL Ellman's buffer (phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25° C.) for measurement of hAChE activity.

[0283] The enzyme activity in the control remained constant during the experiment. The percentage of reactivated enzyme (% E.sub.react) was calculated as the ratio of the recovered enzyme activity and activity in the control. The apparent reactivation rate kobs for each oxime concentration, the dissociation constant K.sub.D of inhibited enzyme-oxime complex (E-POx) and the maximal reactivation rate constant k.sub.r, were calculated by non-linear fit with ProFit (Quantumsoft) using the standard oxime concentration-dependent reactivation equation derived from the following scheme:

[00001]$\mathrm{E—P}+\mathrm{Ox}\stackrel{K_D}{\rightleftharpoons }\mathrm{E—POx}\stackrel{k_r}{.Math.}E+\mathrm{POx}$$\%E_{\mathrm{react}}=100\mathrm{.star-solid.}\left(1-e^{\mathrm{kobs.star-solid.t}}\right)\mathrm{and}{k}_{\mathrm{obs}}=\frac{k_r\mathrm{.star-solid.}\left[\mathrm{Ox}\right]}{K_D+\left[\mathrm{Ox}\right]}$

E-P=enzyme
Ox=oxime compound
E-Pox=enzyme-oxime complex

[0284] The results are as follows (Tables 1 and 2):

TABLE-US-00001 TABLE 1 Reactivation of OP-inhibited human hAChE by oximes 2-PAM, HI6, 57, 78, 25, 26. kr.sub.2 OP Oxime (μM) k.sub.r (min.sup.−1) K.sub.D (μM) (mM.sup.−1 min.sup.−1) VX 2-PAM  0.19 ± 0.013 26 ± 7  7.3 HI6 0.38 ± 0.02 19 ± 4  20 57 0.58 ± 0.07 100 ± 24  6 78  0.2 ± 0.01 98.5 ± 17   2 25  0.05 ± 0.001 1.2 ± 0.1 42 26  0.06 ± 0.001   3 ± 0.3 20 Sarin 2-PAM 0.27 ± 0.02 25 ± 7  10.8 HI6 0.76 ± 0.06 57 ± 11 13.3 57  1.2 ± 0.15 110 ± 31  10.9 78 3.7 ± 0.5 181 ± 46  20.4 25  0.03 ± 0.0006 0.35 ± 0.1  86 26  0.027 ± 0.0006 1.1 ± 0.1 25 Tabun 2-PAM 0.47 ± 0.2  211 ± 113 2.2 HI6 0 0 0 57  1.2 ± 0.07 32 ± 7  38 78 0.15 ± 0.01 5.4 ± 1.8 29 25 0 0 0 26 0 0 0 Paraoxon 2-PAM 0.066 ± 0.02  68 ± 16 1 HI6 290 ± 70   0.1 ± 0.01 0.36 57 0.36 ± 0.16 57 ± 9  6.4 78 0 0 0 25 0 0 0 26 0 0 0

[0285] Table 1 shows that compound 57 shows higher reactivation kinetics (k.sub.r in min.sup.−1) for VX, Tabun, Sarin and Paraoxon, as compared to references 2-PAM and HI6; and that compound 78 shows higher reactivation kinetics (k.sub.r in min.sup.−1) for VX, Tabun and Sarin, as compared to references 2-PAM and HI6.

[0286] Compounds 25 and 26 show strong affinities for AChE inhibited by VX or Sarin. These compounds show higher reactivation (kr2 mM.sup.−1 min.sup.−1) than 2-PAM and HI6.

TABLE-US-00002 TABLE 2 IC50 for AChE of oximes: 2-PAM, HI6, 57, 78, 25, 26. Oxime IC.sub.50 (μM) 2-PAM 580 ± 28  HI6 82 ± 6  57 79% at 1.5 mM 78 840 ± 106 25   4 ± 0.4 26 11 ± 2 

[0287] Table 2 shows that compounds 25 and 26 show very high affinities for AChE, which are higher than the ones of 2-PAM and HI6. Compound 25 shows the best affinity.