, Eur. J. Med. Chem, vol.82, pp.293-307, 2014.
, Eur. J. Med. Chem, vol.89, pp.21-31, 2015.
, Bioorg. Med. Chem. Lett, vol.26, pp.2580-2583, 2016.
,
, J. Med. Chem, vol.59, pp.6455-6469, 2016.
, J. Med. Chem, vol.53, pp.6455-6469, 2010.
, ACS Med. Chem. Letters, vol.5, pp.700-705, 2014.
, Mol. Cell. Encocrinol, vol.57, pp.48-56, 2014.
, Eur. J. Pharmacol, vol.404, pp.213-219, 2000.
, ChemMedChem, vol.7, pp.1057-1070, 2012.
, J. Biol. Chem, vol.279, pp.6952-6958, 2004.
, , vol.25, pp.80-87, 2006.
, J. Struct. Biol, vol.165, pp.88-96, 2009.
, Bioorg. Med. Chem. Lett, vol.23, pp.190-193, 2012.
, J. Immunol, vol.170, pp.4840-4845, 2003.
, Nat. Rev. Immunol, vol.8, pp.327-336, 2008.
, Science, vol.293, pp.306-311, 2001.
, Nature, vol.398, pp.723-728, 1999.
, J. Clin. Invest, vol.115, pp.237-246, 2005.
, Nat. Rev. Cancer, vol.14, pp.769-785, 2014.
, J. Med. Chem, vol.52, pp.1251-1254, 2009.
,
, , vol.29, 1046.
,
, Nat. Biotechnol, vol.26, pp.127-132, 2008.
,
, Invest. New Drug, vol.31, pp.417-424, 2013.
, J. Clin. Oncol, vol.5, pp.1329-1338, 2006.
, J. Med. Chem, vol.55, pp.8721-8734, 2012.
, J. Am. Chem. Soc, vol.135, pp.6218-6221, 2012.
, Chem. Rev, vol.107, pp.294-307, 2007.
, Metal-Catalyzed Cross-Coupling Reactions and More, vol.46, pp.1173-1193, 2007.
, Angew. Chem. Int. Ed, vol.48, pp.12138-12204, 2011.
, Topics in Current Chemistry, 2010.
, Metal-Catalyzed Cross-Coupling Reactions and More, pp.1427-1493, 2014.
, Etat de l'art sur l'alcynylation directe d'hétérocycles
, En effet, les alcynes étant plus pauvres en électrons que leurs analogues alcènes, ils sont moins réactifs en tant que partenaires de couplage. Le développement de précurseurs électrophiles d'alcynes tels qu'halogénures d'alcynes, 88, 103 sulfones acétyléniques, 104 acétylénures de cuivre 87 et acides ?,?ynoïques, 105 ainsi que l'utilisation de dérivés d'iode hypervalent 106 ont permis de pallier à ce manque de réactivité (Schéma 49). 107 En particulier, les alcènes gem-dihalogénés se sont révélés plus intéressants que les monohalogénures d'alcynes correspondants, p.108
, Schéma 49. Précurseurs d'alcynes décrits dans la littérature
, Angew. Chem. Int. Ed, vol.80, pp.4094-4097, 1996.
, Chem. Soc. Rev, vol.41, pp.4165-4179, 2012.
, Chem. Rev, vol.112, pp.1344-1462, 2012.
, J. Med. Chem, vol.55, pp.5291-5310, 2012.
, J. Org. Chem, vol.63, pp.8965-8975, 1998.
, Org. Lett, vol.17, pp.4640-4643, 2015.
, Org. Lett, vol.16, pp.3796-3799, 2014.
, Org. Lett, vol.8, pp.5517-5520, 2006.
, GLAXOSMITHKLINE, WO2005/048999A3, 2005.
, Synthesis, pp.2081-2084, 2001.
, Beilstein J. Org. Chem, vol.9, pp.1781-1790, 2013.
, 2H), 1.04 (s, 3H). 13 C NMR (75 MHz, CDCl3)
, , vol.126
, MS (ES+) m/z (%): 349.1 (100)
, amino-2-fluorophenoxy)-3-benzyl-2isopropyl-3H-imidazo[4,5-b]pyridin-6-yl)-N,N-dimethylaniline 91b (35 mg, 0.07 mmol) to give the corresponding product as a beige solid (23 mg, 46 %), vol.3
, Hz, 1H), 8.31 (s, 1H), 7.73 (dd, vol.9
, Hz, 2H), 7.07 (d, J = 8.9 Hz, 1H), 6.84 (t, J = 8.9 Hz, 1H)
, , vol.135
, methoxybenzyl)-2-ethyl-6-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)oxy)-3fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (107a): The reaction was performed following procedure A on 4, p.300
,
, 37 (s, 2H), 3.74 (s, 3H), 2.71 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3) ? = 162.7 (d, J = 249, Hz, 1H), 7.39 (d, J = 19.7 Hz, 3H), 7.23 (d, J = 8.4 Hz, 3H), 7.09 (d, J = 4.9 Hz, 2H), 6.86-6.71 (m, 3H), 6.54 (t, J = 7.5 Hz, 1H), vol.5
, , vol.152
, (dimethylamino)phenyl)-2-isopropyl-3H-imidazo[4,5-b]pyridin-7yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (108b): The reaction was performed following procedure A on 4, p.33
, DMF (3 mL) to give the corresponding product as a brown solid (158 mg, 64 %), p.122
, °C. 1 H NMR (300 MHz, CDCl3) ? = 11.72 (bs, 1H)
, 82 (d, J = 8.6 Hz, 2H), 6.74-6.61 (m, 2H), 6.56 (s, 1H), 5.45 (s, 2H), 3.76 (s, 3H), 3.15-3.05 (m, 1H), 2.92 (s, 6H), 1.20 (s, 3H), 1.18 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 162, Hz, 1H), 7.67-7.53 (m, 2H), 7.43-7.17 (m, 6H), 7.09 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 1H), vol.6
, Hz, 1H), 7.41-7.37 (m, 2H), 7.32-7.15 (m, 3H)
, MHz, CDCl3) ? = 162.9 (d, J = 249.0 Hz)
, methoxybenzyl)-6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridin-7-yl)oxy)-3-fluorophenyl)-1-(4fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 111a' (415 mg, 0.60 mmol) to give the corresponding product 111a as a white solid (300 mg, 71 %)
, 54 (s, 1H), 8.54 (d, J = 5.8 Hz, 1H), 8.29 (s, 1H), 8.08 (d, Hz, 1H), 7.86 (d, J = 11.4 Hz, 1H), 7.60-7.56 (m, 2H), vol.9
,
, methoxybenzyl)-6-(4-hydroxyphenyl)-2-isopropyl-3H-imidazo[4,5-b]pyridin-7-yl)oxy)-3fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (111b) (two steps): Reaction was performed following procedure A on 4, Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6) ? = 161.8 (d, J = 244.7 Hz), 161.8, 161.2, 158.7, 156.9, vol.151
, Hz, 1H), 7.41-7.37 (m, 2H), 7.29-7.16 (m, 3H), 7.03 (m, 3H), vol.6
, 75 (s, 3H), 3.07-2.92 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 162.8 (d, J = 248, Hz, 1H), 5.35 (s, 2H), vol.3
, 3 Hz), 135.48 (d, J = 9, vol.135
, methoxybenzyl)-6-bromo-2-isopropyl-3H-imidazo[4,5-b]pyridin-7-yl)oxy)-3-fluorophenyl)-1-(4fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 111b' (656 mg, 0.94 mmol) to give the corresponding product 111b as a beige solid (410 mg, 61 %), HRMS (ESI) calculated for, vol.9
, Hz, 1H), 7.85 (dd, J = 13.2, 2.1 Hz, 1H), 7.59 (dd, J = 8.7, 4.9 Hz, 2H), 7.43-7.34 (m, 4H), vol.7
, The reaction was performed following procedure H on 6-bromo-7-chloro-3H-imidazo[4,5-b]pyridine 118 (2.5 g, 10.75 mmol) in DMF (25 mL) to give the corresponding product as a light yellow solid (1.71 g, 45 %)
, 36 (s, 2H), 3.77 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 159, Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), vol.5
, Mp: 162-164 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.50 (s, 1H), 7.73 (s, 1H, 3H-imidazo
, Hz, 2H), 6.57 (s, 1H), 5.31 (s, 2H), 3.78 (s, 3H), 1.49 (s, 9H). 13 C NMR (75 MHz, CDCl3) ? = 159, vol.7
, methyl-3H-imidazo[4,5-b]pyridin-7-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1
, methoxybenzyl)-6-methyl3H-imidazo[4,5-b]pyridin-7-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3carboxamide 153 (260 mg, The reaction was performed following procedure I on N, p.36
, Chloroform-d) ? = 8.55 (dd
, 13 C NMR (75 MHz, DMSO-d6) ? = 161.9 (d, J = 245, Hz, 2H), 7.22 (d, J = 8.9 Hz, 1H), 6.94 (s, 1H), 6.70 (t, J = 7.0 Hz, 1H), vol.2
, 107.1, 99.6, 12.7. MS (ES+) m/z (%)
, (phenylethynyl)-3H-imidazo
, 25 mmol) afforded the corresponding product (30 mg, 40 %) as a beige solid, The reaction carried out following procedure M starting from C2-alkynylated 3H-imidazo[4,5b]pyridine 166a (95 mg
, Benzyl-6-bromo-3H-imidazo
, Reaction was performed following procedure E on 6-bromo-3H-imidazo, vol.30
, Mp: 106-108 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.47 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H
, Benzyl-6-bromo-2-(phenylethynyl)-3H-imidazo
, mmol) as the copper catalyst in a sealed tube afforded the corresponding product (90 mg, 66 %) as a brown solid after flash chromatography followed by recrystallization in cyclohexane, The reaction carried out following procedure L starting from 3H-imidazo, vol.4, p.75
,
, Benzyl-6-bromo-2-(naphthalen-2-ylethynyl)-3H-imidazo
, mmol) as the copper catalyst in a sealed tube afforded the corresponding product (64 mg, 42 %) as a yellow solid after flash chromatography followed by recrystallization in cyclohexane, The reaction carried out following procedure L starting from 3H-imidazo, vol.4
,
, Reaction was performed following procedure H on 6-bromo-3H-imidazo, vol.20
, Mp: 102-104 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.47 (d, J = 1.8 Hz, 1H), vol.8
, (ESI) calculated for C14H13N3OBr 318.0242; found 318.0237. 6-Bromo-3-(4-methoxybenzyl)-2-(phenylethynyl)-3H-imidazo
, 31 mmol) and CuBr.SMe2 (6.46 mg, 0.03 mmol) as the copper catalyst in a sealed tube afforded the corresponding product (84 mg, 65 %) as a brown solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane. Mp: 176-178 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.48 (s, 1H), 8.16 (s, 1H, The reaction carried out following procedure L starting from 3H-imidazo
, ESI) calculated for C22H17N3OBr 418.0555; found 418.0563. 6-Bromo-3-((2-methoxyethoxy)methyl)-2-(p-tolylethynyl)-3H-imidazo
, mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper catalyst in a sealed tube afforded the corresponding product (74 mg, 53 % versus 48 % with Cu(OAc)2of cyclohexane/dichloromethane, The reaction carried out following procedure L starting from 3H-imidazo, vol.4, pp.89-91
, 84 (s, 2H), 3.78-3.75 (m, 2H), 3.58-3.42 (m, 2H), 3.32 (s, 3H), 2.38 (s, 3H), Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), vol.5
, methoxyethoxy)methyl)-2-(o-tolylethynyl)-3H-imidazo
, 35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper catalyst in a sealed tube afforded the corresponding product (84 mg, 60 %) as a brown solid after flash chromatography, The reaction carried out following procedure L starting from 3H-imidazo
, fluorophenyl)ethynyl)-3-((2-methoxyethoxy)methyl)-3H-imidazo
, Mp: 71-73 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.47 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 166 (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (51 mg, vol.117
, chlorophenyl)ethynyl)-3-((2-methoxyethoxy)methyl)-3H-imidazo
, 35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (80 mg, 54 % versus 37 % with Cu(OAc)2) as a yellowish solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane, The reaction carried out following procedure L starting from 3H-imidazo, p.75
, Mp: 121-122 °C. 1 H NMR, vol.169
, Cyclisation following procedure D starting from 2,3-diamino-6-chloropyridine (a) (8.55 g, vol.59, p.55
, 00 g, 98 %) as a grey solid, pp.224-226
, DMSO-d6) ? = 8.50 (s, 1H)
, ESI) calculated for C6H5N3Cl 154.0172; found 154.0172. Protection following procedure J starting from 5-chloro-3H-imidazo, vol.19, p.54
, toluene (300 mL) allowed compound 169 as a yellow oil (2.70 g, 57 %). 1 H NMR (300 MHz, CDCl3) ? = 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.73 (s, 2H)
, methoxyethoxy)methyl)-2-(naphtalen-2-ylethynyl)-3H-imidazo
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 169 (100 mg, 0.41 mmol) and CuBr.SMe2 (8.51 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (80 mg, 50 %) as a brown solid after flash chromatography
, CDCl3) ? = 8.19 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 3H), 7.64 (d, J= 8.5 Hz, 1H), 7.60-7.48 (m, 2H), vol.7
, ESI) calculated for C22H19N3O2Cl392.1166; found 392, 1168.
, J. Med. Chem, vol.43, pp.3052-3066, 2000.
, methoxyethoxy)methyl)-2-((4-methoxyphenyl)ethynyl)-3H-imidazo
, mg, 0.41 mmol) and CuBr.SMe2 (8.51 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (53 mg, 35 %) as a brown solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane, The reaction carried out following procedure L starting from 3H-imidazo, vol.4, pp.114-116
, 84 (s, 2H), 3.85 (s, 3H), 3.83-3.77 (m, 2H), 3.58-3.48 (m, 2H), 3.35 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 161, Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H), vol.5
, methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine 166 afforded the desired compound (0.91 g, 80 %) as a brown solid, Mp: 173-175 °C. 1 H NMR (300 MHz, CDCl3) ?
,
, methoxyethoxy)-methyl)-2-(naphtalen-2-ylethynyl)-3H-imidazo
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 170 (100 mg, 0.31 mmol) and CuBr.SMe2 (6.30 mg, 0.03 mmol) as the copper catalyst afforded the corresponding product (103 mg, 70 %) as a brown solid after flash chromatography
, 91 (s, 2H), 3.94-3.76 (m, 2H), 3.64-3.48 (m, 2H), 3.34 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 163.4 (d, Hz, 3H), 7.67 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.53-7.40 (m, 4H), vol.5, pp.29-51
, methoxyethoxy)-methyl)-2-((4-methoxyphenyl)ethynyl)-3H-imidazo
, 31 mmol) and CuBr.SMe2 (6.30 mg, 0.03 mmol) as the copper catalyst in a sealed tube afforded the corresponding product (50 mg, 35 %) as a brown solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane, The reaction carried out following procedure L starting from 3H-imidazo, p.75
,
, Methoxyethoxy)methyl)-6-phenyl-3H-imidazo
, methoxyethoxy)methyl)-3H-imidazo, Procedure G using 6-bromo-3
, Hz, 1H), 8.38-8.12 (m, 2H), 7.60 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 5.77 (s, 2H)
, Methoxyethoxy)methyl)-2-(naphtalen-2-ylethynyl)-6-phenyl-3H-imidazo
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 171 (100 mg, 0.35 mmol) and CuBr.SMe2 (7.26 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (109 mg, 72 %) as a brown solid after flash chromatography
, CDCl3) ? = 8.69 (d, J = 1.8 Hz, 1H), 8.21 (s, 2H), 7.92-7.80 (m, 3H), 7.73-7.59 (m, 3H), 7.597.45 (m, 4H), vol.7
,
, 04 mmol) as the copper catalyst afforded 8f (43 mg, 30 %) as a brown solid after flash chromatography, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 171 (100 mg, 0.35 mmol) and CuBr.SMe2 (7.26 mg
, Methoxyethoxy)methyl)-6-(4-methoxyphenyl)-3H-imidazo
, 23 (s, 1H), MHz, CDCl3) ? = 8.58 (d, J = 1.9 Hz, 1H), vol.8
, mmol) and CuBr.SMe2 (6.56 mg, 0.03 mmol) as the copper catalyst in a sealed tube afforded the corresponding product (80 mg, 54 %) as a yellow solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane, The reaction carried out following procedure L starting from 3H-imidazo, vol.4
, 95 (s, 2H), 3.88-3.85 (m, 5H), 3.57-3.54 (m, 2H), 3.37 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 159, Hz, 1H), 7.55 (dd, J = 9.1, 3.7 Hz, 4H), 7.03 (d, J = 8.7 Hz, 2H), vol.5, 1953.
, Methoxyethoxy)methyl)-6-((4-methoxyphenyl)-2-((4-methoxyphenyl)ethynyl)-3Himidazo
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 172 (100 mg, 0.32 mmol) and CuBr.SMe2 (6.56 mg, 0.03 mmol) as the copper catalyst afforded the corresponding product (43 mg, 30 %) as a brown solid after flash chromatography
, CDCl3) ? = 8.62 (s, 1H), 8.13 (s, 1H
, (m, 2H), 3.35 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 161, 1925.
, Methoxyethoxy)methyl)-6-(pyridine-4-yl)-3H-imidazo
, methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine 166 (744 mg, 2.60 mmol) in a mixture of 1,4-dioxane/H2O 4/1 (15 mL) followed by K2CO3 (1.08 g, 7.80 mmol) and the pyridin-4ylboronic acid acid (639 mg, 5.20 mmol). The reaction mixture was stirred at 110 °C for 12 hours, Pd(PPh3)4 (300 mg, 0.26mmol) was added to a solution of 6bromo-3, vol.8
, Methoxyethoxy)methyl)-2-(naphthalen-2-ylethynyl)-6-(pyridin-4-yl)-3H-imidazo
, 35 mmol) and Cu(OAc)2 (6.39 mg, 0.04 mmol) as the copper catalyst afforded the corresponding product (94 mg, 62 %) as a beige solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane. Mp: 117-119 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.22 (s, 1H), The reaction carried out following procedure L starting from 3H-imidazo, vol.7
, Methoxyethoxy)methyl)-2-((4-methoxyphenyl)ethynyl)-6-(pyridin-4-yl)-3H-imidazo
, 04 mmol) as the copper catalyst afforded the corresponding product (86 mg, 59 %) as a yellow solid after flash chromatography followed by recrystallization in a mixture of cyclohexane/dichloromethane. Mp: 125-127 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.70 (s, 1H), 8.26 (s, 1H, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 173 (100 mg, 0.35 mmol) and CuBr.SMe2 (7.23 mg
, Methoxyethoxy)methyl)-3H-imidazo
, 33 mmol) to give a dark red solid (1.63 g, 74 %), vol.18
, Spectroscopic data were in agreement with those reported in the literature, vol.168
, pyridine (c) (0.60 g, 5.04 mmol) in toluene (80 mL) allowed compound 174 as a yellow oil (0.63 g, 60 %). 1 H NMR (300 MHz, CDCl3) ? = 8, Procedure J starting from 3H-imidazo
, Hz, 1H), 7.98 (s, 1H)
, Methoxyethoxy)methyl)-2-(naphthalen-2-ylethynyl)-3H-imidazo
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 174 (100 mg, 0.48 mmol) and CuBr.SMe2 (9.92 mg, 0.05 mmol) as the copper catalyst afforded the corresponding product (72 mg, 42 %) as a brown solid after flash chromatography
, Hz, 1H), 7.85 (d, J = 8.4 Hz, 3H), 7.65 (d, J = 8.5 Hz, 1H), 7.58-7.49 (m, 2H), vol.7, pp.31-38
, The reaction carried out following procedure L starting from 3H-imidazo[4,5-b]pyridine 174 (100 mg, 0.48 mmol) and CuBr.SMe2 (9.92 mg, 0.05 mmol) as the copper catalyst afforded the corresponding product (91 mg, 56 %) as a brown solid after flash chromatography
, Hz, 1H), 7.96 (dd, J = 7.8, 1.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), vol.7
, Methoxyethoxy)methyl)-1H-indole, vol.182
, The reaction was carried out following procedure J on indole (1 g, 8.54 mmol), MEMCl (1.60 g, vol.12
, mmol) and NaH (0.55 g, 13.7 mmol) to give the corresponding product as a red oil (625 mg, 36 %). 1 H NMR (300 MHz, CDCl3) ? = 7.58 (d, J = 7.8 Hz, 1H), vol.7
, Methoxyethoxy)methyl)-1H-pyrrolo
, The reaction was carried out following procedure J on 7-azaindole (2.5 g, 21.16 mmol), MEMCl, p.30
, 32 mmol) and triethylamine (4.40 mL) to give the corresponding product as a bright red oil
, 300 MHz, CDCl3) ? = 8.33 (dd, J = 4.8, 1.4 Hz, 1H), 7.91 (dd, J = 7.8, 1.5 Hz, 1H), vol.7
, Methoxyethoxy)methyl)-1H-benzo
, MEMCl (5.3 g, 42.32 mmol) and triethylamine (4.4 mL) to give the corresponding product as an brown oil (500 mg, 11 %). 1 H NMR (300 MHz, CDCl3) ? = 8.00 (s, 1H, The reaction was carried out following procedure J on benzimidazole (2.5 g, 21.16 mmol), p.75
,
, MS (ES+) m/z (%): 207.1 (100) [M+H] +. HRMS (ESI) calculated for C19H20N3O3 207, 1134.
, 2-dibromovinyl)-1,2phenylene)bis(oxy))bis(tert-butyldimethylsilane) (1.4 g, 2.6 mmol) to allow the desired product as a yellow oil (760 mg, 65 %). 1 H NMR (300 MHz, CDCl3) ? = 6, bromovinyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane)
, ESI) calculated for C20H35BrO2Si2 442, 1359.
, The reaction was carried out following general procedure N using 1,3-dichloro-5, p.2
, NMR (300 MHz, CDCl3) ? = 7.28 (t, 4 JH-H = 1.8 Hz, 1H), vol.7
,
, Bromo-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo
, To a mixture of 6-bromo-3H-imidazo[4,5-b]pyridine 125 (1.1 g, 5.6 mmol) in AcOEt (15 mL) was added p-toluenesulfonic acid monohydrate (106 mg, 0. 56 mmol) and the reaction was, p.65
, Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (100 mg, 0.4 mmol) using beta-bromostyrene 196a (127 mg, 0.7 mmol) to allow the desired product as a beige solid (91 mg, 66 %), °C under argon atmosphere for 30 min. Subsequently, DHP (1.5 mL, 16.7 mmol) was added and the reaction mixture was refluxed under argon atmosphere overnight. The mixture was then taken in H2O and pH was adjusted to 7 with a 3 M NaOH aqueous solution
, 01 (d, 3 JH-H = 15.9 Hz, 1H), 5.59 (s, 2H). 13 C NMR (75 MHz, JH-H = 1.8 Hz, 1H), 8.14 (d, 4 JH-H = 1.8 Hz, 1H), 7.98 (d, 3 JH-H = 15.8 Hz, 1H), 7.50 (m, 2H), 7.38-7.21 (m, 8H), vol.7
, bromovinyl)-1,1'-biphenyl 196c (180 mg, 0.7 mmol) to allow the desired product as a light yellow solid (90 mg, 59 %), Mp: 168-170 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.37 (d, 4 JH-H = 1.8 Hz, 1H), 8.13 (d, 4 JH-H = 1.5 Hz, 1H), 7.96 (d, 3 JH-H = 15.6 Hz, 1H), 7.41 (d, 3 JH-H = 8.1 Hz, 2H), 7.32-7.26 (m, 3H), 7.23-7.17 (m, 4H), vol.6
, Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo
, CDCl3) ? = 8.77 (d, 3 JH-H = 15.5 Hz, 1H), vol.8
, Hz, 2H), 7.67 (d, J = 6.7 Hz, 1H), 7.62-7.43 (m, 4H), 7.36-7.29 (m, 3H), 7.23 (s, 1H), vol.7
, Hz, 1H), 5.63 (s, 2H). 13 C NMR (75 MHz, CDCl3) ? = 152
, Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (100 mg, 0.4 mmol) using alpha-bromostyrene 196e (127 mg, 0.7 mmol) to allow the desired product as a brownish oil (94 mg, 69 %). 1 H NMR (300 MHz, CDCl3) ? = 8, vol.46, p.3
, 73 (s, 1H), 5.19 (s, 2H), JH-H = 3.6 Hz, 2H), 5.97 (s, 1H), vol.5
, ESI) calculated for C21H17N3Br 390.0606; found 390.0602. (E)-3-benzyl-6-bromo-2-(3-methoxystyryl)-3H-imidazo[4,5-b]pyridine (201f): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo, MS (ES+) m/z (%)
, mmol) to allow the desired product as a yellow solid (87 mg, 62 %)
, CDCl3) ? = 8.39 (d, 4 JH-H = 1.6 Hz, 1H), 8.14 (d, 4 JH-H = 1.8 Hz, 1H), 7.94 (d, 3 JH-H = 15.8 Hz, 1H), 7.30 (t, 3 JH-H = 7.8 Hz, 4H), vol.7
, 59 (s, 2H), 3.83 (s, 3H). 13 C NMR (75 MHz, CDCl3) ? = 159, Hz, 1H), 6.90 (dd, 3 JH-H = 8.4 Hz, 4 JH-H = 1.8 Hz, 1H), vol.5, p.420
, Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (100 mg, 0.4 mmol) using (E)-((4-(2-bromovinyl)-1,2-phenylene)bis(oxy))bis(tertbutyldimethylsilane) 196g (308 mg, 0.7 mmol) to allow the desired product as a light yellow solid (120 mg, 49 %), tert-butyldimethylsilyl)oxy)styryl)-6-bromo-3H-imidazo, vol.3, p.4
, Hz, 1H), 7.31-7.15 (m, 5H), 7.03-6.93 (m, 2H), vol.6
, HRMS (ESI) calculated for C33H45N3O2BrSi2 650.2234; found 650.2226. (E)-3-benzyl-6-bromo-2-(4-(diethoxymethyl)styryl)-3H-imidazo[4,5-b]pyridine (201h): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (100 mg, 0.4 mmol) using (E)-1-(2-bromovinyl)-4-(diethoxymethyl)benzene 196h (198 mg, 0.7 mmol) to allow the desired product as a yellow solid (110 mg, 60 %), Mp: 115-117 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.39 (d, 4 JH-H = 2.0 Hz, 1H)
, HRMS (ESI) calculated for C26H27N3O2Br 492.1287; found 492.1266. (E)-3-benzyl-6-bromo-2-(3-fluorostyryl)-3H-imidazo[4,5-b]pyridine (201i): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo
, mmol) to allow the desired product as a beige solid (85 mg, 58 %)
, CDCl3) ? = 8.40 (s, 1H), 8.15 (s, 1H), 7.93 (d, 3 JH-H = 15.6 Hz, 1H), 7.38-7.26 (m, 5H), 7.23-7.14 (m, 3H)
,
, Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo
, mmol) to allow the desired product as a beige solid (104 mg, 64 %)
, CDCl3) ? = 8.40 (d, 4 JH-H = 1.9 Hz, 1H), 8.15 (d, 4 JH-H = 1.9 Hz, 1H), 7.89 (d, 3 JH-H = 15.8 Hz, 1H), 7.62 (s, 1H), 7.47 (d, 3 JH-H = 7.6 Hz, 1H), 7.41 (d, 3 JH-H = 7.6 Hz, 1H)
, ESI) calculated for C21H16N3Br2 467.9711; found 467.9712. (E)-3-benzyl-6-bromo-2-(3-nitrostyryl)-3H-imidazo[4,5-b]pyridine (201k): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo, MS (ES+) m/z (%)
, mmol) to allow the desired product as a brown solid (40 mg, 26 %)
, CDCl3) ? = 8.43 (s, 1H), 8.34 (s, 1H), 8.17 (s, 2H), 8.00 (d, 3 JH-H = 15.8 Hz, 1H), 7.75 (d, J = 6.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38-7.28 (m, 2H), 7.28-7.19 (m, 3H)
, 5-b]pyridin-2-yl)vinyl)benzonitrile (201l): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (90 mg, 0.3 mmol) using (E)-4-(2-bromovinyl)benzonitrile 196l (130 mg, 0.6 mmol) to allow the desired product as a light yellow solid (60 mg, 47 %), Mp: 186-188 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.44 (d, 4 JH-H = 1.9 Hz, 1H), vol.476, p.3
, 62 (s, 2H), Hz, 2H), 7.57 (d, 3 JH-H = 8.5 Hz, 2H), 7.33 (m, 2H), 7.22 (m, 3H), 7.08 (d, 3 JH-H = 15.7 Hz, 1H), vol.5
, mmol) using (E)-1-(2-bromovinyl)-4-(trifluoromethyl)benzene 196m (174 mg, 0.7 mmol) to allow the desired product as a beige solid (90 mg, 60 %), 0 Hz, 1H), 8.16 (d, 4 JH-H = 2.0 Hz, 1H), 7.98 (d, 3 JH-H = 15.8 Hz, 1H), 7.63 (d, 3 JH-H = 8.4 Hz, 2H), 7.58 (d, 3 JH-H = 8.4 Hz, 2H), 7.40-7.28 (m, 3H), 7.24-7.17 (m, 2H), 7.07 (d, 3 JH-H = 15.8 Hz, 1H), vol.4
, mmol) to allow the desired product as a beige solid (74 mg, 45 %)
, )-3-benzyl-6-bromo-2-(2-(thiophen-3-yl)vinyl)-3H-imidazo[4,5-b]pyridine (201o): Reaction was performed following general procedure O on 3-benzyl-6-bromo-3H-imidazo, CDCl3) ? = 8.42 (d, 4 JH-H = 2.0 Hz, 1H), 8.16 (d, 4 JH-H = 2.0 Hz, 1H), 7.83 (d, 3 JH-H = 15.8 Hz, 1H), 7.37-7.28 (m, 6H), vol.7
, 1H), 7.97 (d, 3 JH-H = 15.4 Hz, 1H), 7.45 (s, 1H), 7.35-7.26 (m, 5H), 7.21 (m, 2H), 6.81 (d, 3 JH-H = 15.6 Hz, 1H), 5.57 (s, 2H). 13 C NMR (75 MHz, CDCl3) ? = 153
, The first step was carried out following procedure D on commercially available 2,3-diamino-5chloropyridine (6 g, 41.8 mmol) in trimethyl orthoformate (137 mL) to give the corresponding 6chloro-3H-imidazo
, HRMS (ESI) calculated for C6H5N3Cl 154.0172, found 154.0175. Protection following procedure E on 6-chloro-3H-imidazo[4,5-b]pyridine (d) (4 g, 26.1 mmol) in DMF (64 mL) allowed the corresponding product as a beige solid (2.35 g, 37 %), Mp: 166-168 °C. 1 H NMR (300 MHz, CDCl3) ? = 8.31 (d, 4 JH-H = 2.1 Hz, 1H), 8.00 (d, 4 JH-H = 1.9 Hz, 1H), 8.00 (d, 3 JH-H = 15.9 Hz, 1H), 7.51 (m, 2H), 7.41-7.27 (m, 6H), 7.25-7.19 (m, 2H), 1111.
, Benzyl-5-chloro-3H-imidazo
, The protection was then carried out following general procedure E using 6-chloro-3H-imidazo[4,5b]pyridine (b) (6 g, 39.1 mmol) in DMF (112 mL). Chromatography using cyclohexane to, vol.40, p.60
, ESI) calculated for C13H11N3Cl 244.0642; found 244.0638. (E)-3-benzyl-5-chloro-2-styryl-3H-imidazo[4,5-b]pyridine (203a): Reaction was performed following general procedure O on 3-benzyl-5-chloro-3H-imidazo[4,5b]pyridine 203 (100 mg, 0.4 mmol) using styryl bromide 196a (150 mg, 0.8 mmol) to allow the desired product as a beige solid (114 mg, 79 %), Mp: 149-151 °C. 1 H NMR (300 MHz, CDCl3) ? = 7.97 (d, 3 JH-H = 8.4 Hz, 1H), 7.96 (d, 3 JH-H = 15.3 Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.27 (m, 6H), 7.25-7.15 (m, 3H), 6.99 (d, 3 JH-H = 15.9 Hz, 1H), 5.60 (s, 2H). 13 C NMR (75 MHz, CDCl3) ? =
, 59 (s, 2H). 13 C NMR (75 MHz, CDCl3) ? = 153, 3 JH-H = 15.4 Hz, 1H), 7.51 (s, 2H), 7.36-7,22 (m, 8H), 7.00 (d, 3 JH-H = 14.7 Hz, 1H), vol.5
, HRMS (ESI) calculated for C21H16N3ClBr 424.0216
, The reaction was performed following procedure E on 3H-imidazo
, mg, 23 %). 1 H NMR (300 MHz, CDCl3) ? = 8, DMF (9 mL) to give the corresponding product as a light brown solid
, Compound showed satisfactory spectroscopic data in agreement with those reported in the literature. 85a (E)-3-benzyl-2-styryl-3H-imidazo[4,5-b]pyridine (205a): Reaction was performed following general procedure O on 3-benzyl-3H-imidazo[4,5-b]pyridine 205 (100 mg, 0.5 mmol) using beta-bromostyrene 196a (175 mg, 1 mmol) to allow the desired product as a light brown solid (58 mg, 42 %), Hz, 1H), 8.03 (s, 1H), 7.36-7.27 (m, 5H), 7.24 (d, 3 JH-H = 4.8 Hz, 1H), vol.5
, 65 (s, 2H), Hz, 1H), 8.04 (d, 3 JH-H = 8.4 Hz, 1H), 7.96 (d, 3 JH-H = 15.9 Hz, 1H), 7.50 (m, 2H), 7.41-7.21 (m, 9H), 7.04 (d, 3 JH-H = 15.6 Hz, 1H), vol.5
, Reaction was performed following general procedure G on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (150 mg, 0.52 mmol) using 2-methoxyphenylboronic acid (119 mg, 0.8 mmol) to allow the desired product as a yellow oil (120 mg, 73 %). 1 H NMR (300 MHz
, Hz, 1H), 8.26 (d, 4 JH-H = 1.8 Hz, 1H), 8.04 (s, 1H)
, 128.3, 127.8, 127.8, 121.1, 111.2, 55.5, 47.1. MS (ES+) m/z (%): 316.1 (100) [M+H] +. HRMS (ESI) calculated for C20H18N3O 316.1450; found 316.1451. (E)-3-benzyl-6-(2-methoxyphenyl)-2-styryl-3H-imidazo[4,5-b]pyridine (206a): Reaction was performed following general procedure O on 3-benzyl-6-(2-methoxyphenyl)-3Himidazo[4,5-b]pyridine 206 (100 mg, 0.3 mmol) using beta-bromostyrene 196a (116 mg, 0.6 mmol) to allow the desired product as a yellow oil (12 mg, 9 %). 1 H NMR (300 MHz, CDCl3) ? = 8.53 (s, 1H), 8.24 (s, 1H), 1909.
, Reaction was performed following general procedure G on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (300 mg, 1.04 mmol) using phenylboronic acid (190 mg, 1.6 mmol) to allow the desired product as a beige solid (242 mg, 81 %)
, MS (ES+) m/z (%): 286.1 (100) [M+H] +. HRMS (ESI) calculated for C19H16N3 286.1344; found 286.1331. (E)-3-benzyl-6-phenyl-2-styryl-3H-imidazo[4,5-b]pyridine (207a): Reaction was performed following general procedure O on 3-benzyl-6-phenyl-3H-imidazo[4,5b]pyridine 207 (100 mg, 0.4 mmol) using beta-bromostyrene 196a (104 mg, 0.6 mmol) to allow the desired product as a beige solid (42 mg, 35 %)
, Reaction was performed following general procedure G on 3-benzyl-6-bromo-3H-imidazo[4,5b]pyridine 164 (300 mg, 1.04 mmol) using 4-cyano-3-fluorophenylboronic acid (258 mg, 1,6 mmol) to allow the desired product as a beige solid (290 mg, 85 %)
,
, 5-b]pyridin-6-yl)-2-fluorobenzonitrile (208a): Reaction was performed following general procedure O on 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6yl)-2-fluorobenzonitrile 208 (120 mg, 0.4 mmol) using styryl bromide 196a (134 mg, 0.7 mmol) to allow the desired product as a light yellow solid (106 mg, 68 %), MS (ES+) m/z (%), vol.4, p.3
, Hz, 1H), 7.57-7.47 (m, 4H)
,
, Reaction was performed following general procedure G with doubled equivalents of catalyst and base, on 3-benzyl-6-bromo-3H-imidazo[4,5-b]pyridine 164 (300 mg, 1.04 mmol) using 4dimethylaminophenylboronic acid (515 mg, 3.1 mmol) to allow the desired product as a grey solid (100 mg, 34 %)
, 33 (s, 5H), 6.85 (d, 3 JH-H = 8.8 Hz, 2H), 5.50 (s, 2H), 3.01 (s, 6H). 13 C NMR (75 MHz, CDCl3) ? = 149.0, 144.9, = 1.5 Hz, 1H), 8.06 (s, 1H), 7.53 (d, 3 JH-H = 8.7 Hz, 2H), vol.7
, trifluoromethyl)styryl)-3H-imidazo[4,5-b]pyridin-6-yl)-N,N-dimethylaniline (213): Reaction was performed on 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-N,N-dimethylaniline 210 (85 mg, 0.3 mmol) following general procedure O using (E)-1-(2-bromovinyl)-4-(trifluoromethyl)benzene 196m
, Compound 213 was additionally purified by recrystallization in EtOH/Dioxane prior to photophysical analysis, °C. 1 H NMR (300 MHz, CDCl3) ? = 8.61 (d, 4 JH-H = 1.7 Hz, 1H), vol.8, pp.184-186
, 86 (d, 3 JH-H = 8.5 Hz, 2H), 5.66 (s, 2H), 3.01 (s, 6H). 13 C NMR (75 MHz, CDCl3) ? = 151, Hz, 1H), 7.99 (d, 3 JH-H = 16.0 Hz, 1H), 7.61-7.54 (m, 7H), 7.34-7.24 (m, 4H), 7.10 (d, 3 JH-H = 15.9 Hz, 1H), vol.6
, (ESI) calculated for C30H24N4F3 protéines Met (code PDB : 3F82, résolution 2.50 Å) et cKit (code PDB : 1T46, résolution 1.60 Å) humaines sans molécule d'eau. La modélisation de Tyro3 par homologie a été réalisée par le logiciel MODELLER à l'aide d'un protocole automatisé d'optimisation et de minimisation, N-dimethylaniline 210 (100 mg, 0.3 mmol) following general procedure L using 1-(2,2-dibromoethenyl)-4(trifluoromethyl)benzene 167l (200 mg, 2 eq.) to allow the desired product as a yellow solid (43 mg, 28 %), vol.7
, Les expériences d'amarrage moléculaire ont été réalisées avec le logiciel FRED en utilisant la fonction de score Chemgauss4. 65 Pour chaque candidat, une banque de conformères a été générée avec OMEGA puis soumise à FRED, OMEGA, p.5000
, Nucleic Acids Res, vol.37, pp.510-514, 2009.
, Nucleic Acids Res, pp.375-383, 2007.