3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-
N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide (JP-3) (68 mg, 0.064 mmol, 47 %
yield) as a white gum. νmax (neat): 3280, 2928, 2856, 1630, 1607, 1574, 1490 cm─1; 1H NMR (400 MHz,
DMSO-d6) δ = 9.04 (1H, br s), 8.45 (1H, d, J = 8.6 Hz), 8.25 - 8.38 (2H, m), 7.90 - 8.00 (2H, m), 7.69 (1H,
br s), 7.24 - 7.35 (2H, m), 7.05 - 7.20 (4H, m), 7.01 (1H, ddd, J = 10.0, 6.7, 3.1 Hz), 6.53 - 6.62 (1H, m),
4.90 - 4.99 (1H, m), 4.65 (2H, br d, J = 5.9 Hz), 4.42 - 4.49 (1H, m), 4.32 - 4.41 (2H, m), 4.14 - 4.22 (2H,
m), 4.03 (1H, dd, J = 10.0, 6.4 Hz), 3.90 (2H, s), 3.73 - 3.78 (3H, m), 3.68 - 3.73 (3H, m), 3.56 - 3.60 (6H,
m), 3.47 - 3.50 (3H, m), 3.02 (1H, q, J = 6.8 Hz), 2.67 - 2.78 (2H, m), 2.35 - 2.44 (1H, m), 2.20 (3H, s),
1.62 - 1.88 (12H, m), 0.95 - 1.22 (10H, m); 13C NMR (101 MHz, DMSO-d6) δ = 174.5, 171.6, 170.4, 169.5,
158.0, 158.4 (d, J = 238.4 Hz), 154.0, 147.6 (t, J = 11.7 Hz), 144.9, 137.8, 137.4, 129.9 (2C), 129.0, 128.9,
127.1, 126.1 (2C), 123.9, 105.0, 101.6 (d, J = 27.1 Hz), 70.9 (2C), 70.5 (2C), 70.4, 70.3, 70.2, 70.1, 69.3,
69.2, 59.3, 59.0, 54.8, 53.4, 47.9, 47.2, 38.9 (2C), 38.0, 34.7, 34.4 (3C), 30.2, 29.2, 28.5, 26.4, 26.2, 26.0,
20.7, 19.3; 19F NMR (376 MHz, DMSO-d6) δ = -116.10 (s), -145.60 (s); LCMS (Method B): tR = 1.21 min,
[M+H]+ 1067 & 1069 (99 % purity); HRMS: (C52H72ClF2N11O9) [(M+2H)/2]+ requires 533.7586, found
[(M+2H)/2]+ 533.7592.
(2S,4S)-4-(10-(3-(((5-Chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-2,5-
difluorophenoxy)decanamido)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-
((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide (JP-4, 13)
10-(3-(((5-Chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-2,5-difluoro-
phenoxy)decanoic acid (100 mg, 0.186 mmol), tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1,2,3,4-
tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-
2-yl)(methyl)carbamate (130 mg, 0.223 mmol), triethylamine (78 µL, 0.559 mmol) and HATU (106 mg,
0.279 mmol) were stirred together in DMF (3.72 mL) for 16 h at room temperature. The reaction
mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The solvent was
concentrated in vacuo. TFA (143 µL, 1.862 mmol) was added and the reaction mixture was stirred at
room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with
DCM (3 x 10 mL). The solvent was concentrated in vacuo and purified by reverse phase prep column
chromatography (40 – 95 % MeCN in H2O + 0.1 % NH4HCO3, XBridge C18, 42 mL/min, 45 min) to afford
(2S,4S)-4-(10-(3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-methyl)-2,5-
difluorophenoxy)decanamido)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)-acetyl)-N-
((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide (JP-4) (100 mg, 0.100 mmol, 54 %
yield) as a white solid. M.pt.: 103 – 105 °C; νmax (neat): 3296, 2927, 2854, 1634, 1574, 1430, 778 cm─1;
1H NMR (400 MHz, MeOD) δ = 7.83 (1H, s), 7.55 (1H, s), 7.35 - 7.40 (1H, m), 7.34 (1H, s), 7.08 - 7.15
(2H, m), 7.01 - 7.06 (1H, m), 6.72 (1H, ddd, J = 9.9, 6.7, 2.9 Hz), 6.49 - 6.56 (1H, m), 5.02 - 5.07 (1H, m),
4.71 (2H, s), 4.42 - 4.55 (3H, m), 4.12 - 4.20 (1H, m), 3.97 (2H, t, J = 6.4 Hz), 3.75 (3H, s), 3.60 (1H, dd,
J = 10.4, 5.3 Hz), 3.09 - 3.16 (1H, m), 2.67 - 2.83 (2H, m), 2.50 (1H, ddd, J = 13.2, 8.8, 6.6 Hz), 2.29 (2H,
s), 2.28 (1H, s), 2.19 (2H, t, J = 7.6 Hz), 1.69 - 2.03 (14H, m), 1.57 - 1.68 (4H, m), 1.38 - 1.55 (3H, m),
1.34 (8H, s), 0.99 - 1.31 (10H, m); 13C NMR (101 MHz, MeOD) δ = 175.8, 174.3, 172.0, 171.3, 158.3,
157.8, 158.7 (dd, J = 241.0, 2.6 Hz), 152.8, 147.8 (dd, J = 11.7, 10.3 Hz), 146.2 (dd, J = 238.4, 2.2 Hz),
137.1, 136.1, 129.9, 128.5, 128.4, 128.3, 128.2, 128.2, 126.7, 125.7, 123.6, 121.1, 104.3 (dd, J = 24.9,
2.2 Hz), 103.2, 100.5 (d, J = 27.9 Hz), 69.2, 59.4, 58.9, 55.5, 53.2, 48.6, 47.8, 40.1, 37.6, 36.0, 34.2, 33.5
(dd, J = 6.6, 2.2 Hz), 33.2, 29.8, 29.2, 29.1, 29.0, 28.9, 28.9, 28.8, 28.6, 28.5, 25.9, 25.7, 25.5, 20.2, 17.9;
LCMS (Method B): tR = 1.49 min, [M+H]+ 1003 & 1005 (100 % purity); HRMS: (C52H71ClF2N11O5) [M+H]+
requires 1002.5296, found [M+H]+ 1002.5303.
13