Rezatapopt

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Rezatapopt, PC 14586

CAS 2636846-41-6

Molecular Weight	545.57
Synonyms	PC14586
Formula	C₂₈H₃₁F₄N₅O₂
CAS No.	2636846-41-6

4-[3-[4-[[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino]-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]-3-methoxy-N-methylbenzamide

5W59S33KC9

Rezatapopt (PC14586) is an orally active antineoplastic agent. Rezatapopt binds to a pocket created by the TP53 Y220C mutation. Rezatapopt restores p53 tumor suppressor functions by stabilization of the p53 protein structure. Rezatapopt demonstrates tumor inhibition and regression in mouse models with established human tumor xenografts harboring the TP53 Y220C mutation.

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COUPLER

COUPLER

MAIN

REF

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00379

2-Iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine 15 was prepared from 4-nitroindole as described in
WO2017143291. 1
H NMR (400 MHz, dimethylsulfoxide [DMSO]-d6) δ ppm 9.19–10.88 (m, 2 H), 7.63
(d, J=8.34 Hz, 1 H), 7.16–7.25 (m, 1 H), 7.04–7.14 (m, 2 H), 5.14–5.33 (m, 2 H). LCMS (ES+
, m/z):
340.9 [(M+H)+
].

SnCl2.2H2O (398.11 mg, 1.76 mmol, 0.20 eq.) was added to a solution of 2-iodo-1-(2,2,2-trifluoroethyl)-
1H-indol-4-amine 15 (3.00 g, 8.82 mmol, 1.00 eq.) and 1-methylpiperidin-4-one (1.20 g, 10.61 mmol,
1.20 eq.) in MeOH (10.00 mL). The mixture was stirred at 25 °C for 3 hours (h), and then NaBH3CN
(2.77 g, 44.1 mmol, 5.00 eq.) was added, stirring at 25 °C for 69 h. Thin-layer chromatography (TLC)
indicated that the starting material was consumed, and the reaction mixture was filtered. The filtrate was
poured into H2O (200 mL) and extracted with ethyl acetate ([EtOAc] 200 mL2). The combined organic layers were washed with H2O (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The crude material was purified by flash column chromatography (Silica gel, petroleum ether (PE) : EtOAc = 0:1) and then by preparative high performance chromatography ([prep-HPLC] column: Phenomenex Luna C18 10040mm5 um; mobile phase: [H2O (0.2% Formic acid-acetonitrile [ACN])]; gradient: 10%–50% acetonitrile over 8.0 minutes) to yield 2-iodo-N-(1-methylpiperidin-4-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-amine 16 (2.50 g, 5.72 mmol, 64.93% yield) as a light-brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (br s, 1 H, formic acid salt), 7.17 (s, 1 H), 6.85–6.95 (m, 1 H), 6.78 (br d, J = 7.99 Hz, 1 H), 6.16 (br d, J = 7.63 Hz, 1 H), 5.44 (br d, J = 2.62 Hz, 1 H), 4.99 (q, J = 8.54 Hz, 2 H), 3.33 (br s, 1 H), 2.85 (br d, J = 9.66 Hz, 2 H), 2.25 (br s, 3 H), 2.07–2.18 (m, 2 H), 1.94 (br d, J = 12.04 Hz, 2 H), 1.46–1.58 (m, 2 H). LCMS (ES+, m/z): 438.0 [(M+H)+]. Boc2O (26.03 g, 119.26 mmol, 6.00 eq.) was added to a solution of 2-methoxy-4-(methylsulfonyl)aniline 17 (4.00 g, 19.88 mmol, 1.00 eq.) in dioxane (40.00 mL) at 25 o C (room temperature). The reaction mixture was stirred at 110 °C for 16 h. TLC and LCMS indicated that the reaction was completed, and it was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EtOAc = 10/1 to 1:1) to yield tert-butyl (2-methoxy-4-(methylsulfonyl)phenyl)carbamate (6.00 g, 19.92 mmol, 72.6% purity, 72% yield) as a yellow gum. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 8.03 (d, J = 8.38 Hz, 1 H), 7.47 (dd, J = 8.38, 2.00 Hz, 1 H), 7.44 (d, J = 2.00 Hz, 1 H), 3.91 (s, 3 H), 3.18 (s, 3 H), 1.47 (s, 9 H). LCMS (ES+, m/z): 324.1 [(M+Na)+ ]. NaH (867.27 mg, 60% purity, 21.69 mmol, 3.00 eq.) was added in portions at 0 °C to a mixture of tert-butyl (2-methoxy-4-(methylsulfonyl)phenyl)carbamate (3.00 g, 7.23 mmol, 1.00 eq.) in dimethylformamide ([DMF] 30.00 mL) and stirred at 0 °C for 0.5 h. 3-Bromoprop-1-yne (3.23 g, 21.69 mmol, 3.00 eq.) was added to the reaction mixture, stirring at 0 °C for 2.5 h. TLC (Plate 1: PE : EtOAc = 1:1) and LCMS indicated that the starting material was consumed, and the product was detected. The reaction mixture was poured into a saturated solution of NH4Cl (200 mL) at 0 o C and was extracted with EtOAc (200 mL3). The combined organic phase was dried over Na2SO4, filtered, and concentrated

in vacuo. The residue was purified by column chromatography (SiO2, PE : EtOAc = 5:1 to 1:2) to give
tert-butyl (2-methoxy-4-(methylsulfonyl)phenyl)(prop-2-yn-1-yl)carbamate (3.00 g, 8.85 mmol,
74% purity, 90% yield) as a light-yellow gum.
1
H NMR (400 MHz, DMSO-d6) δ ppm 7.53–7.56 (m, 1 H), 7.46–7.53 (m, 2 H), 4.10–4.51 (m, 2 H), 3.90
(s, 3 H), 3.27 (s, 3 H), 3.17 (t, J = 2.32 Hz, 1 H), 1.27–1.39 (m, 9 H). LCMS (ES+
, m/z): 283.9 [(M+H-tBu)+].
A solution of 4M HCl/EtOAc (20.00 mL) was added to the solution of tert-butyl (2-methoxy-4-
(methylsulfonyl)phenyl)(prop-2-yn-1-yl)carbamate (3.00 g, 6.54 mmol, 1.00 eq.) in EtOAc (1.00 mL).
The reaction mixture was stirred at 25 °C for 2 h. TLC indicated that the starting material was consumed
completely. The reaction mixture was concentrated in vacuo to yield 2-methoxy-4-(methylsulfonyl)-N-
(prop-2-yn-1-yl)aniline 18 (1.80 g, 7.53 mmol, 85.3% yield, HCl salt) as a yellow solid.
1
H NMR (400 MHz, DMSO-d6) δ ppm 7.38 (dd, J = 8.40, 1.60 Hz, 1 H), 7.22 (d, J = 1.60 Hz, 1 H), 6.75
(d, J = 8.80 Hz, 1 H), 3.99 (d, J = 2.4 Hz, 2 H), 3.87 (s, 3 H) 3.10 (s, 3 H), 3.08 (t, J = 2.31 Hz, 1 H).
LCMS (ES+
, m/z): 240.1 [(M+H)+
].
i-Pr2NH (2.08 g, 20.58 mmol, 2.91 mL, 10 eq.), CuI (392.02 mg, 2.06 mmol, 1 eq), 2-iodo-N-(1-
methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine 16 (0.9 g, 2.06 mmol, 1 eq.) and
Pd(PPh3)4 (475.71 mg, 411.67 μmol, 0.2 eq.) was added to a solution of 2-methoxy-4-(methylsulfonyl)-N-
(prop-2-yn-1-yl)aniline 18 (622.16 mg, 2.47 mmol, 1.2 eq.) in DMSO (10 mL) at 45 °C under N2. The
reaction mixture was stirred at 45 °C for 1 h. TLC (DCM/MeOH=10:1, Rf = 0.3) indicated that the
starting material was consumed completely. It was poured into ethylenediaminetetraacetic acid ([EDTA]
20 mL) and stirred for 1 h, then extracted with EtOAc (40 mL3). The combined organic phase was washed with brine (40 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE : EtOAc = 1:1 to dichloromethane (DCM) / MeOH = 10:1, Rf = 0.3), then by prep-HPLC (column: Phenomenex Luna(2) C18 25050 10u; mobile
phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 30%–50%, 20 min) to yield compound 13 (0.6 g,
1.09 mmol, 53.08% yield, 99.9% purity) as a light-yellow solid.
1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41–1.54 (m, 2 H), 1.91 (br d, J = 11.00 Hz, 2 H), 1.95–2.08 (m,
2 H) 2.17 (s, 3 H), 2.68–2.80 (m, 2 H), 3.10 (s, 3 H), 3.20–3.29 (m, 1 H), 3.89 (s, 3 H), 4.36 (d,
J = 6.24 Hz, 2 H), 4.92 (q, J = 9.09 Hz, 2 H), 5.49 (d, J = 7.95 Hz, 1 H), 6.15 (d, J = 7.83 Hz, 1 H),
6.50 (t, J = 6.24 Hz, 1 H), 6.68 (d, J = 8.19 Hz, 1 H), 6.89 (d, J = 8.44 Hz, 1 H), 6.99 (t, J = 8.01 Hz,
1 H), 7.09 (s, 1 H), 7.25 (d, J = 1.83 Hz, 1 H), 7.39 (dd, J = 8.31, 1.83 Hz, 1 H). LCMS (ES+, m/z):
549.3 [(M+H)+
]

a
Reagents and conditions: (a) Pd(PPh3)4, CuI, diisopropylamine, DMSO, 20 °C, 1 h; (b) TMSCl, DMF, 0 °C, 0.5 h;
(c) BH3.THF, 0 °C, 0.5 h; (d) EtOAc/HCl, 20 °C, 1 h; (e) 10 eq. (CH2O)n, NaBH3CN, MeOH, 20 °C, 16 h; f)
LiOH.H2O, MeOH, 40 °C, 12 h; g) MeNH3Cl, HOBT, EDCI, TEA, DCM, RT, 16 h; h) Chiral SFC separation

PATENTS

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