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Resigratinib

July 13, 2025 2:44 am / Leave a comment

Resigratinib, KIN 3248

CAS 2750709-91-0

C₂₆H₂₇F₂N₇O₃

523.5 g/mol

3-[2-(1-cyclopropyl-4,6-difluorobenzimidazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-prop-2-enoylpyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

Resigratinib (KIN-3248) is an experimental anticancer medication which acts as a fibroblast growth factor receptor inhibitor (FGFRi) and is in early stage human clinical trials.^[1][2][3]

KIN-3248 is a small molecule that targets and inhibits oncogenic fibroblast growth factor receptors (FGFRs). It was designed to mainly target FGFR2 and FGFR3 alterations, which act as oncogenic drivers in 10-20% of cholangiocarcinoma and 20-35% of urothelial cancers, respectively. While effective, disease progression may occur 6 to 8 months after treatment with currently approved FGFR inhibitors is started, and this effect is usually associated with on-target resistance mutations in the kinase domain of FGFR. Therefore, the broad inhibition of FGFR isoforms may be effective against different types of tumors. The safety, tolerability, pharmacokinetics, and preliminary efficacy of KIN-3248 are currently being evaluated in adults with advanced tumors harboring FGFR2 and/or FGFR3 gene alterations. In February 2023, Kinnate Biopharma received Fast Track designation from the FDA for KIN-3248 to treat unresectable, locally advanced or metastatic cholangiocarcinoma (CCA).

SCHEME

COUPLER

COUPLER

MAIN

CONTINUED………….

REF

US11345681,

https://patents.google.com/patent/US11345681B1/en

Example 78

3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

Step 1: 1-(Tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (8.00 g, 32.62 mmol) and imidazole (4.44 g, 65.23 mmol) in DMF (80.00 mL) was added tert-butyl(chloro)diphenylsilane (13.45 g, 48.93 mmol) at 0° C. over 30 min. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with EA (3×300 mL). The combined organic layers was washed with brine (5×500 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1). The fractions contained desired product were combined and concentrated to afford 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (14.20 g, 90%) as a colorless oil. MS ESI calculated for C ₂₇H ₃₇NO ₅Si [M+H] ⁺, 484.24, found 484.25.

Step 2: Tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (30.00 g, 62.02 mmol) in THF (300.00 mL) was added LiBFi ₄(6.08 g, 0.28 mol) in portions at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was acidified to pH 5 with HCl (1M) at 0° C. and then basified to pH 8 with saturated NaHCO ₃(aq.). The resulting mixture was extracted with EA (4×500 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pynolidine-1-carboxylate (24.00 g, 85%) as a light yellow oil. MS ESI calculated for C ₂₆H ₃₇NO ₄Si [M+H] ⁺, 456.25, found 456.30.

Step 3: Tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a suspension of NaH (0.20 g, 8.33 mmol) in THF (18 mL) was added a solution of tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.50 g, 5.49 mmol) in THF (64.00 mL) slowly at 0° C. under nitrogen atmosphere. After stirred at 0° C. for 1 h, to the above mixture was added CH ₃I (1.17 g, 8.23 mmol) dropwise at 0° C. The reaction mixture was stirred for additional 3 h at room temperature. The resulting mixture was diluted with water (60 mL), and then extracted with EA (3×30 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (2.30 g, 89%) as a light yellow solid. MS ESI calculated for C ₂₇H ₃₉NO ₄Si [M+H] ⁺, 470.26, found 470.30.

Step 4: Tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(methoxymethyl)pyrrolidine-1-carboxylate (46.30 g, 98.57 mmol) in THF (375.00 mL) was added tetra-n-butylammonium fluoride (1 M in THF) (146.70 mL, 0.14 mol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (1 L) and extracted with EA (3×500 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (16.60 g, 73%) as a light yellow oil. MS ESI calculated for C ₁₁H ₂₁NO ₄[M+H] ⁺, 232.15, found 232.20.

Step 5: Tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 3.5-dibromo-1H-pyrazole-4-carbonitrile (2.00 g, 7.97 mmol), tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.84 g, 7.97 mmol) and triphenylphosphine (3.14 g, 11.95 mmol) in THF (40.00 mL) was added diisopropyi azodicarboxylate (2.42 g, 11.95 mmol) dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (3.50 g, 94%) as a dark yellow solid. MS ESI calculated for C ₁₅H ₂₀Br ₂N ₄O ₃[M+H−100] ⁺, 361.99, 363.99, 365.99; found 362.10, 364.10, 366.10.

Step 6: Tert-butyl (2S,4R)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrollidine-1-carboxylate

To a stirred solution of tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.00 g, 2.15 mmol) in NMP (10.00 mL) was added CH ₃NH ₂(2.98 mL, 5.96 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 50° C. under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EA (3×50 mL). The combined organic layers was washed with brine (3×20 mL), dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2S,4R)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.67 g, 35%) as an off-white solid. MS ESI calculated for C ₁₆H ₂₄BrN ₅O ₃[M+H−100] ⁺, 314.11, 316.11, found 314.10, 316.10.

Step 7: (2R,4S)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4S)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrollidine-1-carboxylate (20.30 g, 49.00 mmol) in DCM (300.00 mL) were added Boc ₂O (20.97 mL, 98.01 mmol), DMAP (0.60 g, 4.90 mmol) and Et ₃N (20.43 mL, 0.14 mol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (3×200 mL) and extracted with DCM (3×200 mL). The combined organic layers was washed with brine (3×100 mL). The organic layer was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford (2R,4R)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 95%) as an off-white solid. MS ESI calculated for C ₂₁H ₃₂BrN ₅O ₅[M+H] ⁺, 514.16, 516.16, found 514.15, 516.15; ¹H NMR (400 MHz, CDCl ₃) δ 4.94-4.90 (m, 1H), 4.23-4.19 (m, 1H), 3.75-3.66 (m, 3H), 3.44-3.40 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 2.62-2.58 (m, 1H), 2.41-2.19 (m, 1H), 1.48 (s, 18H).

Step 8: Tert-butyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred mixture of (2R,4S)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 46.65 mmol), CuI (1.78 g, 9.33 mmol), Pd(PPh ₃) ₂Cl ₂(3,27 g, 4.67 mmol) and trimethylsilylacetylene (19.78 mL, 0.20 mol) in DMF (240.00 mL) was added TEA (19,45 mL, 0.19 inol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with EA (4×500 mL). The combined organic layers was washed with brine (2×500 mL), dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R, 4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylisilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (2.4.00 g, 96%) as a brown solid. MS ESI calculated for C ₂₆H ₄₁N ₅O ₅Si [M+H]+, 532.29, found 532.40; ¹H NMR (400 MHz, CDCl ₃) δ 4.93-4.89 (m, 1H), 4.23-4.17 (m, 1H), 3.68-3.52 (m, 3H), 3.42-3.37 (m, 1H), 3.35-3.33 (m, 3H), 3.25-3.20 (m, 3H), 2.63-2.58 (m, 1H), 2.33-2.13 (m, 1H), 1.46 (s, 18H), 0.27 (s, 9H).

Step 9: Tert-butyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4S)-4-[5-[(tert-(butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 45.14 mmol) in THF (200.00 mL) was added TBAF (67.70 mL, 67.70 mmol, 1 M in THF) at 0° C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×500 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.40 g, 83%) as an off-white solid, MS ESI calculated for C ₂₃H ₃₃N ₅O ₅[M+H] ⁺, 460.25, found 460.40; ¹H NMR (400 MHz, CDCl ₃) δ 4.93-4.89 (m, 1H), 4.22-4.18 (m, 1H), 3.84-3.46 (m, 3H), 3.42-3.37 (m, 1H), 3.37-3.31 (m, 4H), 3.24 (s, 3H), 2.62-2.59 (m, 1H), 2.28-2.24 (m, 1H), 1.46 (s, 18H).

Step 10: Tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of ter tyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.40 g, 37.86 mmol) in DMSO (30.00 mL) and EtOH (150.00 mL) were added 0.5 M NaOH (87.09 mL, 43.54 mmol) and H ₂O ₂(10.26 mL, 0.13 mol) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. Then the reaction mixture was warmed up to room temperature and stirred for another 0.5 h at room temperature. The resulting mixture was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×300 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/2). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.20 g, 95%) as an off-white solid. MS ESI calculated for C ₂₃H ₃₅N ₅O ₆[M+H] ⁺, 478.26, found 478.25; ¹H NMR (300 MHz, CDCl ₃) δ 6.80-6.74 (m, 1H), 5.69-5.62 (m, 1H), 5.04-5.00 (m, 1H), 4.23-4.19 (m, 1H), 3.75-3.67 (m, 3H), 3.49-3.42 (m, 1H), 3.39-3.32 (m, 3H), 3.14 (s, 3H), 2.72-2.60 (m, 1H), 2.32-2.21 (m, 1H), 1.62-1.31 (m, 18H).

Step 11: 3-Ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride

To a stirred mixture of tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.20 g, 36.02 minor) in DCM (170,00 mL) was added HCl (180.08 mL, 0.72 mol, 4 M in EA). The reaction mixture was stirred for 1 h at room temperature under argon atmosphere. The resulting mixture was concentrated and dried to afford 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride (12.50 g, crude) as an off-white solid which was used in the next step directly without further purification. MS ESI calculated for C ₁₃H ₂₁Cl ₂N ₅O ₂[M+H−2 HCl] ⁺, 278.15, found 278.05.

Step 12: 3-Ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

To a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride (12.50 g, 35.69 mmol) and K ₂CO ₃(172 mL, 0.43 mol, 2.5 M) in THF (250.00 mL) was added acryloyl chloride (2.89 g, 32.15 mmol) dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred for 10 min at 0° C. The resulting mixture was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×300 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (11.10 g, 84%) as an off-white solid. MS ESI calculated for C ₁₆H ₂₁N ₅O ₃[M+H] ⁺, 332.16, found 332.20; ¹H NMR (400 MHz, CDCl ₃) δ 6.76 (s, 1H), 6.60-6.36 (m, 2H), 5.74-5.68 (m, 1H), 5.50-5.20 (m, 2H), 4.55-4.39 (m, 1H), 4.06-3.83 (m, 3H), 3.53-3.40 (m, 2H), 3.36-3.35 (m, 3H), 3.03-2.99 (m, 3H), 2.68-2.60 (m, 1H), 2.37-2.23 (m, 1H).

Step 13: N-cyclopropyl-3,5-difluoro-2-nitroaniline

To a stirred solution of 1,3,5-trifluoro-2-nitrobenzene (4.50 g, 25.41 mmol) in EtOH (45.00 mL) was added aminocyclopropane (2.90 g, 50.82 mmol) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0° C. The resulting mixture was diluted with water (100 mL) and extracted with EA (3×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford N-cyclopropyl-3,5-difluoro-2-nitroaniline (4.11 g, 85%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.64 (s, 6.80-6.74 (m, 1H), 6.30-6.27 (m, 1H), 2.59-2.54 (m, 1H), 1.01-0.83 (m, 2H), 0.76-0.61 (m, 2H).

Step 14: N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline

To a stirred mixture of N-cyclopropyl-3,5-difluoro-2-nitroaniline (4.11 g, 19.19 mmol) in methanesulfonic acid (45.00 mL) was added NIS (4.53 g, 20.15 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with ice/water (100 mL) at 0° C. The resulting mixture was basified to pH 8 with sat. NaOH and extracted with EA (3×100 mL). The combined organic layers was washed with brine (3×100 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline (4.50 g, 69%) a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.53 (s, 1H), 6.90-6.88 (m, 1H), 2.57-2.54 (m, 1H), 1.07-0.85 (m, 2H ), 0.83-0.58 (m, 2H).

Step 15: N1-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine

To a stirred mixture of N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline (4.40 g, 12.94 mmol) and NH ₄Cl (2.77 g, 51.76 mmol) in EtOH (44.00 mL) and H ₂O (8.80 mL) was added Fe (2.89 g, 51.76 mmol). The reaction mixtue was stirred at 70° C. for 6 h. The resulting mixture was diluted with water (150 mL) and extracted with EA×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure to afford N-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine (3.30 g, crude) as a brown oil which was used in the next step directly without further purification. MS ESI calculated for C ₉H ₉F ₂IN ₂[M+H] ⁺, 310.98, found 311.00; ¹H NMR (300 MHz, CDCl ₃) δ 6.68-6.61 (m, 1H), 2.50-2.41 (m, 1H), 0.89-0.73 (m, 2H), 0.78-0.51 (m, 2H).

Step 16: 1-Cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole

To a stirred solution of N ¹-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine (3.30 g, 10.64 mmol) in MeOH (33.00 mL) was added trimethyl orthoformate (3.39 g, 31.92 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 70° C. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/2). The fractions contained desired product were combined and concentrated to afford 1-cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole (1.70 g, 50%) as a yellow solid. MS ESI calculated for C ₁₁H ₇F ₂N ₂[M+H] ⁺, 320.96, found 321.00; ¹H NMR (300 MHz, CDCl ₃) δ 7.91 (s, 1H), 7.22-7.18 (m, 1H), 3.41-3.36 (m, 1H), 1.31-1.02 (m, 4H).

Step 17: 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

To a stirred solution of 1-cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole (0.97 g, 3.02 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (1.00 g, 3.02 mmol), Pd(PPh ₃) ₂Cl ₂(0.21 g, 0.30 mmol) and CuI (0.11 g, 0.60 mmol) in DMF (15.00 mL) was added TEA (0.92 g, 9.05 mmol) dropwise at room temperature. The reaction mixture was degassed with argon for three times and stirred for 40 min at 90° C. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. Then the crude product was further purified by reverse phase flash with the following conditions: column: C18 silica gel; mobile phase: ACN in water (10 mmol/L NH ₃HCO ₃), 10% to 50% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(1-cyclopropyl-4,6-difluoro-1,3-b enzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.51 g, 33%) as a white solid. MS ESI calculated for C ₂₆H ₂₇F ₂N ₇O ₃[M+H] ⁺, 524.21, found 524.35; ¹H NMR (300 MHz, CDCl ₃) δ 7.99 (s, 1H), 7.30-7.12 (m, 2H), 6.83 (brs, EH), 6.67-6.32 (m, 2H), 5.84-5.73 (m, 1H), 5.64-5.12 (m, 2H), 4.71-4.38 (m, 1H), 4.25-3.84 (m, 3H), 3.60-3.33 (m, 5H), 3.20-3.08 (m, 3H), 2.86-2.70 (m, 1H), 2.37-2.31 (m, 1H), 1.40-0.89 (m, 4H).

PATENT

WO2021247969 Kinnate Biopharma Inc EG78

WO2023107980 solid state forms, Kinnate Biopharma Inc

WO2023107979 FGFR kinase inhibitor, Kinnate Biopharma Inc

References

Franovic A, Mohan A, Uryu S, Wu Q, Jiang P, Miller N, et al. (February 2022). “Activity of KIN-3248, a next-generation pan-FGFR inhibitor, against acquired FGFR-gatekeeper and molecular-brake drug resistance mutations”. Journal of Clinical Oncology. 40 (4_suppl): 461. doi:10.1200/JCO.2022.40.4_suppl.461.
Harding JJ, Perez CA, Kato S, Sharma M, Garmezy B, Quah CS, et al. (February 2023). “First in human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced cholangiocarcinoma (CCA) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations”. Journal of Clinical Oncology. 41 (4_suppl): TPS637-TPS637. doi:10.1200/JCO.2023.41.4_suppl.TPS637. S2CID 256257314.
Wang Z, Anderson KS (2022). “Therapeutic Targeting of FGFR Signaling in Head and Neck Cancer”. Cancer Journal (Sudbury, Mass.). 28 (5): 354–362. doi:10.1097/PPO.0000000000000615. PMC 9523489. PMID 36165723.

Identifiers

CAS Number	2750709-91-0
PubChem CID	162381323
UNII	W728TB393W
Chemical and physical data
Formula	C₂₆H₂₇F₂N₇O₃
Molar mass	523.545 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

[1]. Tyhonas JS, et al. Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations. J Med Chem. 2024 Feb 8;67(3):1734-1746. [Content Brief][2]. Balasooriya ER, et al. The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations. Clin Cancer Res. 2024 May 15;30(10):2181-2192. [Content Brief]

/////////Resigratinib, Pan-FGFR Inhibitor KIN-3248, KIN 3248, Pan-fibroblast Growth Factor Receptor Inhibitor KIN-3248, W728TB393W

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Sebetralstat

July 11, 2025 6:13 am / Leave a comment

Sebetralstat, KVD 900

CAS 1933514-13-6

491.5 g/mol

O5ZD2TU2B7

FDA 7/3/2025, Ekterly, To treat acute attacks of hereditary angioedema

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide

Sebetralstat, sold under the brand name Ekterly, is a medication used for the treatment of hereditary angioedema.^[1] Sebetralstat is a plasma kallikrein inhibitor.^[1]

Sebetralstat was approved for medical use in the United States in July 2025.^[1]^[2]

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00921

^aReagents and conditions: (a) 2-Hydroxypyridine (1.2 equiv), K₂CO₃ (3.0 equiv), acetone, 50 °C, 18 h, 78%; (b) methanesulfonyl chloride (1.3 equiv), Et₃N, (1.4 equiv), dichloromethane, rt, 18h, 93%; (c) methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (0.83 equiv), K₂CO₃ (2.0 equiv), DMF, 60 °C, 18 h, 54%; (d) NaOH (3.0 equiv), THF-MeOH-H₂O, rt, 18 h, 34%; (e) 22a (1.0 equiv), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (1.0 equiv), HATU (1.1 equiv), Et₃N (6.0 equiv), dichloromethane, rt, 4 h, 64%.

Synthesis of Sebetralstat

1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (19)

4-(Chloromethyl)benzyl alcohol 18 (5.0 g, 31.9 mmol) was added to a solution of potassium carbonate (13.2 g, 96 mmol) and 2-hydroxypyridine (3.6 g, 38.3 mmol) in acetone (250 mL). The reaction mixture was heated at 50 °C for 18 h and then concentrated in vacuo. The residue was partitioned between dichloromethane (300 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica (0–10% methanol in dichloromethane) to afford 19 (5.4 g, 25.1 mmol, 78% yield) as a white solid. MS (ESI) m/z 216.0 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.34–7.21 (m, 4H), 6.41 (dd, J = 9.1, 1.3 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.15 (t, J = 5.7 Hz, 1H), 5.07 (s, 2H), 4.46 (d, J = 5.7 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 161.4, 141.9, 140.0, 139.0, 135.7, 127.5, 126.6, 119.8, 105.4, 62.6, 50.8.

1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one (20)

A reaction flask containing 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (19) (8.45 g, 39.3 mmol), dry dichloromethane (80 mL), and triethylamine (7.66 mL, 55.0 mmol) was cooled in an ice–water bath. Methanesulfonyl chloride (3.95 mL, 51.0 mmol) was added to the reaction at 0 °C, and ice–water bath cooling continued. After 15 min, the ice–water bath was removed and stirring continued at room temperature overnight. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with further dichloromethane (2 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford 20 (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid. MS (ESI) m/z 234.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.49–7.39 (m, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.42 (ddd, J = 9.2, 1.3, 0.7 Hz, 1H), 6.24 (td, J = 6.7, 1.4 Hz, 1H), 5.09 (s, 2H), 4.73 (s, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.4, 140.1, 139.1, 137.6, 136.9, 129.0, 127.9, 119.9, 105.5, 50.8, 45.8.

Methyl 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21a) and Methyl 5-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21b)

Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.11 g, 11.77 mmol; CAS No. 318496-66-1) was added to a solution of potassium carbonate (3.25 g, 23.54 mmol) and 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one 20 (3.30 g, 14.12 mmol) in N,N-dimethylformamide (5 mL) and heated at 70 °C for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 × 100 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (120 g column, 0–100% (10% ethanol in ethyl acetate) in isohexanes to afford two regioisomers: 21a (2.03 g, 5.47 mmol, 47% yield) as an off-white solid and 21b (350 mg, 0.92 mmol, 8% yield). 21a MS (ESI) m/z 368.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.41 (ddd, J = 8.9, 6.5, 2.1 Hz, 1H), 7.25 (d, J = 1.2 Hz, 4H), 6.40 (dt, J = 9.1, 1.0 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.49 (s, 2H), 3.72 (s, 3H), 3.23 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 163.2, 161.8, 150.5, 140.6, 139.6, 137.6, 136.3, 135.6, 128.5, 128.4, 120.3, 111.8, 106.0, 66.0, 58.0, 55.1, 51.5, 51.2. 21b MS (ESI) m/z 368.1 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.28–7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.43–6.36 (m, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.35 (s, 2H), 5.06 (s, 2H), 4.78 (s, 2H), 3.75 (s, 3H), 3.25 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 163.4, 161.8, 142.4, 140.9, 140.5, 139.6, 137.4, 136.2, 128.3, 120.3, 112.8, 106.0, 61.7, 58.2, 53.0, 51.7, 51.2.

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (22a)

To methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate 21a (3.77 g, 10.26 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (15.39 mL, 30.80 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1 M aqueous HCl solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 22a (1.22 g, 3.45 mmol, 34% yield) as a white solid. MS (ESI) m/z 354.2 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.32 (s, 1H), 7.76 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.30–7.20 (m, 4H), 6.40 (ddd, J = 9.1, 1.4, 0.7 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.50 (s, 2H), 3.22 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 164.3, 161.8, 150.5, 140.6, 139.6, 137.6, 136.4, 135.6, 128.5, 128.4, 120.3, 113.0, 106.0, 66.0, 58.0, 55.1, 51.2.

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic Acid (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-amide (14w)

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid 22a (75 mg, 0.212 mmol), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (49 mg, 0.212 mmol; CAS No. 1256812-75-5), and HATU (89 mg, 0.233 mmol) were suspended in anhydrous dichloromethane (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated, and then left to stir at room temperature for 4 h. The solvent was removed under reduced pressure, and the resulting residue was quenched with saturated aqueous ammonium chloride solution (5 mL). An off-white solid resulted, which was sonicated, filtered under reduced pressure, washed with water, and dried in a vacuum oven at 40 °C overnight. The residue was purified by chromatography eluting with 1% NH₃ in MeOH/dichloromethane to afford 14w as a white solid (67 mg, 64% yield). MS (ESI) m/z 492.0 (M + H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.42 (t, J = 5.4 Hz, 1H), 8.29–8.21 (m, 2H), 7.75 (ddd, J = 0.7, 2.1, 6.8 Hz, 1H), 7.41 (ddd, J = 2.1, 6.6, 8.9 Hz,1H), 7.28–7.17 (m, 5H), 6.39 (ddd, J = 0.7, 1.4, 9.2 Hz, 1H), 6.22 (td, J = 1.4, 6.7 Hz, 1H), 5.28 (s, 2H), 5.07 (s, 2H), 4.57–4.46 (m, 4H), 3.92 (s, 3H), 3.25 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9, 161.3, 153.0 (J_C–F = 8.7 Hz), 147.5, 146.8 (J_C–F = 253.5 Hz), 146.0 (J_C–F = 7.2 Hz), 145.2 (J_C–F = 11.6 Hz), 140.1, 139.1, 137.1, 136.0, 133.2, 128.1, 127.9, 119.9, 116.3, 108.7, 105.5, 66.3, 57.5, 56.4, 54.6, 50.7, 38.3.

PATENT

US10364238,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US232820883&_cid=P22-MCYEU3-92408-1

Example 41

3-Fluoro-4-methoxy-pyridine-2-carbonitrile

To a large microwave vial, cyanocopper (1.304 g, 14.56 mmol) was added to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100° C. for 16 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and required additional water (40 mL) and EtOAc (2×50 mL) with sonication to break-up the solid precipitated. The combined layers were filtered through a plug of celite and the organic layer isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a pale green solid identified as the desired compound 3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield)

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester

3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled in an ice-salt bath to −5° C. and then sodium borohydride (153 mg, 4.05 mmol) was added portionwise maintaining the reaction temperature ˜0° C. The deep brown solution was left to stir at 0° C. and slowly allowed to warm to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40° C. to afford a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (10 mL). An emulsion formed so the organics were separated via a phase separating cartridge and concentrated. The crude liquid was purified by chromatography eluting with EtOAc/iso-Hexane to afford the title compound, (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62% yield)

[MH] ⁺=257

C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt and left to stir at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and then triturated with ether, sonicated and then decanted to give a cream coloured solid (75 mg, 55% yield) identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt.

[MH] ⁺=157

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (75 mg, 0.212 mmol), C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt (49 mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were suspended in anhydrous DCM (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated and then left to stir at rt for 4 hours. The solvent was removed under reduced pressure and the resulting residue was quenched with ammonium chloride solution (5 mL). An off white solid resulted which was sonicated, filtered under reduced pressure washed with water and then placed in the vac oven at 40° C. overnight. The crude material was purified by chromatography eluting with (1% ammonia-methanol)/DCM to afford the 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide as a white solid (67 mg, 64% yield)

[MH] ⁺=492

NMR (d ⁶-DMSO) δ: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J=1.4, 6.7 Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9 Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.8 Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J=5.4 Hz)

Medical uses

Sebetralstat is indicated for the treatment of acute attacks of hereditary angioedema.^[1]

Pharmacology

Sebetralstat is a plasma kallikrein inhibitor that contains the unusual 2-pyridone heterocycle.^[3]

Society and culture

Legal status

Sebetralstat was approved for medical use in the United States in July 2025.^[1] The US Food and Drug Administration granted the application for sebetralstat orphan drug designation.^[4]

Names

Sebetralstat is the international nonproprietary name.^[5]

Sebetralstat is sold under the brand name Ekterly.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Ekterly- sebetralstat tablet”. DailyMed. 7 July 2025. Retrieved 9 July 2025.
^ “KalVista Pharmaceuticals Announces FDA Approval of Ekterly (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema” (Press release). Kalvista. 7 July 2025. Retrieved 9 July 2025 – via Business Wire.
^ Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, et al. (October 2022). “Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema”. Journal of Medicinal Chemistry. 65 (20): 13629–13644. doi:10.1021/acs.jmedchem.2c00921. PMC 9620001. PMID 36251573.
^ “Sebetralstat Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 9 July 2025.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.

External links

“Sebetralstat (Code – C184930)”. EVS Explore.
Clinical trial number NCT05259917 for “A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)” at ClinicalTrials.gov

Clinical data

Trade names	Ekterly
Other names	KVD-900, KVD900
License data	US DailyMed: Sebetralstat
Routes of administration	By mouth
ATC code	B06AC08 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1933514-13-6
PubChem CID	121365142
IUPHAR/BPS	11947
DrugBank	DB18305
ChemSpider	115006749
UNII	O5ZD2TU2B7
KEGG	D12396
ChEMBL	ChEMBL5095248
Chemical and physical data
Formula	C₂₆H₂₆FN₅O₄
Molar mass	491.523 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

//////////Sebetralstat, FDA 2025, APPROVALS 2025, Ekterly, angioedema, KVD 900, O5ZD2TU2B7

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Redafamdastat

July 11, 2025 2:46 am / Leave a comment

Redafamdastat

cas 1020315-31-4, PF 04457845

JZP-150; JZP150; PF-04457845; PF-4457845; PF04457845; PF4457845, Q7119045

WeightAverage: 455.441
Monoisotopic: 455.156909393

Chemical FormulaC₂₃H₂₀F₃N₅O₂

1-Piperidinecarboxamide, N-3-pyridazinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methylene]-
N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide

Redafamdastat (INNTooltip International Nonproprietary Name; developmental code names JZP-150, PF-04457845) is an inhibitor of the enzyme fatty acid amide hydrolase (FAAH), with an IC₅₀Tooltip half-maximal inhibitory concentration of 7.2 nM, and both analgesic and anti-inflammatory effects in animal studies comparable to those of the cyclooxygenase inhibitor naproxen.^[1] It was being developed by Jazz Pharmaceuticals for the treatment of alcoholism, pain, and post-traumatic stress disorder (PTSD) and reached phase 2 clinical trials.^[2][3] However, development of the drug was discontinued in December 2023.^[2]

SCHEME

PAPER

ACS Medicinal Chemistry Letters (2011), 2(2), 91-96 86%

PATENT

WO2008047229 86%

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2008047229&_cid=P11-MCY7EC-33944-1

Example 1a
Synthesis of N-pyridin-3-yl-4-(3-(f5-(trifluoromethyl)pyridin-2-ylloxy)benzylidene)piperidine-1-carboxamide

Phenyl pyridin-3-ylcarbamate
To a stirred solution of 3-aminopyridine (51.7 g, 0.549 moles) in THF (900 mL) at -10 ⁰C was added pyridine (52.1 g, 0.659 moles) in a stream over a 10 min period, followed by the dropwise addition of phenyl chloroformate (90 g, 0.575 moles) over a 20 min period. The reaction tempature increased to 5 ⁰C. A precipitate formed during the addition. The resulting suspension was stirred at temperatures reaching ambient temperature over the next 3 h. The reaction mixture was partitioned between water (2 L) and EtOAc (1.5 L). The aqueous portion was extracted with EtOAc (1 L). The combined organic portions were dried (MgSO₄) and concentrated in vacuo to a damp solid residue. This was suspended in
EtOAc:ether (1 :1 , 600 ml_). The resulting suspension was stirred at -10 ⁰C for 2 h and filtered. The solid was rinsed with EtOAσether (1 :1 , 100 ml.) and pressed dry under suction. Further drying in vacuo at 35 ⁰C for 7 h provided 104 g (88%) of product. Analysis, Calcd for Ci₂H₁₀N₂O₂: C, 67.28; H, 4.71 ; N, 13.08. Found: C, 67.15; H, 4.76; N, 12.87.

Step i
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol
3-Hydroxymethyl-phenol (5.00 g, 40.3 mmol, from Lancaster Synthesis), 2-chloro-5-trifluoromethyl-pyridine (7.31 g, 40.3 mmol, from TCI America) and potassium carbonate (6.96 g, 50.3 mmol) were suspended in dimethylformamide (80 mL) and heated to 95 ⁰C. After stirring for 16 h, the solvent was distilled off in vacuo at 65 ⁰C, and a residue was partitioned between water and heptane/ethyl acetate (1 :1 ). The organic layer was separated and the aqueous was extracted again with heptane/ethyl acetate (1 :1 ). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-60%, EtOAc:heptane) to afford the desired product (5.70 g, 53% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 4.73 (s, 2 H) 7.02 (dt, J=8.66, 0.57 Hz, 1 H) 7.04 – 7.11 (m, J=8.06, 2.40, 0.50, 0.50 Hz, 1 H) 7.15 – 7.19 (m, 1 H) 7.25 (ddd, J=8.39, 1.60, 0.80 Hz, 1 H) 7.42 (t, J=7.87 Hz, 1 H) 7.90 (ddd, J=8.67, 2.55, 0.50 Hz, 1 H) 8.43 (td, J=1.68, 0.84 Hz, 1 H).
Step 2
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.68 g, 17.4 mmol), in
dichloromethane (46 mL), was cooled to 0 ⁰C, and treated dropwise with thionyl chloride (1.40 mL, 19.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 30 rηjn. Toluene (10 mL) was added and the mixture was concentrated by evaporation to form a residue. The residue was evaporated again from toluene and dried under high vacuum to afford the desired product (4.88 g, 98% yield) as an oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 4.60 (s, 2 H) 7.03 (d, J=8.70 Hz, 1 H) 7.11 (ddd, J=8.09, 2.35, 0.94 Hz, 1 H) 7.20 (t, J=2.03 Hz, 1 H) 7.26 – 7.31 (m, 1 H) 7.42 (t, J=7.88 Hz, 1 H) 7.91 (dd, J=8.67, 2.53 Hz, 1 H) 8.44 (dd, J=1.51 , 0.90 Hz, 1 H).
Step 3
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine (4.88 g, 17.0 mmol) from Step 2 was treated neat with triethylphosphite (4.36 mL, 25.4 mmol) and heated to 150 ⁰C. After 6 h, the reaction mixture was cooled, treated with an additional 0.5 mL triethylphosphite (2.9 mmol) and reheated to 150 ⁰C. After 6 h, the reaction mixture was removed from the heat and slowly treated with heptane (about 60 mL) while stirring to afford a white solid. The solid was collected by filtration, washed with heptane and dried in a vacuum oven for 16 h at 45 ⁰C to afford a white powder (5.99 g, 91% yield). MS (APCI) M+1= 390.1 ; ¹H NMR (400 MHz, CDCI₃) δ ppm 1.26 (t, J=7.02 Hz, 6 H) 3.18 (d, J=21.83 Hz, 2 H) 3.99 – 4.10 (m, 4 H) 7.01 (d, J=8.58 Hz, 1 H) 7.03 – 7.08 (m, 1 H) 7.12 (q, J=2.21 Hz, 1 H) 7.19 – 7.24 (m, 1 H) 7.38 (t, J=7.90 Hz, 1 H) 7.90 (dd, J=8.58, 2.53 Hz, 1 H) 8.43 (dd, J=1.66, 0.88 Hz, 1 H).
Step 4
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1 -carboxylic acid tert-butyl ester
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.3 g, 6.0 mmol) from Step 3 and 1 ,4,7,10, IS-pentaoxacyclopentadecane (15-Crown-5, 0.03 ml_, 0.15 mmol) were combined in THF (10 ml_). The mixture was cooled to 0 °C and sodium hydride (240 mg, 60% dispersion in mineral oil, 6.0 mmol) was added. The reaction was warmed to room temperature, stirred for 30 minutes and then cooled back to 0 ⁰C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.0 mmol) in THF (6 ml_) was added and the reaction was warmed to room temperature. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2X200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a thick oil. Treatment of the oil with hot isopropyl ether (45 mL) provided the title compound as a white solid (1.88 g). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.46 (s, 9 H) 2.34 (td, J=5.85, 1.18 Hz, 2 H) 2.46 (td, J=5.87, 1.07 Hz, 2 H) 3.37 – 3.44 (m, 2 H) 3.45 – 3.57 (m, 2 H) 6.41 (s, 1 H) 6.92 – 7.04 (m, 2 H) 7.06 – 7.17 (m, 2 H) 7.31 – 7.54 (m, 1 H) 8.08 (ddd, J=8.74, 2.59, 0.56 Hz, 1 H) 8.42 (td, J=1.73, 0.90 Hz, 1 H).
Step 5
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 3.11 mmol) from Step 4 was dissolved in CH₂CI₂ (30 mL) and treated with HCI in diethyl ether (10 mL, 2.0 M, 20 mmol). After 16 hours the reaction was concentrated in vacuo to form a residue and the residue was suspended in acetonitrile (10 mL) to yield a solid. Filtration of the solid provided the title compound as a white solid (1.1 g). ¹H NMR (400 MHz, CD₃OD) δ ppm 2.62 (td, J=6.11 , 0.91 Hz, 2 H) 2.67 – 2.81 (m, 2 H) 3.14 – 3.21 (m, 2 H) 3.22 – 3.29 (m, 2 H) 6.56 (s, 1 H) 6.99 – 7.09 (m, 2 H) 7.10 – 7.18 (m, 2 H) 7.42 (t, J=7.91 Hz, 1 H) 8.09 (ddd, J=8.74, 2.60, 0.33 Hz, 1 H) 8.41 (td, J=1.63, 0.74 Hz, 1 H).
Step 6
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (800 mg, 2.16 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (508 mg, 2.37 mmol) and diisopropylethylamine (0.75 mL, 4.52 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with 5% NaOH (aq), dried over anhydrous sodium sulfate, filtered and concentrated. Treatment of the residue with hot isopropyl ether and purified from isopropyl ether/methanol provided the title compound as a white solid (574 mg). MS (APCI 10V) AP+ 455.3, 376.2, 335.2, AP- 453.2; ¹H NMR (400 MHz, CD₃OD) δ ppm 2.46 (td, J=5.86, 0.97 Hz, 2 H) 2.58 (td, J=5.82, 1.16 Hz, 2 H) 3.51 – 3.60 (m, 2 H) 3.61 – 3.70 (m, 2 H) 6.46 (s, 1 H) 6.98 – 7.07 (m, 2 H) 7.09 – 7.19 (m, 2 H) 7.34 (ddd, J=8.41 , 4.81 , 0.65 Hz, 1 H) 7.40 (td, J=7.69, 0.74 Hz, 1 H) 7.91 (ddd, J=8.38, 2.58, 1.44 Hz, 1 H) 8.08 (ddd, J=8.73, 2.61 , 0.55 Hz, 1 H) 8.16 (dd, J=4.84, 1.06 Hz, 1 H) 8.43 (td, J=1.74, 0.91 Hz, 1 H) 8.58 (d, J=1.88 Hz, 1 H).

Example 1b
Large scale synthesis of N-pyridin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-ylloxy)benzylidene)piperidine-1- carboxamide
Step 1 : Preparation of r3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyll-methanol
To a solution of S-trifluoromethyl^-chloro-pyridine (150.0 g, 0.826 mol) in DMF (1.9 L) was added 3-hydroxy-phenyl-methanol (112.5 g, 0.906 mol) and of potassium carbonate (171.0 g, 1.237 mol). The solids were washed into the flask with 100 mL of DMF. The stirred mixture was heated to 95-105 ⁰C for 5 h. It was cooled to ambient temperature and then poured into 5 L of stirred ice-water. The mixture was extracted with etheπhexane (2:1 , 1.5 L, 1.0 L). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to dryness to give the product (222.5 g, 100%).

Step 2: Preparation of 2-(3-chloromethyl-phenoxy)-5-trifluoromethylpyridine
To a solution of [3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol (281.0 g, 1.044 moles) in dichloromethane (2.0 L) at -5 ⁰C was added dropwise over a 25 min period thionyl chloride (136.6 g, 1.148 mol). A few minutes into the addition, a white substance separated but this went into solution several minutes later. The reaction was stirred at ambient temperature for 1 h and then was concentrated in vacuo to near dryness (357 g). 200 mL of toluene was added to the residue and the solution was again concentrated in vacuo to near dryness. 200 mL of toluene was added and some solid (-8 g) was filtered off. The filtrate was concentrated in vacuo to -390 g of dark yellow liquid.

Step 3: Preparation of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyll-phosphonic acid diethyl ester
A solution of 2-(3-chloromethyl-phenoxy)-5-trifluoromethylpyridine (-298 g, -1.036 mol) containing some toluene in triethyl phosphite (267.0 g, 1.551 mol) was heated to 135 °C-140 ⁰C for 7 h. Boiling began at -110 ⁰C and continued throughout the reaction. The solution was left standing at ambient temperature overnight and it solidified. The solid was suspended in etheπhexane (1 :2, 450 mL), and the suspension was stirred at ambient temperature for 3 h and filtered. The solid was rinsed with etherhexane (1 :2, 150 mL) and pressed dry under suction. Further drying in vacuo at 32 ⁰C for 7 h provided 286.3 g (71 % – 2 steps from crude chloride) of product. The filtrate was concentrated in vacuo to remove the low boiling solvents. Triethyl phosphite (36.0 g, 0.217 mol) was added and the solution was heated to 130 ⁰C for 2 h. The reaction was cooled to 100 ⁰C and 300 mL of heptane was added slowly. A solid separated. As the temperature decreased to -30 ⁰C, 150 mL of ether was added. The resulting suspension was left standing at ambient temperature overnight and was filtered. The solid was rinsed with etherheptane (1 :2, 75 mL) and pressed dry under suction. Further drying in vacuo at 32 ⁰C for 7 h afforded and additional 35.7 g (9%) of product. Total yield = 322 g (80%). Anal. Calcd for C17H19 F3NO4P (389.31 ) : C, 52.45; H, 4.92; N, 3.60; F, 14.64; P, 7.96. Found : C, 52.73; H, 5.04; N, 3.58; F, 14.35; P, 7.74; chloride, <0.10%.

Step 4: Preparation of 4-f3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidenel-piperidine-1-carboxylic acid tert-butyl ester
To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at -10 ⁰C was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to -3 °C during the addition. The resulting red mixture was stirred between -6 ⁰C and -10 ⁰C for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2 ⁰C. The resulting red mixture was stirred at temperatures reaching 21 ⁰C over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at -10 ⁰C for 2 h and filtered. Drying in vacuo at 25 ^CC for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at -10 ⁰C for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl etherheptane (1 :3) and pressed dry under suction. Further drying in vacuo at 34 °C for 6 h provided an additional 34.2 g (19.5%) of product. Total yield = 119.2 g (68.5%).

Step 5: Preparation of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine, hydrochloride

To a mixture of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid fert-butyl ester (312 g, 0.718 mol) in ethyl acetate (2.8 L) at 0 ⁰C to -5 ⁰C was added streamwise over a 20 min period, 4.0 M hydrogen chloride in dioxane (800 mL, 3.2 mol). No significant temperature change was noted. The resulting suspension was stirred at temperatures reaching 22 ⁰C over the next 17 h. The suspension was filtered. The solid was washed with EtOAc (500 mL) and pressed as dry as possible under suction. The damp solid was dried in vacuo at 33 ⁰C for 7 h to afford 225 g (84%) of product.

Step 6: Preparation of N-pyridin-3-yl-4-(3-(f5-(trifluoromethyl)pyridin-2-ylloxy}benzylidene)piperidine-1-carboxamide
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine (80.0 g, 0.216 mol) and phenyl pyridin-3-ylcarbamate (48.6 g, 0.227 mol) in acetonitrile (650 mL) was added dropwise diisopropylethyl amine (55.8 g, 0.432 mol). A solution formed after -45 min of stirring. The slightly turbid solution was stirred at ambient temperature for 18 h. TLC showed a prominent product spot with traces of both starting materials and two other fast moving spots. The solution was concentrated in vacuo to a viscous oil. This was partitioned between dichloromethane (600 mL) and water (500 mL). The aqueous layer was extracted with 200 mL of dichloromethane. The combined organic layers were washed with successive portions of 500 mL of 5% sodium hydroxide, and 200 mL of water, then dried over magnesium sulfate and concentrated in vacuo to 139.5 g of a viscous oil. This was dissolved in 350 ml_ of warm (50 ⁰C) methyl t-butyl ether. Soon after a solution formed, solid began separating. The crystallizing mixture was kept at -10 ⁰C for 4 h and filtered. The solid was rinsed with 60 ml_ of methyl t-butyl ether and pressed dry under suction. Further drying in vacuo at 28 ⁰C for 16 h and then at 35 °C for 6 h provided 93.2 g (95%) of product.

PAPER

ACS Medicinal Chemistry Letters (2011), 2(2), 91-96

https://pubs.acs.org/doi/10.1021/ml100190t

PAPER

Science (Washington, DC, United States) (2017), 356(6342), 1084-1087

Pfizer Products Inc.WO2008047229

References

^ Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, et al. (February 2011). “Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor”. ACS Medicinal Chemistry Letters. 2 (2): 91–96. doi:10.1021/ml100190t. PMC 3109749. PMID 21666860.
^ Jump up to:^a ^b “JZP 150”. AdisInsight. 26 December 2023. Retrieved 16 August 2024.
^ “A Study of JZP150 in Adults With Posttraumatic Stress Disorder – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov.
[1]. Johnson DS, et al. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett. 2011 Feb 10;2(2):91-96. [Content Brief][2]. Ahn K, et al. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther. 2011 Jul;338(1):114-24. [Content Brief][3]. Buntyn RW, et al. Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Jan 1:1091581817725272. [Content Brief]

////////Redafamdastat, PF 04457845, JZP-150, JZP150, PF-04457845, PF-4457845, PF04457845, PF4457845, Q7119045

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ARAZASETRON BESYLATE

July 10, 2025 9:40 am / Leave a comment

ARAZASETRON BESYLATE

R-Azasetron besylate, SENS-401

Cas 2025360-91-0

C₁₇H₂₀ClN₃O₃.C₆H₆O₃S, 507.99, UXP39EQ477

2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-, benzenesulfonate (1:1)

N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide; benzenesulfonic acid

X HCL SALT, CAS , 2139305-21-6, Name2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,…

BASE: 2025360-90-9

.HCL SALT CAS, 2566443-39-6

Name 2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,…

BASE: 2025360-90-9

Base CHIRAL 2025360-90-9

N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide

(R)-Azasetron besylate (SENS-401) is an orally active calcineurin inhibitor. (R)-Azasetron besylate reduces Cisplatin (HY-17394)-induced hearing loss and cochlear damage.

Arazasetron Besylate is the besylate salt form of the R-enantiomer of azasetron, a benzamide derivative and selective serotonin (5-hydroxytryptamine; 5-HT) receptor and calcineurin antagonist, with potential antinauseant and antiemetic, and otoprotective activities. Upon administration, arazasetron selectively binds to and inhibits 5-HT subtype 3 receptors (5-HT3R) located peripherally on vagus nerve terminals and centrally in the chemoreceptor trigger zone (CTZ) of the area postrema, which may result in suppression of nausea and vomiting. R-azasetron also targets and inhibits the activation of calcineurin, thereby preventing inner ear lesions, nerve degeneration, induction of apoptosis and sensory hair loss. This may prevent hearing loss. Calcineurin activation plays a key role in structural degeneration, swelling, synaptic uncoupling and the induction of apoptosis in the inner ear leading to hair cell loss and hearing loss.

SCHEME

PATENTS

WO2017178645

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017178645&_cid=P22-MCX71S-95827-1

PATENTS

US20190083503

https://patentscope.wipo.int/search/en/detail.jsf?docId=US239434911&_cid=P22-MCX73M-97768-1

PATENTS

WO2010/133663

CN101786963

CN104557906

WO201717864

WO2021014014

WO2023175078

WO2023122719

Base WO2017178645

WO2021014014

WO2023175078

[1]. Petremann M, et al. SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours. Otol Neurotol. 2019 Feb;40(2):254-263. [Content Brief][2]. Petremann M, et al. Oral Administration of Clinical Stage Drug Candidate SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in Rats. Otol Neurotol. 2017 Oct;38(9):1355-1361. [Content Brief]

//////////ARAZASETRON BESYLATE, R-Azasetron besylate, UXP39EQ477, SENS-401, SENS 401

Sunvozertinib

July 10, 2025 2:51 am / Leave a comment

Sunvozertinib

CAS 2370013-12-8

DZD9008, 584.1 g/mol, C₂₉H₃₅ClFN₇O₃, A-1801, L1Q2K5JYO8

N-[5-[[4-[5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)anilino]pyrimidin-2-yl]amino]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-4-methoxyphenyl]prop-2-enamide

FDA Zegfrovy, 7/2/2025

To treat locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations, as detected by an FDA-approved test, with disease progression on or after platinum-based chemotherapy

Sunvozertinib (DZD9008) is a potent ErbBs (EGFR, Her2, especially mutant forms) and BTK inhibitor. Sunvozertinib shows IC₅₀s of 20.4, 20.4, 1.1, 7.5, and 80.4 nM for EGFR exon 20 NPH insertion, EGFR exon 20 ASV insertion, EGFR L858R and T790M mutations, and Her2 Exon20 YVMA, and EGFR WT A431, respectively (patent WO2019149164A1, example 52).

Sunvozertinib, sold under the brand name 舒沃哲, among others is an anti-cancer medication used for the treatment of non-small-cell lung cancer.^[2]^[3] It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.^[2]^[4]

Sunvozertinib was approved for medical use in the United States in July 2025.^[1]

Medical uses

In the US, sunvozertinib is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.^[1]

Side effects

The US FDA prescribing information for sunvozertinib includes warnings and precautions for interstitial lung disease/pneumonitis, gastrointestinal adverse reactions, dermatologic adverse reactions, ocular toxicity, and embryo-fetal toxicity.^[1]

History

Sunvozertinib is being developed by Dizal Pharmaceutical.^[5] In China, it was conditionally approved in 2023 for the treatment of NSCLC and full approval is contingent on results of phase 3 clinical trials.^[6] In the United States, it has been designated by the Food and Drug Administration as a breakthrough therapy for patients with locally advanced or metastatic NSCLCs with an EGFR exon 20 insertion mutation.^[7]

Efficacy was evaluated in WU-KONG1B (NCT03974022), a multinational, open-label, dose randomization trial.^[1] Eligible participants had locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations with disease progression on or after platinum-based chemotherapy.^[1] The primary efficacy population was in 85 participants who received sunvozertinib 200 mg orally once daily with food until disease progression or intolerable toxicity.^[1]

The US Food and Drug Administration granted the application for sunvozertinib priority review and breakthrough therapy designations.^[1]

SYN

Example 52 [WO2019149164A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019149164&_cid=P10-MCWSEU-52423-1

Example 52

[1286]

(R) -N- (5- (4- (5-chloro-4-fluoro-2- (2-hydroxypropan-2-yl) phenylamino) pyrimidin-2-ylamino) -2- (3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide

Procedure for the preparation of compound 52a:

[1289]

To a solution of compound 36b (200 mg, 0.429 mmol) and K ₂CO ₃(119 mg, 0.858 mmol) in DMSO (3 mL) was added (R) -N, N-dimethylpyrrolidin-3-amine (59 mg, 0.515 mmol) . The reaction mixture was stired at 22-30℃ for 4 h, then 50℃ for 1 h while color changed from brown to deep orange. The reaction mixture was added drop wise into H ₂O (40 mL) under ice water bath. The precipitated solid was collected by filtration and washed with H ₂O (15 mL × 3) , the filter cake was dissolved with CH ₂Cl ₂(20 mL) , dried over Na ₂SO ₄and concentrated in vacuum to give compound 52a (210 mg, 87.4%yield) as an orange solid.

[1290]

LCMS: R _t=0.677 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2mm) , MS (ESI) m/z=559.9 [M+H] ⁺.

[1291]

¹H NMR (400MHz, Methanol-d ₄) δ 8.42 (s, 1H) , 7.99 (d, J=7.6 Hz, 1H) , 7.96 (d, J=5.6 Hz, 1H) , 7.24 (d, J=10.8 Hz, 1H) , 6.50 (s, 1H) , 6.15 (d, J=5.6 Hz, 1H) , 3.96 (s, 3H) , 3.54 (dt, J=6.4, 10.4 Hz, 1H) , 3.36 (t, J=9.2 Hz, 1H) , 3.28 -3.24 (m, 1H) , 3.09 (dd, J=6.8, 10.0 Hz, 1H) , 2.93 -2.81 (m, 1H) , 2.33 (s, 6H) , 2.30 -2.25 (m, 1H) , 1.97 -1.82 (m, 1H) , 1.59 (d, J=3.6 Hz, 6H) .

[1292]

Procedure for the preparation of compound 52b:

[1293]

To a solution of compound 52a (210 mg, 0.375 mmol) in 5 mL MeOH/H ₂O=5/1 (v/v) was added Zn (147 mg, 2.25 mmol) and NH ₄Cl (120 mg, 2.25 mmol) . The resulting mixture was heated at 90℃ for 2 h while color changed from orange to brown. The reaction mixture was filtered, and the filtrate was concentrated in vacuum to give the crude residue, which was dissolved with CH ₂Cl ₂(20 mL) , washed with water (15 mL×3) , then dried over Na ₂SO ₄and concentrated in vacuum to give compound 52b (125 mg, 63%yield) as a brown solid.

[1294]

LCMS: R _t=0.629 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2mm) , MS (ESI) m/z=530.1 [M+H] ⁺.

[1295]

¹H NMR (400MHz, CDCl ₃) δ 8.85 (s, 1H) , 8.15 (d, J=7.2 Hz, 1H) , 8.03 (d, J=6.0 Hz, 1H) , 7.87 (s, 1H) , 7.43 (s, 1H) , 7.08 (d, J=10.4 Hz, 1H) , 6.66 (s, 1H) , 6.05 (d, J=5.6 Hz, 1H) , 3.81 (s, 3H) , 3.20 -3.11 (m, 2H) , 3.06 -2.97 (m, 2H) , 2.91 -2.83 (m, 1H) , 2.28 (s, 6H) , 2.17 -2.09 (m, 1H) , 1.92 -1.81 (m, 1H) , 1.65 (s, 6H) .

[1296]

Procedure for the preparation of Example 52:

[1297]

To a solution of compound 52b (125 mg, 0.236 mmol) and DIEA (46 mg, 0.354 mmol) in DMF (1.5 mL) was added acryloyl chloride (21 mg, 0.236 mmol) in ice water bath. The resulting mixture was stirred at 5-10℃ for 15 min. The reaction was quenched by H ₂O (0.1 mL) and then filtered, the filtrate was purified by pre-HPLC directly (Column: Xtimate C18 150*25mm*5um; Condition: 35-65%B (A: 0.04%NH ₃·H ₂O+10mM NH ₄HCO ₃, B: CH ₃CN) ; Flow Rate: 30 ml/min) and then lyophilized to give Example 52 (14.5 mg, 10.5%yield) as an off-white solid.

[1298]

LCMS: R _t=2.028 min in 10-80CD_3min_220&254. lcm chromatography (XBrige Shield RP18 2.1*50mm, 5um) , MS (ESI) m/z=584.3 [M+H] ⁺.

[1299]

¹H NMR (400MHz, CDCl ₃) δ 9.62 (s, 1H) , 9.43 (br s, 1H) , 8.59 (br s, 1H) , 8.08 (d, J=5.2 Hz, 1H) , 7.53 (d, J=6.8 Hz, 1H) , 7.47 (br s, 1H) , 7.14 (d, J=10.8 Hz, 1H) , 6.75 (s, 1H) , 6.41 -6.31 (m, 3H) , 5.77 (t, J=5.4 Hz, 1H) , 3.86 (s, 3H) , 3.15 -3.02 (m, 4H) , 2.97 -2.84 (m, 1H) , 2.30 (s, 6H) , 2.21 -2.14 (m, 1H) , 1.99 -1.94 (m, 1H) , 1.72 (s, 6H) .

PATENT

PAPER

https://www.mdpi.com/1420-3049/29/7/1448

Sunvozertinib, a novel TKI manufactured by Dizal Pharmaceuticals, represents an advancement arising from the need to overcome resistance mechanisms and thereby replaces previous generations of EGFR inhibitors. As marketed under the proprietary name DZD9008, this therapeutic entity embodies an innovative modality aimed at addressing NSCLC characterized by distinct mutations within the EGFR gene [24]. The pharmacological efficacy of sunvozertinib is predicated upon its specific capacity to inhibit EGFR with Exon 20 mutations, alongside targeting human epidermal growth factor receptor 2 (HER2) with Exon 20 insertions. This targeted inhibition is of significance due to the diminished responsiveness of cancer cells with these mutations to earlier generations of EGFR inhibitors. By competitively obstructing the ATP-binding site of these mutated tyrosine kinases, sunvozertinib effectively hinders the proliferative signaling pathways, exhibiting potent anti-tumor activity (ClinicalTrials.gov Identifier: NCT03974022). Preclinical models have demonstrated sunvozertinib’s capacity to inhibit tumor growth, especially in NSCLC models harboring Exon 20 insertions. Moreover, its substantiated ability to traverse the blood–brain barrier has provided favorable support for its prospective efficacy in managing central nervous system metastases. In clinical settings, sunvozertinib has shown promising efficacy, with ongoing trials further assessing its utility as a targeted intervention for individuals presenting specific EGFR mutations. The toxicity profile has been comparable to other EGFR inhibitors, with manageable side effects that do not significantly diminish its therapeutic value [25].

The preparation of sunvozertinib is shown in Scheme 1 [26]. SUNV-001 and SUNV-002 engage in nucleophilic substitution reactions under alkaline conditions, yielding the formation of SUNV-003 through a subsequent nucleophilic substitution process involving SUNV-004, ultimately leading to the generation of SUNV-005. SUNV-005 and SUNV-006 consecutively engage in nucleophilic substitution reactions, culminating in the formation of SUNV-007. The nitro moiety present in SUNV-007 undergoes a reduction process to yield an amino functional group, through the utilization of hydrogen gas as the reducing agent and platinum carbon as the catalytic mediator, ultimately affording the formation of SUNV-008. The amino moiety present in SUNV-008 and the acyl chloride functionality of SUNV-009 engage in a condensation reaction, leading to the formation of the amide compound SUNV-010. SUNV-010 is subjected to an elimination reaction in alkaline environments, leading to the formation of sunvozertinib.

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References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations”. U.S. Food and Drug Administration (FDA). 2 July 2025. Retrieved 7 July 2025. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b Wang M, Yang JC, Mitchell PL, Fang J, Camidge DR, Nian W, et al. (2022). “Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations”. Cancer Discovery. 12 (7): 1676–1689. doi:10.1158/2159-8290.CD-21-1615. PMC 9262839. PMID 35404393.
^ Wang M, Fan Y, Sun M, Wang Y, Zhao Y, Jin B, et al. (2024). “Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): Single-arm, open-label, multicentre, phase 2 trial”. The Lancet Respiratory Medicine. 12 (3): 217–224. doi:10.1016/S2213-2600(23)00379-X. PMID 38101437.
^ Hidetoshi Hayashi (2024). “Sunvozertinib: the next candidate of TKI for NSCLC”. The Lancet Respiratory Medicine. 12 (3): 185–186. doi:10.1016/S2213-2600(23)00419-8. PMID 38101435.
^ “ASH: With high tumor response, AstraZeneca spinout Dizal explores FDA path and US partner for PTCL drug”. Fierce Biotech. 11 December 2023.
^ Dhillon S (2023). “Sunvozertinib: First Approval”. Drugs. 83 (17): 1629–1634. doi:10.1007/s40265-023-01959-5. PMID 37962831.
^ “FDA Grants Breakthrough Therapy Designation to Sunvozertinib in EGFR Exon20+ NSCLC”. targetedonc.com. 9 April 2024.

External links

Clinical trial number NCT03974022 for “Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer with EGFR or HER2 Mutation (WU-KONG1)” at ClinicalTrials.gov

Clinical data

Trade names	舒沃哲, Zegfrovy
Routes of administration	Oral
ATC code	None
Legal status
Legal status	US: ℞-only^[1]Rx in China
Identifiers
showIUPAC name
CAS Number	2370013-12-8
PubChem CID	139377809
DrugBank	DB18925
UNII	L1Q2K5JYO8
Chemical and physical data
Formula	C₂₉H₃₅ClFN₇O₃
Molar mass	584.09 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES

//////////Sunvozertinib, DZD9008, DZD 9008, FDA 2025, APPROVALS 2025, A-1801, A 1801, L1Q2K5JYO8

PRITELIVIR MESYLATE

July 9, 2025 2:43 am / Leave a comment

PRITELIVIR MESYLATE

CAS 1428333-96-3

1428321-10-1 HYDRATE

FREE FORM

348086-71-5

AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate

BAY57-1293; BAY 57-1293; BAY-57-1293; BAY571293; BAY 571293; BAY-571293; AIC-316; AIC 316

Molecular Weight	516.61
Synonyms	AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate
Formula	C₁₉H₂₄N₄O₇S₃
CAS No.	1428321-10-1

Pritelivir mesylate is an antiviral drug currently under development, specifically targeting herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). It functions by inhibiting the viral helicase-primase enzyme, a crucial component for HSV replication. It is being investigated as a potential treatment for various herpes infections, including those resistant to traditional antivirals like acyclovir.

Key aspects of Pritelivir mesylate:

Mechanism of Action:Pritelivir is a helicase-primase inhibitor, meaning it blocks the activity of an enzyme essential for the replication of herpes viruses.
Target Viruses:It is effective against both HSV-1 and HSV-2, the viruses responsible for cold sores and genital herpes, respectively.
Potential for Resistance:Pritelivir has shown promise in preclinical studies against acyclovir-resistant strains of HSV, making it a potential alternative for patients with drug-resistant infections.
Clinical Trials:Pritelivir is currently in phase II clinical trials, with ongoing research into its effectiveness and safety.
Route of Administration:It is being investigated for oral, topical, and vaginal administration.
Research and Development:Pritelivir is being developed by AiCuris Anti-infective Cures, building upon research from Bayer.

Pritelivir (development codes AIC316 or BAY 57-1293) is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.

SCHEME

Pritelivir mesylate, an antiviral drug used to treat herpes simplex virus (HSV) infections, is synthesized through a series of chemical reactions, including palladium-catalyzed coupling, ester saponification, and amide coupling reactions. The mesylate salt is then formed by reacting the free base with methanesulfonic acid.

Detailed Synthesis Steps:

1. Diaryl Acetic Acid Synthesis:Diaryl acetic acid reagents are synthesized using palladium-catalyzed coupling reactions. These reactions involve the use of organometallic intermediates derived from halo-aryl esters.
2. Ester Saponification:The ester group in the synthesized compounds is then converted to a carboxylic acid group through saponification.
3. Amide Coupling:The resulting carboxylic acids are coupled with thiazolyl sulfonamides using amide coupling conditions to form the pritelivir molecule.
4. Salt Formation:The pritelivir free base is then reacted with methanesulfonic acid to form the mesylate salt, which is the active pharmaceutical ingredient (API).

Key Aspects of Pritelivir Mesylate Synthesis:

Targeted Mechanism:Pritelivir mesylate inhibits the herpes simplex virus by targeting the viral helicase-primase complex, essential for DNA replication, unlike traditional antivirals that target DNA polymerase.
Salt and Polymorph Screening:An extensive salt and polymorph screening is performed to optimize the pharmaceutical development of pritelivir, resulting in various salt forms including the mesylate, maleate, and sulfate.
Solubility and Stability:Pritelivir mesylate is a BCS Class II drug substance with pH-dependent solubility. It exhibits high solubility below pH 3 and poor solubility at neutral pH.
Formulation Considerations:Due to its limited water solubility, pritelivir mesylate is often formulated with solvents like DMSO, PEG300, Tween-80, and saline or with cyclodextrins like SBE-β-CD.
Clinical Trials:Pritelivir mesylate is currently under extensive study to evaluate its efficacy and safety profile, with promising results in early clinical trials.

PATENT

WO2018096170

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018096170&_cid=P20-MCVCP5-34284-1

PATENT

WO2018096177

PATENT

https://patents.google.com/patent/WO2018096177A1/en

Likewise, EP 2 598 502 Al describes the crystalline mono mesylate monohydrate salt of N- [5-(aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetar^ in a definite particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said N-[5- (aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide mono mesylate monohydrate having the afore-mentioned particle size distribution and specific surface area range.

WO 2013/045479 Al describes an improved and shortened synthesis process of N-[5- (ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide and the mesylate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds. Moreover, also the crystalline mesylate monohydrate salt of N- [5 -(aminosulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)-phenyl] – acetamide is described therein with increased long-term stability and release kinetics from pharmaceutical compositions thereof.

Said pritelivir is an innovative, highly active and specific inhibitor of herpes simplex virus (HSV) infections. As a compound derived from the chemical class of thiazolylamides, pritelivir is active against both types of herpes simplex virus causing labial and genital herpes, respectively, and retains activity against viruses which have become resistant to marketed drugs. Pritelivir has a mode of action that is distinct from other antiviral agents currently in use for treatment of HSV infections (i.e., the nucleoside analogues acyclovir and its prodrug valacyclovir as well as famciclovir, the prodrug of penciclovix). Whereas nucleoside analogs terminate ongoing DNA chain elongation through inhibition of viral DNA polymerase, pritelivir prevents de novo synthesis of virus DNA through inhibition of the helicase-primase complex. In addition, it does not require activation within an HSV infected cell by viral thymidine kinase and therefore, is also protective to uninfected cells.

With the context of the invention, similar expressions which all would denote the compound pritelivir are “BAY 57-1293”, “AIC090096” and “AIC316”.

Likewise, the terms ”pritelivir”, “BAY 57-1293”, “AIC090096” and “AIC316″ or the compound *’N-[5-(ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridm phenyl] -acetamide” would reflect throughout the text a compound having the structural formula:

Synthetic route – Manufacture of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-Yl]-N-methyl- 2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate

The starting materials (4-pyridine-2-yl-phenyl)-acetic acid (PP-acetic acid; C-023930) and aminothiazole sulfonic acid amide (C-023936) are coupled using standard reaction conditions

(N-Ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCl), tetrahydrofuran (THF)/N-methylpyrrolidone (NMP) to deliver N-[5-(aminosulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (C-023931). To obtain the hemihydrate, N-[5-(aminosulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate free base is recrystallized from THF/water. A flowchart showing the synthesis of N-[5-(aminosulfonyl)- 4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is provided in below in the reaction scheme below 1.

Description of the manufacturing process of N-r5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate

PP-acetic acid and aminothiazole sulfonic acid amide are mixed in THF/NMP, the mixture is cooled and then EDC x HCl is added in portions. The reaction mixture is stirred for several hours, and then added slowly to purified water. The suspension is stirred and filtered; the product cake is washed with purified water and dried at room temperature in a nitrogen stream and then under vacuum. Purified water is added slowly at elevated temperature, the suspension is stirred for several hours. The suspension is cooled to 5°C and stirred further for several hours. The product is isolated by filtration and washed with purified water. The product is dried at 65°C under vacuum until the criterion for water content is reached. A major advantage of the synthesis of free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate is the absence impurities related to the presence of mesylate ester that might be present in the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate.

PAPER

By: Carta, Fabrizio ; et al. Journal of Medicinal Chemistry (2017), 60(7), 3154-3164

SULPHURIC ACID FOR SULPHATE A SIMILAR REACTION BUT NOT SAME

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00668

Chemistry of Pritelivir

Synthesis of pritelivir and its analogues is based on the reported methods in the literature (18−20) and presented in Figure 4. A simple retrosynthetic disconnection of the target compound suggests a coupling of the thiazolyl sulfonamide and diaryl acetic acid (Figure 4a). During the course of development an optimized route applying the principles of green chemistry was developed and will be used for the commercial phase.

Figure 4. Synthesis of pritelivir (16) and analogues: (a) disconnection approach to target molecules; (b) synthesis of thiazolyl sulfonamide reagents; (c) synthesis of diaryl acetic acids; (d) synthesis of some representative examples of pritelivir and analogues. (18−20)

The synthesis of the thiazolyl sulfonamide reagents begins with a reaction of chloroacetone (17) and potassium thiocyanide to give an intermediate ketone which was cyclized to the thiazole 18 by treatment with gaseous hydrochloride (Figure 4b). Chlorosulfonylation with chlorosulfonic acid and thionyl chloride resulted in the sulfonyl chloride 19 that was converted to the corresponding sulfonamides 20 and 21 after treatment with ammonia or methylamine, respectively. The 2-chloro substituent in 20 and 21 was converted to the methyl amine in an S_NAr reaction to deliver the building blocks 22–23. Diaryl acetic acid reagents were synthesized using palladium catalyzed coupling reactions with organometallic intermediates formed from the corresponding halo-aryl esters (Figure 4c). Ester saponification then delivered the corresponding carboxylic acids (e.g., 26 and 28, Figure 4c). Finally, the target molecules, for instance, 5, 11, 16, and 9, were obtained using amide coupling reaction conditions with corresponding diaryl acetic acids and the thiazolyl sulfonamides (Figure 4d). (18−20)

Medical use

Pritelivir is currently being developed for the treatment of immunocompromised patients with mucocutaneous HSV lesions that are resistant to acyclovir.

HSV in immunocompromised patients

Although HSV infection is very common in the general population, it rarely causes serious disease and is effectively contained by the immune system. In those with a weakened immune system such as transplant recipients, people receiving chemo- or radiotherapy, or HIV patients, an active HSV infection can cause disease in 35-68% of patients and may become severe or even life-threatening.^[1]

Standard of care treatments

HSV treatment revolves around the use of nucleoside analogues (NA) which act via the viral DNA polymerase, causing DNA chain termination and prevention of viral replication. First-line treatment is generally acyclovir or its prodrug valacyclovir. Resistance to acyclovir is more common in HSV patients with weakened or suppressed immune systems, affecting between 4 and 25% of cases.^[2]^[3]^[4]^[5]^[6]

Resistance to standard treatments

If HSV drug resistance is mediated by mutation(s) of the viral UL23 gene, which encodes the viral thymidine kinase (TK), then the pyrophosphate analogue foscarnet may be effective as a rescue treatment, since it does not require activation by TK. The use of foscarnet is commonly accompanied by restrictive toxicity, particularly nephrotoxicity.^[7] If the virus also acquires resistance to foscarnet, then there is currently no FDA approved treatment.

Clinical research

Completed phase II clinical trials in otherwise healthy patients with genital herpes

A Double-blind Randomized Placebo Controlled Dose-finding Trial to Investigate Different Doses of a New Antiviral Drug in Subjects With Genital HSV Type 2 Infection.^[8]^[9]
A Double-blind, Double Dummy, Randomized Crossover Trial to Compare the Effect of “AIC316 (Pritelivir)” 100 mg Once Daily Versus Valacyclovir 500 mg Once Daily on Genital HSV Shedding in HSV-2 Seropositive Adults.^[10]^[11]

Ongoing phase II / phase III clinical trials with pritelivir

A phase II / III multinational, comparator-controlled, clinical trial in immunocompromised patients with acyclovir-resistant mucocutaneous lesions is listed on ClinicalTrials.gov^[12] and EudraCT.^[13]

Pharmacology

Mechanism of action

Pritelivir is a member of the helicase-primase inhibitors (HPI), a novel class of direct-acting antiviral drugs acting specifically against HSV-1 and HSV-2.^[14]^[15] As the name suggests, the drugs act through inhibition of the viral helicase primase complex, encoded by the UL5 (helicase), UL8 (scaffold protein) and UL52 (primase) genes, which is essential for HSV replication.^[16] The helicase primase complex is encoded separately from the viral DNA polymerase (encoded by the UL30 gene). Because HPIs i) do not target the viral DNA polymerase and ii) do not require activation by the viral thymidine kinase enzyme (encoded by the UL23 gene), mutations causing resistance to NAs are not protective against HPIs. Similarly, resistance to HPIs does not confer resistance to NAs.

References

^ Wilck, M.B.; Zuckerman, R.A.; A. S. T. Infectious Diseases Community of Practice (2013). “Herpes simplex virus in solid organ transplantation”. Am J Transplant. 13 (Suppl 4): 121–7. doi:10.1111/ajt.12105. PMID 23465005. S2CID 44969727.
^ Zuckerman, R.; Wald, A.; A. S. T. Infectious Diseases Community of Practice (2009). “Herpes simplex virus infections in solid organ transplant recipients”. Am J Transplant. 9 (Suppl 4): S104-7. doi:10.1111/j.1600-6143.2009.02900.x. PMID 20070669. S2CID 205846431.
^ Frobert, E.; Burrel, S.; Ducastelle-Lepretre, S.; Billaud, G.; Ader, F.; Casalegno, J.S. (2014). “Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France”. Antiviral Res. 111: 36–41. doi:10.1016/j.antiviral.2014.08.013. PMID 25218782.
^ Patel, D.; Marchaim, D.; Marcus, G.; Gayathri, R.; Lephart, P.R.; Lazarovitch, T.; Zaidenstein, R.; Chandrasekar, P. (2014). “Predictors and outcomes of acyclovir-resistant herpes simplex virus infection among hematopoietic cell transplant recipients: case-case-control investigation”. Clin Transplant. 28 (1): 1–5. doi:10.1111/ctr.12227. PMID 24033498. S2CID 37729458.
^ Danve-Szatanek, C.; Aymard, M.; Thouvenot, D.; Morfin, F.; Agius, G.; Bertin, I. (2004). “Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up”. J Clin Microbiol. 42 (1): 242–9. doi:10.1128/JCM.42.1.242-249.2004. PMC 321677. PMID 14715760.
^ Chakrabarti, R.; Pillay, D.; Ratcliffe, D.; Cane, P.A.; Collingham, K.E.; Milligan, D.W. (2000). “Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance”. J Infect Dis. 181 (6): 2055–8. doi:10.1086/315524. PMID 10837192.
^ SmPC
^ NCT01047540
^ Wald, A.; Timmler, B.; Magaret, A.; Warren, T.; Trying, S. (2014). “Helicase-primase inhibitor pritelivir for HSV-2 infection”. N Engl J Med. 370 (3): 201–10. doi:10.1056/NEJMoa1301150. PMID 24428466.
^ NCT01658826
^ Wald, A.; Timmler, B.; Warren, T.; Trying, S.; Johnston, C. (2016). “Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial”. JAMA. 316 (23): 2495–2503. doi:10.1001/jama.2016.18189. hdl:1805/14200. PMID 27997653.
^ NCT03073967
^ 2020-004940-27
^ Biswas, S.; Jennens, L.; Field, H.J. (2007). “Single amino acid substitutions in the HSV-1 helicase protein that confer resistance to the helicase-primase inhibitor BAY 57-1293 are associated with increased or decreased virus growth characteristics in tissue culture”. Arch Virol. 152 (8): 1489–500. doi:10.1007/s00705-007-0964-7. PMID 17404685. S2CID 23688945.
^ Field, H.J.; Biswas, S. (2011). “Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus”. Drug Resist Updat. 14 (1): 45–51. doi:10.1016/j.drup.2010.11.002. PMID 21183396.
^ Crute, J.J.; Tsurumi, T.; Zhu, L.A.; Weller, S.K.; Olivo, P.D.; Challberg, M.D. (1989). “Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products”. Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2186–2189. Bibcode:1989PNAS…86.2186C. doi:10.1073/pnas.86.7.2186. PMC 286876. PMID 2538835.

[1]. Ligat G, et al. Identification of Amino Acids Essential for Viral Replication in the HCMV Helicase-PrimaseComplex. Front Microbiol. 2018 Oct 23;9:2483. [Content Brief][2]. Wald A, et al. Helicase-primase inhibitor Pritelivir for HSV-2 infection. N Engl J Med. 2014 Jan 16;370(3):201-10. [Content Brief][3]. Quenelle DC, et al. Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis. Antiviral Res. 2018 Jan;149:1-6. [Content Brief]

Names

Systematic IUPAC nameN-Methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide
Identifiers
CAS Number	348086-71-5
3D model (JSmol)	Interactive image
ChemSpider	430613
KEGG	D12811
PubChem CID	491941
UNII	07HQ1TJ4JE
CompTox Dashboard (EPA)	DTXSID70188344
showInChI
showSMILES
Properties
Chemical formula	C₁₈H₁₈N₄O₃S₂
Molar mass	402.49 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references

///////////PRITELIVIR MESYLATE, AIC316 mesylate hydrate, BAY 57-1293 mesylate hydrate, AIC 316 mesylate hydrate, BAY 57-1293 mesylate hydrate, BAY57-1293, BAY 57-1293, BAY-57-1293, BAY571293, BAY 571293, BAY-571293, AIC-316, AIC 316

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PIMICOTINIB

July 8, 2025 2:56 am / Leave a comment

PIMICOTINIB

CAS 2253123-16-7

ABSK021

WeightAverage: 420.473
Monoisotopic: 420.190988657

Chemical FormulaC₂₂H₂₄N₆O₃

3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide

CSF-1R inhibitor Pimicotinib (ABSK021) of Abbisko Therapeutics, HV1XI8HST2

Pimicotinib (ABSK021), an oral, highly potent and selective small molecule blocker of the colony-stimulating factor 1 receptor (CSF-1R) independently discovered by Abbisko Therapeutics. A number of studies have shown that blocking the CSF-1R signaling pathway could effectively modulate and change macrophage functions, and potentially treat many macrophage-dependent human diseases.^[1]

Pimicotinib is under investigation in clinical trial NCT05804045 (Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER)).

History

In December 2023, Abbisko Therapeutics entered into a licensing agreement for pimicotinib in all indications for China rights with Merck KGaA.^[2] ^[3]^[4]

In April 2023, a global phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the safety and efficacy of pimicotinib in patients with tenosynovial giant cell tumor was started (NCT05804045).^[5]

Following with pimicotinib for tenosynovial giant cell tumor treatment in phase III, pimicotinib has also entered into a phase II trial in June 2023 for cGVHD treatment in China.^[6]

The U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of NMPA granted pimicotinib breakthrough therapy designation (BTD) for the treatment of tenosynovial giant cell tumor patients that are not amenable to surgery in January 2023 and July 2022, respectively.^[7]

Research

Pimicotinib is being investigated as a treatment for tenosynovial giant cell tumor,^[8]^[9] chronic graft-versus-host-disease (cGVHD), and pancreatic cancer.

PATENTS

example 41 [WO2018214867A9]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214867&_cid=P10-MCTXKZ-70170-1

Example 41: Preparation of 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide

[0463]

[0464]Palladium carbon (50 mg) was added to a solution of 3-(benzyloxy)-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (80 mg, 0.15 mmol) in methanol (10 mL). The reaction was stirred at 50° C. for 2 hours in the presence of hydrogen. Filtered and concentrated. Plate chromatography (dichloromethane/methanol=18:1) gave 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (10 mg, yield 15%). MS m/z(ESI):423[M+1]

⁺ .

[0465]

¹H NMR(400MHz,DMSO-d ₆)δ10.93(s,1H),8.37(d,J＝5.7Hz,1H),8.27(s,1H),8.01–7.85(m,2H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝5.7,2.4Hz,1H),5.89(s,1H),3.86(s,3H),3.83–3.76(m,1H),3.67–3.61(m,1H),2.29(s,3H),2.09–1.98(m,2H),1.34(s,3H)。

PATENTS

EP3643715

WO2018233527

US20200140431

US11180495 WO2018233527 US20200140431

References

^ Vaynrub A, Healey JH, Tap W, Vaynrub M (2022). “Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations”. OncoTargets and Therapy. 15: 53–66. doi:10.2147/OTT.S345878. PMC 8763255. PMID 35046667.
^ Merck Strengthens Oncology Portfolio Through Commercialization Agreement With Abbisko for Phase III Asset, Pimicotinib. (2023) https://www.merckgroup.com/en/news/abbisko-pimicotinib-agreement-04-12-2023.html
^ Merck KGaA buys into Abbisko’s late-stage joint tumor med for $70M upfront. Fierce Biotech. (2023) https://www.fiercebiotech.com/biotech/merck-kgaa-buys-abbiskos-late-stage-joint-tumor-med-70m-upfront
^ “Abbisko Therapeutics Announced the Entry into a Licensing Agreement for Pimicotinib (ABSK021) with Merck”. http://www.prnewswire.com (Press release). Retrieved 18 April 2024.
^ Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER). U. S. National Institutes of Health, National Cancer Institute. https://classic.clinicaltrials.gov/ct2/show/NCT05804045
^ A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)U. S. National Institutes of Health, National Cancer Institute.https://classic.clinicaltrials.gov/ct2/show/NCT06186804
^ “FDA Grants Breakthrough Therapy Designation to Abbisko’s Pimicotinib”. Global genes. Retrieved 18 April 2024.
^ “Pimicotinib”. TGCT Support. Retrieved 18 April 2024.
^ “A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study of ABSK021 to Assess the Efficacy and Safety in Patients With Tenosynovial Giant Cell Tumor”. clinicaltrials. clinicaltrials.gov. 10 April 2024. Retrieved 18 April 2024.

External links

“Pimicotinib”. NCI Drug Dictionary. National Cancer Institute.
Clinical trial number NCT06186804 for “A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)” at ClinicalTrials.gov

Clinical data

Other names	ABSK021
Routes of administration	Oral
Identifiers
showIUPAC name
CAS Number	2253123-16-7
PubChem CID	139549388
ChemSpider	128942304
UNII	HV1XI8HST2
KEGG	D12938
Chemical and physical data
Formula	C₂₂H₂₄N₆O₃
Molar mass	420.473 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

[1]. Zhao BW, et al. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29.[2]. Yang S, et al. Abstract LB-288: A highly selective small molecule CSF-1R inhibitor demonstrates strong immunomodulatory activity in syngeneic models. Cancer Research, 2018, 78(13_Supplement): LB-288-LB-288.[3]. Zhang N, et al. Abstract LB077: CSF-1R inhibition with Pimicotinib (ABSK021) enhanced anti-tumor efficacy of KRASG12C inhibitors in preclinical non-small cell lung cancer mouse models. Cancer Research, 2024, 84(7_Supplement): LB077-LB077.

//////////PIMICOTINIB, ABSK 021, Abbisko Therapeutics, HV1XI8HST2

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PALTUSOTINE

July 7, 2025 2:47 am / Leave a comment

PALTUSOTINE

CAS 2172870-89-0

CRN00808
F2IBD1GMD3

WeightAverage: 456.497
Monoisotopic: 456.17616767

Chemical FormulaC₂₇H₂₂F₂N₄O

3-[4-(4-Amino-1-piperidinyl)-3-(3,5-difluorophenyl)-6-quinolinyl]-2-hydroxybenzonitrile

fda 2025, approvals 2025, To treat acromegaly in adults who had an inadequate response to surgery and/or for whom surgery is not an option

OriginatorCrinetics Pharmaceuticals
ClassAmines; Antineoplastics; Antisecretories; Fluorobenzenes; Nitriles; Piperidines; Quinolines; Small molecules
Mechanism of ActionSomatostatin receptor 2 agonists
Orphan Drug Status – Acromegaly
PreregistrationAcromegaly
Phase IIMalignant carcinoid syndrome

08 May 2025Crinetics Pharmaceuticals expects potential EMA decision for paltusotine in Acromegaly, in the first half of 2026
08 May 2025FDA assigns PDUFA action date of 25/09/2025 for paltusotine for acromegaly
08 May 2025Crinetics Pharamceuticals plans the phase III CAREFNDR trial for Malignant carcinoid syndrome (PO), in the second quarter of 2025

Paltusotine is a selective somatostatin receptor type 2 (SST2) agonist in development by Crinetics Pharmaceuticals for the treatment of acromegaly and certain neuroendocrine tumors. It is a small molecule delivered orally.^[1][2][3][4]

SCHEME

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00431

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist

Step 2-1, preparation of [1-(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tertbutyl ester: To a DMSO solution of 6-bromo-3,4-dichloroquinoline (950 mg, 1 Eq, 3.43 mmol)
was added tert-butyl piperidin-4-ylcarbamate (841 mg, 98% Wt, 1.2 Eq, 4.12 mmol) and DIPEA
(1.19 g, 1.60 mL, 3 Eq, 10.3 mmol). The resulting mixture was heated at 60 °C for overnight.
The reaction crude was quenched with water, extracted with EtOAc, washed with brine,
concentrated and purified by silica gel chromatography to afford tert-butyl (1-(6-bromo-3-
chloroquinolin-4-yl)piperidin-4-yl)carbamate (0.95 g, 2.2 mmol, 63 %) as an off-white solid. 1H
NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.25 (d, J=5 Hz, 1H), 7.94 (d, J=10 Hz, 1H), 7.74 (d,
J=10 Hz, 1H), 4.61 (s, 1H), 3.76 (s, 1H), 3.51 (m, 2H), 3.37 (m, 2H), 2.13-2.15 (m, 2H), 1.73-
1.65 (m, 2H), 1.48 (s, 9H). MS [M+H]
+= 442.0.
Step 4-2, preparation of 1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-
quinolin-4-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester: To a THF (5.0 mL) solution of [1-
(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.0 mmol, 440
mg) and 2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
benzonitrile (1.4 eq., 1.4 mmol, 460 mg) was added PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and
KOAc (3.0 eq., 3.0 mmol, 300 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 80 °C for 1 h. LCMS analysis

showed about 50% of the starting material has been converted to the desired product. Additional
2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile
(1.4 eq., 1.4 mmol, 460 mg), PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and KOAc (3.0 eq., 3.0
mmol, 300 mg) were added and the resulting solution was heated at 80 °C for another 2 h. The
reaction solution was combined with silica gel and concentrated. The residue obtained was
purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 0.512 g
of the desired product as white solid. MS [M+H]
+= 567.6.
Step 4-3, preparation of {1-[6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-3-(3,5-difluorophenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester: To a dioxane (5 mL)
solution of (1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-quinolin-4-yl}-
piperidin-4-yl)-carbamic acid tert-butyl ester (0.5 mmol, 283 mg) was added Pd(amphos)Cl2 (0.1
eq., 0.05 mmol, 37 mg), 3, 5-difluorophenyl boronic acid (3.0 eq., 1.5 mmol, 250 mg) and
K2CO3 (4.0 eq., 2.0 mmol, 276 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 95 °C for 0.5 h and LCMS analysis
showed that starting material was completely consumed. The reaction solution was concentrated
with silica gel and purified by silica gel chromatography eluting with ethyl acetate/hexane
(0~50%) to give 0.170 g of the desired product as white solid. MS (M+H)+= 645.6.

Step 4-4, preparation of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile: to the dichloromethane (5.0 mL) solution of {1-[6-[3-cyano-2-(2-methoxyethoxymethoxy)-phenyl]-3-(3,5-difluoro-phenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid
tert-butyl ester (0.264 mmol, 170 mg) was added trifluroroacetic acid (2.0 mL) and the resulting
mixture was stirred at ambient temperature for 2 h. The reaction solution was concentrated and
purified by C18 reversed phase chromatography eluting with MeCN/water (0~40%). Pure
fractions were combined, neutralized with saturated NaHCO3, extracted with ethyl acetate and
dried with MgSO4. The organic solution was concentrated with HCl in ether (2.0 M) to give the
final compound as HCl salt (68 mg, 0.138 mmol, 52%).
1H NMR (500 MHz, DMSO-d6) δ 10.77
(br s, 1H), 8.78 (s, 1H), 8.29-8.15 (m, 5H), 7.79 (dd, J=20 Hz, 5 Hz, 2H), 7.41 (m, 1H), 7.26-
7.19 (m, 3H), 3.59 (t, J=12 Hz, 2H), 3.31 (m, 1H), 3.00 (t, J=12 Hz, 2H), 2.05-1.99 (m, 2H),
1.76-1.74 (m, 2H). MS [M+H]
+= 457.5. 13C NMR (DMSO-d6) δ 30.2, 47.4, 50.8, 102.4, 103.2,
113.4, 117.2, 121.4, 124.6, 130.7, 133.1, 134.6, 136.0, 141.7, 156.6, 161.2, 163.2. LCMS purity

98% (254&220 nM). HRMS m/z [M+H]+ Calcd for C27H23F2N4O 457.1834; found 457.1833.

PATENT

US10351547, Compound 2-2

https://patentscope.wipo.int/search/en/detail.jsf?docId=US235548187&_cid=P20-MCSHXW-73235-1

PATENTS

WO2021011641

WO2018013676

References

^ Madan, Ajay; Markison, Stacy; Betz, Stephen F.; Krasner, Alan; Luo, Rosa; Jochelson, Theresa; Lickliter, Jason; Struthers, R. Scott (April 2022). “Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers”. Pituitary. 25 (2): 328–339. doi:10.1007/s11102-021-01201-z. PMC 8894159. PMID 35000098.
^ Zhao, Jian; Wang, Shimiao; Markison, Stacy; Kim, Sun Hee; Han, Sangdon; Chen, Mi; Kusnetzow, Ana Karin; Rico-Bautista, Elizabeth; Johns, Michael; Luo, Rosa; Struthers, R. Scott; Madan, Ajay; Zhu, Yunfei; Betz, Stephen F. (12 January 2023). “Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist”. ACS Medicinal Chemistry Letters. 14 (1): 66–74. doi:10.1021/acsmedchemlett.2c00431. PMC 9841592. PMID 36655128.
^ Gadelha, Monica R; Gordon, Murray B; Doknic, Mirjana; Mezősi, Emese; Tóth, Miklós; Randeva, Harpal; Marmon, Tonya; Jochelson, Theresa; Luo, Rosa; Monahan, Michael; Madan, Ajay; Ferrara-Cook, Christine; Struthers, R Scott; Krasner, Alan (13 April 2023). “ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly”. The Journal of Clinical Endocrinology & Metabolism. 108 (5): e148 – e159. doi:10.1210/clinem/dgac643. PMC 10099171. PMID 36353760. S2CID 253445337.
^ Zhao, Jie; Fu, Hong; Yu, Jingjing; Hong, Weiqi; Tian, Xiaowen; Qi, Jieyu; Sun, Suyue; Zhao, Chang; Wu, Chao; Xu, Zheng; Cheng, Lin; Chai, Renjie; Yan, Wei; Wei, Xiawei; Shao, Zhenhua (21 February 2023). “Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine”. Nature Communications. 14 (1): 962. Bibcode:2023NatCo..14..962Z. doi:10.1038/s41467-023-36673-z. ISSN 2041-1723. PMC 9944328. PMID 36810324.

Legal status

Legal status	Investigational
Identifiers
showIUPAC name
CAS Number	2172870-89-0
PubChem CID	134168328
ChemSpider	81367268
UNII	F2IBD1GMD3
Chemical and physical data
Formula	C₂₇H₂₂F₂N₄O
Molar mass	456.497 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////////PALTUSOTINE, ORPHAN DRUG, Acromegaly, CRN 00808, F2IBD1GMD3, fda 2025, approvals 2025

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PALAZESTRANT

July 5, 2025 8:26 am / Leave a comment

PALAZESTRANT

CAS 2092925-89-6

OP-1250, VU35KM56Q4

449.6 g/mol, C₂₈H₃₆FN₃O

(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole

Palazestrant (OP-1250) is an investigational drug being developed for estrogen receptor-positive (ER+) breast cancer. It is a small molecule with a dual mechanism of action, acting as both a complete estrogen receptor antagonist and a selective estrogen receptor degrader (SERD). This means it can block estrogen receptor activity and also degrade the receptor itself, potentially offering a more effective treatment approach.

Here’s a more detailed breakdown:

Dual Mechanism:Palazestrant is a complete ER antagonist, meaning it blocks all estrogen receptor activity. It is also a SERD, which means it degrades the estrogen receptor, preventing it from functioning.
Oral Administration:Palazestrant is an orally available drug.
Clinical Trials:Palazestrant is currently in clinical trials, including Phase 1/2 and Phase 3 studies, for the treatment of ER+, HER2- metastatic breast cancer.
Combination Therapy:Palazestrant is being evaluated in combination with other drugs like CDK4/6 inhibitors (e.g., ribociclib).
Promising Results:Preliminary results from clinical trials have shown promising antitumor efficacy and favorable pharmacokinetic properties for palazestrant.
FDA Fast Track Designation:The FDA has granted Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following endocrine therapy with a CDK4/6 inhibitor.
Brain Metastasis:Palazestrant has shown activity in brain metastasis animal models.
ESR1 Mutation Status:Palazestrant has demonstrated activity against both wild-type and mutant ER (ESR1) breast cancer models.

Palazestrant is an investigational new drug which is being evaluated for the treatment of estrogen receptor-positive (ER+) breast cancer, with a dual mechanism of action as both a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD). This orally bioavailable small molecule has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor.^[1]

SCHEME

MAIN

PAPER

https://pubs.acs.org/doi/10.1021/acsomega.4c11023

PATENTS

US11672785, Compound B

https://patentscope.wipo.int/search/en/detail.jsf?docId=US379744130&_cid=P22-MCPZ5L-11621-1

PATENTS’

WO2017059139

WO2023225354

WO2023091550

WO2023283329

WO2021178846

References

^ Parisian AD, Barratt SA, Hodges-Gallagher L, Ortega FE, Peña G, Sapugay J, et al. (March 2024). “Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination”. Molecular Cancer Therapeutics. 23 (3): 285–300. doi:10.1158/1535-7163.MCT-23-0351. PMC 10911704. PMID 38102750.

Clinical data

Other names	OP-1250
Identifiers
showIUPAC name
CAS Number	2092925-89-6
PubChem CID	135351887
DrugBank	DB18971
ChemSpider	128922074
UNII	VU35KM56Q4
KEGG	D12827
ChEMBL	ChEMBL5314475
Chemical and physical data
Formula	C₂₈H₃₆FN₃O
Molar mass	449.614 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

///////////PALAZESTRANT, OP 1250, A1AEA, VU35KM56Q4

Orforglipron’

July 2, 2025 8:23 am / Leave a comment

Orforglipron’

CAS 2212020-52-3

C₄₈H₄₈F₂N₁₀O₅

883.0 g/mol MW

LY-3502970

OWL833
3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

SCHEME

PATENT

JP2019099571

PATENT

WO2018056453

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018056453&_cid=P22-MCLODW-73083-1

<Example Compound 67>
　Main cycle isomer

　 ¹ H-NMR (600 MHz, CDCl

₃ ) δ: 11.32 (1H, s), 8.13 (1H, d, J

_ＨＦ＝0.7 Hz), 7.59 (1H, d, J ＝8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J ＝8.9 Hz, J

_ＨＦ＝6.9 Hz ), 7.28 (1H, d, J ＝8.9 Hz), 7.26 (1H, dd, J ＝8.6, 1.7 Hz), 7.16 (2H, d, J

_ＨＦ =6.1Hz), 6.70 (1H, s), 6.61 (1H, dd, J = 3.0Hz,

_JHF =1.1Hz), 6.31 (1H, d, J = 3.0Hz), 5.79 (1H, q, J = 6.7Hz), 4.4 7 (1H, dd, J=13.5, 5.2Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1 H, m), 3.60 (1H, ddd, J = 13.5, 12.9, 3.6Hz), 3.15 (1H, ddd, J = 15.8, 12.9, 5.2Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J

_HF =1.1Hz), 1.91 (1H, dd, J = 6.1, 5.8Hz), 1.79-1.76 ( 2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8Hz ), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0Hz).

[0437]　Parainversion isomer

　 ¹ H-NMR (600 MHz, CDCl

₃ ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 7.06 (2H, d, J

_HF =6.0Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 ( 1H, d, J=3.0Hz), 5.26 (1H, q, J=6.6Hz), 4. 87 (1H, dd, J = 13.1, 4.8Hz), 4.07 (3H, s), 3 .90-3.80 (2H, m), 3.39 (1H, ddd, J = 13.1, 1 2.2, 4.6Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6H z), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 ( 3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0Hz).

Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.^[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.^[1]

Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.^[2]

Mechanism

Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.^[1]^[3]

Clinical trials

The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.^[4]^[5]

Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.^[3]

Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.^[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.^[1]^[6]

The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.^[6]

Phase III ACHIEVE-1 trial

In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.^[1]^[7]

More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.^[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.^[1]^[8]

Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Lilly’s oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial” (Press release). Eli Lilly. April 17, 2025. Retrieved April 18, 2025.
^ Sidik S (2023). “Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective”. Nature. 619 (7968): 19. Bibcode:2023Natur.619…19S. doi:10.1038/d41586-023-02092-9. PMID 37369789.
^ Jump up to:^a ^b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). “Emerging pharmacotherapies for obesity: A systematic review”. Pharmacological Reviews. 77 (1): 100002. doi:10.1124/pharmrev.123.001045. PMID 39952695.
^ Pratt E, Ma X, Liu R, et al. (June 2023). “Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes”. Diabetes, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
^ Wharton S, Blevins T, Connery L, et al. (June 2023). “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity”. The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
^ Jump up to:^a ^b ^c Frias J, et al. (2023). “Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study”. The Lancet. 402 (10400): 472–83.
^ Constantino AK (April 17, 2025). “Eli Lilly’s weight loss pill succeeds in first late-stage trial on diabetes patients”. CNBC. Retrieved April 17, 2025.
^ Kolata G (April 17, 2025). “Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar”. The New York Times. ISSN 0362-4331. Retrieved April 17, 2025.

External links

What to Know About Eli Lilly’s Daily Pill for Weight Loss, The New York Times, April 17, 2025

Clinical data

Above: molecular structure of orforglipron Below: 3D representation of an orforglipron molecule
Other names	LY-3502970
Routes of administration	Oral
ATC code	None
Pharmacokinetic data
Elimination half-life	29–49 hours
Identifiers
showIUPAC name
CAS Number	2212020-52-3
PubChem CID	137319706
ChemSpider	71117507
UNII	7ZW40D021M
ChEMBL	ChEMBL4446782
Chemical and physical data
Formula	C₄₈H₄₈F₂N₁₀O₅
Molar mass	882.974 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

///////////Orforglipron, LY-3502970, LY 3502970, OWL833, OWL 833

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3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

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Methyl 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21a) and Methyl 5-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21b)

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (22a)

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic Acid (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-amide (14w)

Example 41

3-Fluoro-4-methoxy-pyridine-2-carbonitrile

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester

C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide

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